Conditions: Anaemia
Keywords: Renal Anemia Japanese chronic kidney disease Peritoneal dialysis GSK1278863 Non-dialysis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 355
Healthy volunteers: no

Brief summary:
This is a Phase III, open-label, active-controlled, parallel-group, multi-center study to compare the efficacy and safety of GSK1278863 administered for 52 weeks versus epoetin beta pegol in approximately 286 Japanese ND and 50 PD subjects with renal anemia. The study will consist of three cohorts. Cohort 1 and Cohort 3 will consist of ND subjects (Erythropoiesis-Stimulating Agent \[ESA\] users and ESA non-users) randomized to receive GSK1278863 or epoetin beta pegol in a ratio of 1:1. PD subjects will be enrolled into Cohort 2 and will receive GSK1278863. This study consists of a 4-week screening phase, a 52-week treatment phase (including primary efficacy evaluation period \[Weeks 40 to 52\]), and a 4-week follow-up phase following the treatment phase. The primary objective of this study is to demonstrate non-inferiority of GSK1278863 to epoetin beta pegol based on mean hemoglobin (Hgb) during the primary efficacy evaluation period in ND subjects. ESA non-users from Cohort 1 will be excluded from the primary efficacy analysis. Study results will be used as pivotal study data for an NDA submitted for GSK1278863 for the treatment of renal anemia in Japan.

Detailed description:

Arms:
arm 1: Eligible ND participants will receive oral daprodustat (1, 2, 4, 6, 8, 12, 18 or 24 milligrams \[mg\] as recommended) dose once daily for 52 weeks. arm 2: Eligible ND participants will receive subcutaneous (SC) epoetin beta pegol (25, 50, 75, 100, 150, 200 or 250 microgram \[µg\] as recommended) dose once every 2 or 4 weeks for 52 weeks. arm 3: Eligible PD participants will receive oral daprodustat (1, 2, 4, 6, 8, 12, 18 or 24 mg as recommended) dose once daily for 52 weeks.

Interventions: intervention 1: 1 to 4 mg tablets of GSK1278863 intervention 2: 6 mg GSK1278863 tablet intervention 3: Epoetin beta pegol
Intervention descriptions: intervention 1: 7.0 millimeters (mm) round, standard biconvex, white film coated tablets containing 1 mg, 2 mg, or 4 mg of GSK1278863 as active ingredient, to be orally administered once daily. intervention 2: 9.0 mm round, standard biconvex, white film coated tablets containing 6 mg of GSK1278863 as active ingredient, to be orally administered once daily. intervention 3: An injectable formulation containing 25 micrograms µg, 50 µg, 75 µg, 100 µg, 150 µg, 200 µg, or 250 µg of epoetin beta pegol per syringe (0.3 mL), supplied as a glass syringe prefilled with epoetin beta pegol solution (clear colorless to pale yellow). Epoetin beta pegol will be subcutaneously administered once every 2 or 4 weeks.

Protocol document:
Prot_000.pdf: 
2015N266248_04
CONFIDENTIAL
GlaxoSmithKline group of companies
PHI201753
1
TITLE PAGE
Division：Worldwide Development
Information Type：Clinical Protocol
Title：A 52-week, Phase III, open-label, multi-center study to evaluate efficacy and safety of 
GSK1278863 in Japanese non-dialysis and peritoneal dialysis subjects with anemia associated with 
chronic kidney disease.
Compound Number：
GSK1278863
Development Phase
III
Effective Date：
03-JUL-2017
Protocol Amendment Number: 04
Author(s)：
 
Revision Chronology
GlaxoSmithKline Document Number Date
Version
2015N266248_00
2016-02-18
Original
2015N266248_01
2016-04-12
Amendment No. 1
Clarification of the method of administration of control, clarification of the withdrawal/dropout criteria, 
addition of medical devices, clarification of the time and events, clarification of procedures after 
occurrence of liver events
2015N266248_02
2016-08-01
Amendment No. 2
Clarification of exclusion criteria, clarification of the procedure for the ophthalmology exam at the re-
screening, clarification of analysis populations, updates of risk assessment, updates of the procedures for 
SAE reports
2015N266248_03
2017-03-08
Amendment No. 3
Addition of Cohort3, change of the starting dose for ND subjects, ESA non-users, change of analysis 
population for efficacy analyses, addition of Week 2 visit, clarification of the timing of eligibility 
assessment regarding exclusion criteria, clarification of prohibited medications, correction of adverse 
events of special interest
2015N266248_04
2017-07-03
Amendment No. 4
Addition of target number of ND subjects, change for definition of screen failures, clarification of the 
withdrawal/dropout criteria for prohibited medication, clarification of definition of overdose of
GSK1278863, updates of adverse events of special interest, change of a dropout rate after the start of 
study treatment, addition of details of sensitivity analyses in primary efficacy analysis, updates and 
correction of erroneous description of risk assessment
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
PPD


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Sponsor Signatory:
Kihito Takahashi
Director,
Japan Development and Medical Affairs (JDMA),
GlaxoSmithKline K. K.
The IMMS document approved is as follows:
  Unique ID：090033ec841233f5
  System Version：2.0
  Effective Date：3 Jul 2017
Date


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time 
Phone 
Number
Fax Number
Site Address
Medical Monitor
M.D., Ph.D.
GlaxoSmithKline K.K.
6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-8566 
JAPAN
SAE contact 
information
Person in charge 
of GSK1278863
Clinical 
Operations dept. 
GlaxoSmithKline K.K.
6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-8566 
JAPAN
Emergency Contact
Emergency Contact (Mon to Fri 10am to 6pm, except for national holiday and year-end and New Year
holidays)
Person in charge of GSK1278863, Clinical Operations dept. R&D, Glaxo Smith Kline K.K
TEL:
FAX:
Emergency Contact at night and holiday (Mon to Fri 6pm to 10am, Sat, Sun, national holiday and 
year-end and New Year holidays)
BI medical Inc.
Responsible Person: 
TEL:
(toll free)
FAX:
(toll free)
Sponsor Legal Registered Address:
6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566 JAPAN
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol and the rivision.

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 Signature
Date


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TABLE OF CONTENTS
Page
1.
PROTOCOL SYNOPSIS FOR STUDY PHI201753 ........................................................9
2.
INTRODUCTION............................................................................................................15
2.1.
Study Rationale....................................................................................................15
2.2.
Background..........................................................................................................15
3.
OBJECTIVES AND ENDPOINTS..................................................................................15
4.
STUDY DESIGN.............................................................................................................17
4.1.
Overall Design......................................................................................................17
4.2.
Treatment Groups and Study Periods...............................................................19
4.3.
Study Subjects and Number of Subjects..........................................................20
4.4.
Rationale for Study Design.................................................................................21
4.5.
Rationale for Dose Levels...................................................................................21
4.6.
Benefit: Risk Assessment...................................................................................23
4.6.1.
Risk Assessment ........................................................................................23
4.6.2.
Benefit Assessment....................................................................................23
4.6.3.
Overall Benefit: Risk Conclusion..............................................................23
5.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ...........................................24
5.1.
Inclusion Criteria..................................................................................................24
5.2.
Exclusion Criteria ................................................................................................25
5.3.
Screening Failures...............................................................................................27
5.4.
Withdrawal/Dropout Criteria...............................................................................27
5.4.1.
Liver Chemistry Stopping Criteria.............................................................28
5.4.1.1.
Study Treatment Restart or Rechallenge.........................................30
5.5.
Subject and Study Completion ..........................................................................30
6.
STUDY TREATMENTS..................................................................................................30
6.1.
Investigational Product and Other Study Treatment.......................................30
6.2.
Medical Devices ...................................................................................................31
6.3.
Treatment Assignment........................................................................................31
6.4.
Administration Schedule (Starting Dose, Dose Adjustment, and 
Dosing Frequency) ..............................................................................................32
6.4.1.
GSK1278863 (ND and PD Subjects)..........................................................32
6.4.1.1.
Starting Dose ......................................................................................32
6.4.1.2.
Maintenance Dose..............................................................................32
6.4.2.
Epoetin Beta Pegol (ND Subjects Only) ...................................................33
6.4.2.1.
Starting Dose for ESA Non-users.....................................................33
6.4.2.2.
Dose Conversion for ESA Users ......................................................34


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6.4.2.3.
Maintenance Dose (ESA Non-users and Users) .............................35
6.5.
Blinding.................................................................................................................36
6.6.
Packaging and Labeling......................................................................................36
6.7.
Preparation/Handling/Storage/Accountability..................................................36
6.8.
Compliance with Study Treatment Administration..........................................37
6.9.
Treatment of Study Treatment Overdose..........................................................37
6.10.
Treatment after the End of the Study ................................................................37
6.11.
Concomitant Medications and Non-Drug Therapies .......................................37
6.11.1.
Permitted Medications and Non-Drug Therapies ....................................38
6.11.2.
Prohibited Medications and Non-Drug Therapies...................................38
6.12.
Supplemental Iron Therapy ................................................................................38
7.
Study Assessments and Procedures.........................................................................38
7.1.
Time and Events Table........................................................................................38
7.2.
Screening and Critical Baseline Assessments ................................................41
7.3.
Efficacy .................................................................................................................41
7.4.
Safety ....................................................................................................................41
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)....................41
7.4.1.1.
Time period and Frequency for collecting AE and SAE 
information..........................................................................................42
7.4.1.2.
Method of Detecting AEs and SAEs.................................................42
7.4.1.3.
Follow-up of AEs and SAEs ..............................................................42
7.4.1.4.
Cardiovascular and Death Events....................................................42
7.4.1.5.
Regulatory Reporting Requirements for SAEs...............................43
7.4.2.
Adverse Events of Special Interest...........................................................43
7.4.3.
Pregnancy....................................................................................................43
7.4.4.
Medical Device Incidents (Including Malfunctions) ................................44
7.4.4.1.
Time Period for Detecting Medical Device Incidents......................44
7.4.4.2.
Follow-up of Medical Device Incidents ............................................44
7.4.4.3.
Prompt Reporting of Medical Device Incidents to GSK.................44
7.4.4.4.
Regulatory Reporting Requirements for Medical Device 
Incidents..............................................................................................45
7.4.5.
Vital Signs/Height/Weight ..........................................................................45
7.4.6.
Electrocardiogram (ECG) ...........................................................................45
7.4.7.
Clinical Laboratory Assessments.............................................................45
7.4.8.
Ophthalmology............................................................................................46
7.5.
Pharmacokinetics................................................................................................47
7.6.
Genetics................................................................................................................47


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7.7.
Patient Reported Outcome (PRO)......................................................................47
7.7.1.
SF-36.............................................................................................................47
7.7.2.
EuroQol Health Utility Index (EQ-5D-5L)/EQ Visual Analogue 
Scale (EQ-VAS)............................................................................................47
8.
DATA MANAGEMENT ..................................................................................................48
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .....................................48
9.1.
Hypotheses...........................................................................................................48
9.2.
Sample Size Considerations ..............................................................................49
9.2.1.
Sample Size Assumptions .........................................................................49
9.2.2.
Sample Size Sensitivity ..............................................................................50
9.2.3.
Sample Size Re-estimation or Adjustment...............................................50
9.3.
Data Analysis Considerations............................................................................50
9.3.1.
Analysis Populations..................................................................................50
9.3.2.
Interim Analysis ..........................................................................................51
9.3.3.
Adjustment for Multiplicity.........................................................................51
9.4.
Key Elements of Analysis Plan ..........................................................................51
9.4.1.
Primary Efficacy Analysis..........................................................................51
9.4.2.
Principal Secondary Efficacy Analysis.....................................................52
9.4.3.
Other Secondary Efficacy Analyses .........................................................52
9.4.4.
Safety Analyses...........................................................................................53
9.4.4.1.
Exposure .............................................................................................53
9.4.4.2.
Adverse Events...................................................................................53
9.4.4.3.
Other Safety Parameters ...................................................................53
9.4.5.
Pharmacokinetics Analyses ......................................................................53
9.4.6.
PRO Data Analysis......................................................................................53
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
10.3.
Quality Control (Study Monitoring)....................................................................55
10.4.
Quality Assurance ...............................................................................................55
10.5.
Study and Site Closure .......................................................................................55
10.6.
Records Retention...............................................................................................56
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publicatio....................56
10.8.
Study Period.........................................................................................................57
10.9.
Study Administrative Structure..........................................................................57


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11. REFERENCES...............................................................................................................58
12. APPENDICES ................................................................................................................59
12.1.
Appendix 1: Abbreviations and Trademarks....................................................59
12.2.
Appendix 2:  Risk Assessment.........................................................................61
12.3.
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of reproductive potential.............................................68
12.4.
Appendix 4: Collection of Pregnancy Information...........................................69
12.5.
Appendix 5: Liver Safety Required Actions and Follow up 
Assessments........................................................................................................70
12.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events ...................................................73
12.6.1.
Definition of Adverse Events.....................................................................73
12.6.2.
Definition of Serious Adverse Events.......................................................74
12.6.3.
Definition of Cardiovascular Events.........................................................75
12.6.4.
Recording of AEs and SAEs......................................................................75
12.6.5.
Evaluating AEs and SAEs..........................................................................75
12.6.6.
Reporting of SAEs to GSK.........................................................................77
12.7.
Appendix 7 - Genetic Research..........................................................................78
12.8.
Appendix 8: Definition of and Procedures for Documenting Medical 
Device Incidents...................................................................................................81
12.8.1.
Definitions of a Medical Device Incident ..................................................81
12.8.1.1.
Documenting Medical Device Incidents...........................................81


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1.
PROTOCOL SYNOPSIS FOR STUDY PHI201753
Rationale
This is a Phase III study to evaluate the efficacy and safety of GSK1278863 in Japanese non-dialysis 
(ND) and peritoneal dialysis (PD) subjects with renal anemia. The primary objective is to demonstrate
non-inferiority of GSK1278863 to epoetin beta pegol based on hemoglobin (Hgb) in the ND patient 
population included in this study. Study results will be used as pivotal study data for an NDA 
submitted for GSK1278863 for the treatment of renal anemia in Japan. 
Objective(s)/Endpoint(s)
Objective
Endpoint
Primary (efficacy)

To demonstrate non-inferiority of 
GSK1278863 to epoetin beta pegol based 
on hemoglobin (Hgb) in ND subjects 

Mean Hgb during the primary efficacy 
evaluation period (Weeks 40 to 52)
Principal secondary (efficacy)

To demonstrate superiority of 
GSK1278863 to epoetin beta pegol in 
terms of achievement/maintenance of 
target Hgb in ND subjects

Number (%) of subjects with mean Hgb in the 
target range (11.0-13.0 g/dL) during the 
primary efficacy evaluation period (Weeks 40 
to 52)
Other secondary (efficacy, PK)

To evaluate the appropriateness of the 
starting dose of GSK1278863 in ND 
subjects using epoetin beta pegol as 
control

To evaluate the appropriateness of the 
starting dose of GSK1278863 in PD 
subjects

Change from baseline in Hgb at Week 4 (Hgb 
increase rate)

Number (%) of subjects by Hgb change from 
baseline category at Week 4

To evaluate dose adjustment scheme of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate dose adjustment scheme of 
GSK1278863 in PD subjects

Distribution of the dose level

Duration of treatment interruption due to Hgb 
>13 g/dL

Frequency of dose adjustments

To evaluate the overall Hgb control of
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate the overall Hgb control of
GSK1278863 in PD subjects

Hgb and change from baseline at each 
assessment visit

Number (%) of subjects with Hgb within the 
target range (11.0-13.0 g/dL) at each 
assessment visit

Time (%) in Hgb target range (11.0-13.0 g/dL) 
during the primary efficacy evaluation period 
(Weeks 40 to 52)

Time (in days) to reach the lower Hgb target 


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Objective
Endpoint
(11.0 g/dL) 

Number (%) of subjects who have an Hgb 
level of less than 7.5 g/dL

Number (%) of subjects who have an Hgb 
increase of more than 2 g/dL over any 4 weeks 

Number (%) of subjects who have an Hgb 
level of more than 13.0 g/dL and number of 
episodes

To evaluate the effect on iron use of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate effect on iron use of 
GSK1278863 in PD subjects

Dose of oral iron during the study period and 
the primary efficacy evaluation period 
(Weeks 40 to 52) 

Number (%) of subjects who use oral iron 
during the study period and the primary 
efficacy evaluation period (Weeks 40 to 52)

To evaluate the effect on iron metabolism
of GSK1278863 in ND subjects using
epoetin beta pegol as control

To evaluate the effect on iron metabolism 
of GSK1278863 in PD subjects

Change from baseline in ferritin

Change from baseline in transferrin saturation 
(TSAT)

Changes from baseline in hepcidin, serum iron, 
and total iron binding capacity (TIBC) 

To evaluate the PK of GSK1278863

AUC and Cmax of plasma GSK1278863
Exploratory (efficacy)

To evaluate the effect on progression of 
Chronic Kidney Disease (CKD) of 
GSK1278863 in ND subjects using
epoetin beta pegol as control

Estimated glomerular filtration rate (eGFR) 
and change from baseline

Serum creatinine and change from baseline

Urine creatinine and urine albumin, and 
changes from baseline

Urine albumin/creatinine ratio and change 
from baseline
Patient reported outcome

To evaluate the effect on health-related 
QoL (HR-QoL) of GSK1278863 in ND 
subjects using epoetin beta pegol as 
control

To evaluate the effect on HR-QoL of 
GSK1278863 in PD subjects
SF-36

Changes from baseline in SF-36 HR-QoL 
scores [Physical Component Summary (PCS), 
Mental Component Summary (MCS), and 8 
subscales]
EuroQol Health Utility Index (EQ-5D-5L)

Change from baseline in EQ-5D-5L score 

Change from baseline in EQ-5D-5L Visual 
Analog Scale (VAS) 
Safety

To evaluate the safety and tolerability of 
GSK1278863 in ND and PD subjects

Incidence and severity of AEs and SAEs, 
including AEs of special interest


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Objective
Endpoint

Reasons for discontinuation of study 
medication

Laboratory tests, ECG, vital signs, and 
ophthalmology assessments
Study Design
This is a Phase III, open-label, active-controlled, parallel-group, multi-center study to compare the efficacy 
(demonstration of non-inferiority) and safety of GSK1278863 administered for 52 weeks versus epoetin 
beta pegol in approximately 286 Japanese ND subjects with renal anemia. This study also includes an open-
label, uncontrolled part to evaluate the efficacy and safety of GSK1278863 in approximately 50 Japanese 
PD subjects. Cohort 1 (ND subjects) and Cohort 2 (PD subjects) were set for target population of this study
when the study was planned. Cohort 3 is newly added in Protocol amendment (Amendment No.3). ND 
subjects will be randomized not to Cohort 1 but to Cohort 3 after Protocol amendment No.3.
Patient 
population
Cohort
Treatment group
Target number of subjects
(randomized)
ND patient
Cohort 11
GSK1278863 group (starting dose: 4 mg)
169 subjects4)
286 subjects5)
Epoetin beta pegol group
Cohort 32)
GSK1278863 group (starting dose: 2 mg or 4
mg3))
117 subjects
Epoetin beta pegol group
PD patient
Cohort 2
GSK1278863 group (starting dose: 4 mg)
50 subjects
1) At least 50 ESA users and at least 50 ESA non-users will be randomized to Cohort 1. 
2) ND patients will be randomized to Cohort 3 and at least 80 ESA non-user will be randomized after Protocol Amendment No.3.
3) GSK 1278863 starting dose in Cohort 3 as below

ESA non-user (baseline Hgb 8.0-<9.0 g/dL):4 mg

ESA non-user (baseline Hgb 9.0-<11.0 g/dL):2 mg

ESA user: 4 mg
4) The exact number of ND subjects randomized to Cohort 1 
5) Subjects will be randomized in a 1:1 ratio to one of the two treatment groups
ESA: erythropoiesis-stimulating agent
For the patient populations in either cohort, the Hgb criteria are specified according to the presence or 
absence of prior ESA: ESA non-users with an Hgb level of ≥8.0 to <11.0 g/dL and ESA users with an 
Hgb level of 9.0 to 13.0 g/dL will be included in the study.
In Cohort 1 and Cohort 3, eligible ND subjects [total of 286 subjects (169 subjects in Cohort 1, 117
subjects in Cohort 3)] will be stratified by the current ESA therapy and baseline Hgb (ESA non-users: 
9.5 g/dL, >9.5 g/dL, ESA users: <11.0 g/dL, 11.0 g/dL) and then randomized in a 1:1 ratio to 
GSK1278863 or epoetin beta pegol group. 
In Cohort 2, 50 eligible PD subjects will be included in the GSK1278863 group. 
This study consists of a 4-week screening phase, a 52-week treatment phase [including the primary 
efficacy evaluation period (Weeks 40 to 52)], and a 4-week follow-up phase following the treatment 
phase. The study design is shown below. 


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Screening phase
(4 weeks)
Treatment phase (52 weeks)
Follow-up phase
(4 weeks)
Primary efficacy 
evaluation period
Cohort 1
GSK1278863 group
Non-dialysis (ND)
subjects
Epoetin beta pegol group
Cohort 2
Peritoneal dialysis 
(PD) subjects
GSK1278863 group
Cohort 3
GSK1278863 group
Non-dialysis (ND)
subjects
Epoetin beta pegol group
Week -4                Day 1                            Week 40          Week 52          Week 56
Method of Administration of Study Medication in Each Treatment Group
In each treatment group, study medication will be administered as follows: 
GSK1278863 group:

Cohort 1 (ND subjects) and Cohort 2 (PD subjects)
Treatment with GSK1278863 will be started at a dose of 4 mg once daily on Day 1. 

Cohort 3 (ND subjects)

For ESA non-user with Baseline Hgb 8.0 and <9.0 g/dL, Treatment with 
GSK1278863 will be started at a dose of 4 mg once daily on Day 1.

For ESA non-user with Baseline Hgb 9.0 and <11.0 g/dL, Treatment with 
GSK1278863 will be started at a dose of 2 mg once daily on Day 1.

For ESA users, Treatment with GSK1278863 will be started at a dose of 4 mg once 
daily on Day 1.
After Week 4, dose adjustments will be made within the dose range of 1-24 mg every 4 weeks 
according to the prespecified dose adjustment algorithm to achieve and/or maintain Hgb within the 
target range (11.0-13 0 g/dL).

Epoetin beta pegol group (ND subjects): 

ESA non-users: Subcutaneous treatment with epoetin beta pegol will be started at a dose of 
25 g once every 2 weeks on Day 1. Subsequently, dose adjustments will be made within 
the dose range of 25-150 g every 4 weeks according to the prespecified initial dose 
adjustment criteria to achieve the lower limit of the Hgb target (11.0 g/dL). Once Hgb 
increases to 11.0 g/dL or more, dose adjustments will be made according to the prespecified 
dose adjustment algorithm. After it is confirmed that all of the criteria for dosing interval 


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change are met, dosing frequency will be changed to once every 4 weeks, and dose 
adjustments will be made within the dose range of 25-250 g every 4 weeks according to 
the prespecified dose adjustment algorithm to achieve and/or maintain Hgb within the target 
Hgb range (11.0-13.0 g/dL). 

ESA users: Prior ESA therapy will be replaced with subcutaneous treatment with epoetin 
beta pegol at the equivalent dose once every 4 weeks according to prespecified dose 
conversion. Subsequently, dose adjustments will be made within the dose range of 25-
250 g every 4 weeks according to the prespecified dose adjustment algorithm to achieve 
and/or maintain Hgb within the target range (11.0-13.0 g/dL).
Analysis
Assuming a non-inferiority margin of -1.0 g/dL, a treatment difference of 0.0 g/dL, and a standard 
deviation of 1.5 g/dL for mean Hgb during in the primary efficacy evaluation period in ND subjects, 
two-sample t-test has at least 99% power at a two-sided significance level of 5% with a sample size of 
100 subjects per group. Assuming a dropout rate of approximately 30%, 143 subjects will be 
randomized to each group. For PD subjects, the sample size is based on the feasibility. Assuming a 
sample size of 38 subjects and a standard deviation of 1.5 g/dL, the half the width of the 95% CI for 
mean Hgb during in the primary efficacy evaluation period is 0.493 g/dL. During this study, the 
protocol has been amended accordingto the change in starting dose for ND, ESA non-users in the 
GSK1278863 group; ESA non-users in Cohort 1 will be excluded from primary efficacy analysis 
according to this amendment. Additionally the protocol amendment has been made (Amendment 
No.4), in which the assumption of dropout rate after the start of study treatment was changed from 
25% to 30% and 143 subjects per group (total 286 subjects) will be randomized. (see Section 9.2.1).
The primary endpoint, which is the mean Hgb during the primary efficacy evaluation period, will be 
analyzed to demonstrate the non-inferiority of GSK1278863 to epoetin beta pegol in ND subjects,
including Cohort 1 subjects (only ESA users) and Cohort 3 subjects. A mixed model for repeated 
measurements (MMRM) will be used to estimate the mean Hgb during the primary efficacy 
evaluation period and its 95% CI by treatment groups. As a preliminary assessment, it will be 
confirmed if the lower and upper limit of 95% CI for mean Hgb in GSK1278863 group would lie fully 
within target range (11.0-13.0 g/dL) In addition, the point estimate and 95% CI for the treatment 
difference (GSK1278863-epoetin beta pegol) in mean Hgb during the primary efficacy evaluation 
period will be estimated. Non-inferiority will be established if the lower limit of the 95% CI is greater 
than -1.0 g/dL. Even if the 95% CI for the difference is completely negative (i.e. lies fully within the 
range -1.0 to 0 g/dL) non-inferiority would still be concluded on condition that the mean Hgb estimate 
in the GSK1278863 group is within the target range.
The primary efficacy population will be the ITT Population (excluding non-ESA users from Cohort 1),
and the analysis will be repeated in the mITT and PP Population to evaluate the robustness of the 
conclusion. The subgroup analysis by the current ESA therapy (presence or absence) will also be 
conducted.
Following sensitivity analyses will be conducted to assess robustness of the study result. 

If ND, ESA users whose dose level was decreased by one step at Week 2 exist in cohort 3,
sensitivity analysis excluding these subjects from primary analysis will be conducted.


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
Sensitivity analysis to primary efficacy analysis for all ND patients in Cohort 1 and Cohort 3 will 
be conducted.

If there are Hgb considered to be impacted by blood transfusion or marketed ESAs, sensitivity 
analysis excluding the Hgb values from the analyses of primary endpoint will be conducted.

Analysis of covariance (ANCOVA) will be conducted as sensitivity analysis to MMRM. This 
model includes treatment group and baseline Hgb level. The analysis population will be mITT 
population and the same analysis will be repeated in the PP population.

A tipping point analysis based on multiple imputation will be conducted as sensitivity analysis to 
missing data assumption. This analysis explores a point where non-inferiority is not confirmed
(tipping point) by changing assumption to missing data and repeating imputation. The analysis 
population will be ITT population and the same analysis will be repeated in the mITT and PP 
population.
Further details of sensitivity analyses will be provided in the Reporting and Analysis Plan (RAP).
The principal secondary endpoint, which is the proportion of subjects whose mean Hgb during the 
primary efficacy evaluation period is within the target range will be analyzed to demonstrate the 
superiority of GSK1278863 to epoetin beta pegol in ND subjects. 
In the mITT Population, a logistic regression model including treatment group, baseline Hgb, and the 
current ESA therapy (presence or absence) as covariates will be used to estimate the point estimate 
and 95% CI for the odds ratio (GSK1278863/epoetin beta pegol). This analysis will be performed to 
demonstrate the superiority at a two-sided significance level of 5%, conditional on the primary 
endpoint achieving noninferiority. Superiority will be established if the lower limit of the 95% CI for 
the odds ratio is greater than 1.0.


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2.
INTRODUCTION
GSK1278863 is a hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (PHI) that stimulates 
erythropoiesis in the same manner as innate response to hypoxia and is currently being developed as a 
new treatment for renal anemia.
2.1.
Study Rationale
This is a Phase III study to evaluate the efficacy and safety of GSK1278863 in Japanese non-dialysis 
(ND) and peritoneal dialysis (PD) subjects with renal anemia. The primary objective is to demonstrate 
non-inferiority of GSK1278863 to epoetin beta pegol based on hemoglobin (Hgb) in the ND patient 
population included in this study. Study results will be used as pivotal study data for an NDA 
submitted for GSK1278863 for the treatment of renal anemia in Japan. 
2.2.
Background
Renal anemia is diagnosed in many patients with CKD, and the prevalence of renal anemia increases 
with progression of CKD [Akizawa, 2011]. Causes of anemia in CKD patients include absolute or 
relative deficiency of erythropoietin (EPO), shortened erythrocyte survival, and reduced iron 
availability. Anemia is further exacerbated by chronic blood loss associated with hemodialysis 
procedure, infection, and functional hemolysis [Japanese Society for Dialysis Therapy, 2008]. 
GSK1278863 is a hypoxia-inducible factor-prolyl hydroxylase inhibitor that is currently being 
developed as a treatment for renal anemia. Data in Japanese patients have been collected from a 
Japanese Phase II 4-week treatment study in Japanese hemodialysis (HD) subjects (PHI116099: 97 
Japanese subjects), an international multi-center Phase II 24-week treatment study in HD subjects 
(PHI113633: including 24 Japanese subjects), and an international multi-center Phase II 24-week 
treatment study in ND subjects (PHI113747: including 42 Japanese subjects). In these clinical studies, 
GSK1278863 increased endogenous EPO, reduced hepcidin, and increased Hgb in HD and ND 
subjects including Japanese subjects. In addition, GSK1278863 increased Hgb at lower blood EPO 
concentrations than existing erythropoiesis-stimulating agents (ESAs). 
Data from completed clinical and clinical pharmacology studies and the preclinical data safety 
package are provided in the Development Core Safety Information found in the current GSK1278863 
Investigator Brochure (IB). A benefit: risk assessment, including risk mitigation strategies, is outlined 
in Section 4.6.
3.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary (efficacy)

To demonstrate non-inferiority of 
GSK1278863 to epoetin beta pegol based 
on hemoglobin (Hgb) in ND subjects 

Mean Hgb during the primary efficacy 
evaluation period (Weeks 40 to 52)
Principal secondary (efficacy)

To demonstrate superiority of 

Number (%) of subjects with mean Hgb in the 


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Objective
Endpoint
GSK1278863 to epoetin beta pegol in 
terms of achievement/maintenance of 
target Hgb in ND subjects
target range (11.0-13.0 g/dL) during the 
primary efficacy evaluation period (Weeks 40 
to 52)
Other secondary (efficacy, PK)

To evaluate the appropriateness of the 
starting dose of GSK1278863 in ND 
subjects using epoetin beta pegol as 
control

To evaluate the appropriateness of the 
starting dose of GSK1278863 in PD 
subjects

Change in Hgb from baseline to Week 4 (Hgb 
increase rate)

Number (%) of subjects by Hgb change from 
baseline category to Week 4

To evaluate dose adjustments of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate dose adjustments of 
GSK1278863 in PD subjects

Distribution of the dose level

Duration of treatment interruption due to Hgb 
>13 g/dL

Frequency of dose adjustments

To evaluate the overall Hgb control by 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate the overall Hgb control by 
GSK1278863 in PD subjects

Hgb at each assessment time point and change 
in Hgb from baseline to each assessment time 
point

Number (%) of subjects with Hgb within the 
target range (11.0-13.0 g/dL) at each 
assessment time point

Proportion (%) of time with Hgb within the 
target range (11.0-13.0 g/dL) in the primary 
efficacy evaluation period (Weeks 40 to 52)

Time (number of days) to the lower Hgb target 
(11.0 g/dL) 

Number (%) of subjects who have an Hgb 
level of less than 7.5 g/dL

Number (%) of subjects who have an Hgb 
increase of more than 2 g/dL over any 4 weeks 
before Week 52

Number (%) of subjects who achieve an Hgb 
level of more than 13.0 g/dL and number of 
episodes

To compare the effect of GSK1278863 
versus epoetin beta pegol on iron use in 
ND subjects

To evaluate the effect of GSK1278863 on 
iron use in PD subjects

Dose of oral iron in the study period and the 
primary efficacy evaluation period (Weeks 40 
to 52) 

Number (%) of subjects who use oral iron 
during the study period and the primary 
efficacy evaluation period (Weeks 40 to 52)

To compare the effect of GSK1278863 

Change in ferritin from baseline


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Objective
Endpoint
versus epoetin beta pegol on iron 
metabolism in ND subjects

To evaluate the effect of GSK1278863 on 
iron metabolism in PD subjects

Change in transferrin saturation (TSAT) from 
baseline

Changes in hepcidin, serum iron, and total iron 
binding capacity (TIBC) from baseline

To evaluate the PK of GSK1278863

AUC and Cmax of plasma GSK1278863
Exploratory (efficacy)

To compare the effect of GSK1278863 
versus epoetin beta pegol on progression 
of CKD in ND subjects

Estimated glomerular filtration rate (eGFR) 
and change from baseline

Serum creatinine and change from baseline

Urine creatinine and urine albumin, and 
changes from baseline

Urine albumin/creatinine ratio and change 
from baseline
Patient reported outcome

To compare the effect of GSK1278863 
versus epoetin beta pegol on health-
related QoL (HR-QoL) in ND subjects

To evaluate the effect of GSK1278863 on 
H-RQoL in PD subjects
SF-36

Changes in SF-36 HR-QoL scores (PCS, MCS,
and 8 subscales) from baseline
EuroQol Health Utility Index (EQ-5D-5L)

Change in EQ-5D-5L score from baseline

Change in EQ-5D-5L Visual Analog Scale 
(VAS) from baseline
Safety

To evaluate the safety and tolerability of 
GSK1278863 in ND and PD subjects

Incidence and severity of AEs and SAEs, 
including AEs of special interest

Reasons for discontinuation of study 
medication

Laboratory tests, ECG, vital signs, and 
ophthalmology assessments
4.
STUDY DESIGN
4.1.
Overall Design 
This is a Phase III, open-label, active-controlled, parallel-group, multi-center study to compare the 
efficacy (verification of noninferiority) and safety of GSK1278863 administered for 52 weeks versus 
epoetin beta pegol in approximately 286 Japanese ND subjects with renal anemia. This study also 
includes an open-label, uncontrolled part to evaluate the efficacy and safety of GSK1278863 in 
approximately 50 Japanese PD subjects. Cohort 1 (ND subjects) and Cohort 2 (PD subjects) were set 
for target population of this study when the study was planned. Cohort 3 is newly added in
amendment (Amendment No.3). ND subjects will be randomized not to Cohort 1 but to Cohort 3 after 
amendment No.3. 


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Table 1    Composition of each cohort 
[Including target number of subjects (randomized)]
Patient 
population
Cohort
Treatment group
Target number of subjects
(randomized)
ND patient
Cohort 11)
GSK1278863 group (starting dose: 4 mg)
169 subjects4)
286 subjects5)
Epoetin beta pegol group
Cohort 32)
GSK1278863 group (starting dose: 2 mg or 4
mg3))
117 subjects
Epoetin beta pegol group
PD patient
Cohort 2
GSK1278863 group (starting dose: 4 mg)
50 subjects
1) At least 50 ESA users and at least 50 ESA non-users will be randomized to Cohort 1. 
2) ND patients will be randomized to cohort3 and at least 80 ESA non-user will be randomized after Protocol amendment 
(Amendment No.3).
3) GSK 1278863 starting dose in Cohort3 as below

ESA non-user (baseline Hgb 8.0-<9.0 g/dL):4 mg

ESA non-user (baseline Hgb 9.0-<11.0 g/dL):2 mg

ESA user: 4 mg
4) The exact number of ND subjects randomized to cohort 1 
5) Subjects will be randomized in a 1:1 ratio to one of the two treatment groups
ESA: erythropoiesis-stimulating agent
For the patient populations in either cohort, the Hgb criteria are specified according to the presence or 
absence of prior ESA: ESA non-users with an Hgb level of ≥8.0 to <11.0 g/dL and ESA users with an 
Hgb level of 9.0 to 13.0 g/dL will be included in the study.
In Cohort 1and Cohort 3, eligible ND subjects [total of 286 subjects (169 subjects in Cohort 1, 117
subjects in Cohort 3)] will be stratified by the current ESA therapy (ESA non-user or ESA user) and 
baseline Hgb (ESA non-users: 9.5 g/dL, >9.5 g/dL, ESA users: <11.0 g/dL, 11.0 g/dL) and then 
randomized in a 1:1 ratio to GSK1278863 or epoetin beta pegol group. 
In Cohort 2, 50 eligible PD subjects will be included in the GSK1278863 group. 
This study consists of a 4-week screening phase, a 52-week treatment phase [including the primary 
efficacy evaluation period (Weeks 40 to 52)], and a 4-week follow-up phase following the treatment 
phase. The study design is shown in Figure 1.


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Screening phase
(4 weeks)
Treatment phase (52 weeks)
Follow-up phase
(4 weeks)
Primary efficacy 
evaluation period
Cohort 1
GSK1278863 group
Non-dialysis (ND)
subjects
Epoetin beta pegol group
Cohort 2
Peritoneal dialysis 
(PD) subjects
GSK1278863 group
Cohort 3
GSK1278863 group
Non-dialysis (ND)
subjects
Epoetin beta pegol group
Week -4                Day 1                            Week 40          Week 52          Week 56
Figure 1 Study Design
4.2.
Treatment Groups and Study Periods
Details for each study period and treatments are described below. In this study, a point-of-care Hgb 
analyzer (HemoCue®) will consistently be utilized for confirmation of subjects’ eligibility, withdrawal 
criteria and dose adjustments of study medication.
Screening phase
Subjects who have provided informed consent and meet all of the eligibility criteria at screening 
(Week -4) (Sections 5.1 and 5.2) will be provisionally enrolled in the study. Subjects who have used 
ESA and/or oral iron since before the start of the study must remain on the same regimen throughout 
the screening phase (intravenous iron will not be allowed). 
Treatment phase
Subjects who meet all of the eligibility criteria at the start of the treatment phase (Day 1) will be 
enrolled in the study. Study medication (either GSK1278863 or epoetin beta pegol group) will be 
administered for 52 weeks according to randomization in Cohort 1and Cohort 3. GSK1278863 will be 
administered in Cohort 2 for 52 weeks. For ESA users, prior ESA will be replaced with study 
medication on Day 1. GSK1278863 will be orally administered once daily, and epoetin beta pegol will 
be subcutaneously administered once every 2 or 4 weeks. In both groups, dose adjustments for study 
medication during the treatment phase will be made according to the administration schedule specified 
in Section 6.4. to achieve and/or maintain Hgb within the target range (11.0-13.0 g/dL). In addition, 


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supplemental iron therapy will be administered according to the standard initiation criteria as 
described in Section 6.12.. It should be noted that intravenous iron or dose change for oral iron will 
not be allowed from Day 1 to Week 4. 
Follow-up phase
Subjects will visit the site for follow-up assessments and observations 4 weeks after the 
completion/discontinuation of study treatment. During the follow-up phase, treatment of renal anemia 
will be allowed as necessary at the discretion of the investigator (or subinvestigator). 
4.3.
Study Subjects and Number of Subjects
For ND subjects, a total of 286 subjects will be randomized (143 subjects in GSK1278863 group, 143
subjects in epoetin beta pegol group). The minimum target number of subjects is 50 ESA non-users 
and 50 ESA users to allow for evaluations by the current ESA therapy (ESA non-user or ESA user) in 
Cohort 1. At least 80 ESA non-user will be randomized to Cohort 3 defined in Protocol (Amendment 
No.3). Assuming a dropout rate of 35% during the screening phase, approximately 440 ND subjects 
need to be screened. Assuming a dropout rate of 30% after the start of study treatment, a total of 200
subjects are expected to complete the 52-week treatment. At planning the study, since a dropout rate 
after the start of study treatment was assumed to be approximately 25%, 135 subjects per group (total 
270 subjects) were going to be randomized. After the start of study, however, the assumption of 
dropout rate after the start of study treatment was changed from 25% to 30% then the protocol 
amendment has been made (Amendment No.4). In the amended protocol, 143 subjects per group (total 
286 subjects) will be randomized as mentioned above. If dropout rate is greater than the assumed, 
number of randomized subjects may be adjusted to ensure 100 subjects per group (total 200 subjects) 
to complete 52 week treatment.
In Cohort 2 involving PD subjects, 50 subjects will be enrolled (GSK1278863 group only). Since the 
number of PD patients is very limited in Japan, the target number of subjects is not set for either ESA 
non-users or users. Assuming a dropout rate of 35% during the screening phase, approximately 77 
subjects need to be screened. Assuming a dropout rate of 25% after the start of study treatment, 38 
subjects are expected to complete the 52-week treatment. 
Table 2    Target Number of Subjects
ND subjects
PD subjects 
Cohort 1
Cohort 3
Cohort 2
Screened
440
77
Randomized/enrolled
286
50
169*1
117*2
Expected tocomplete 52-week 
treatment
200
38
*1: In Cohort 1, at least 50 ESA non-users and at least 50 ESA users will be randomized.
*2: In Cohort 3, at least 80 ESA non-user will be randomized 


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4.4.
Rationale for Study Design
Objectives and evaluations
This is a Phase III study to evaluate the efficacy and safety of GSK1278863 in Japanese ND and PD 
subjects with renal anemia. For Cohort 1 and Cohort 3, the study is designed as an active-controlled, 
parallel-group comparative study to meet the primary objective, that is, to demonstrate non-inferiority 
of GSK1278863 to the existing drug in ND, ESA user subjects in Cohort 1 or ND subjects in Cohort 3, 
depending on a change of the starting dose for ND, ESA non-users. For Cohort 2, the study is 
designed as an uncontrolled study because there are not many PD patients. The target Hgb range was 
set for study treatment in line with the Guidelines for Renal Anemia in Chronic Kidney Disease issued 
by the Japanese Society for Dialysis Therapy in 2008 [The Japanese Society for Dialysis Therapy, 
2008] to demonstrate that treatment with GSK1278863 can result in achievement and/or maintenance 
of target Hgb in ND and PD subjects, and evaluate the appropriateness of the starting dose of 
GSK1278863. 
Control
For the ND patient population (Cohort 1 and Cohort 3), epoetin beta pegol, which has been widely 
used in Japanese patients with renal anemia, primarily ND patients, since its approval in Japan in 2011, 
was selected as control. 
Open-label
If the study is conducted as a double-blind study, it is necessary to not only administer GSK1278863 
orally (once daily) or epoetin beta pegol subcutaneously (once every 2 or 4 weeks), but also 
administer the matching placebo subcutaneously or orally. It will be more stressful for subjects and 
complicate treatment procedures to use both active drug and matching placebo for two drugs with 
different routes and intervals of administration for the purpose of maintaining the blind, and make 
dose adjustments for individual subjects according to the change in Hgb over time. Accordingly, this 
study is designed as an open-label study rather than a double-blind study, which seems infeasible. 
Since Hgb used for efficacy evaluation is an objective measure, and dose adjustments for study 
medication will be made according to the prespecified Hgb-based dose adjustment method in both 
GSK1278863 and epoetin beta pegol groups, it is unlikely that the open-label design will create any 
bias in the primary evaluation. 
4.5.
Rationale for Dose Levels
Starting dose and dose adjustments of GSK1278863
The starting dose and the dose adjustment method (maintenance dose range: 1-24 mg) for 
GSK1278863 are described in Section 6.4..
The starting dose and the dose adjustment algorithm selected for Japanese ND subjects in the present 
study are based on the results from a review of the longitudinal model constructed using Hgb data 
from six Japanese or overseas Phase II studies (PHI112844, PHI116581, PHI116582, PHI113633, 
PHI113747, and PHI116099) as well as the results from clinical studies. The data set used in the 
model analyses was based on the data of GSK1278863 administered in a wide dose range (0-25 mg) 
and included a Japanese Phase II 4-week treatment study (PHI116099) and international multi-center 
late Phase II 24-week treatment studies (PHI113633 and PHI113747) in which subjects in Japan 
participated. For PD subjects, the starting dose and the dose adjustment algorithm for ND subjects will 


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be applied based on the PK/PD profiles in PD subjects determined from an interim analysis in an 
overseas 14-day treatment clinical pharmacology study (PHI200942). 
Starting dose
Simulation results using the longitudinal model in ND subjects as well as the results from clinical 
studies indicated that GSK1278863 given at a dose of 4 mg may slowly increase Hgb (0.5-1.0 g/dL on 
average) without a rapid increase greater than 2 g/dL after 4 weeks of treatment in ESA non-users. 
4 mg GSK1278863 may also maintain Hgb without a rapid increase greater than 2 g/dL for 4 weeks 
after switching from prior ESA in ESA users. Therefore, 4 mg was set as starting dose of 
GSK1278863 when study was planned.
As of Dec 2016 during this study, from the result of a review of blinded data, it was determined that 
the percentage of ND, ESA-non-user subjects with an Hgb increases of >2.0 g/dL from baseline to 
Week 4 was higher than expectation dedscribed above. This finding was not observed in ND, ESA-
user subjects and PD subjects.
Therefore, in the protocol amendment No.3, 

For ND, ESA non-user subjects with baseline Hgb ≥9.0 g/dL and <11.0 g/dL, the starting dose of 
GSK1278863 is changed from 4 mg to 2 mg.

For ND, ESA non-user subjects with baseline Hgb ≥8.0 g/dL and <9.0 g/dL, the starting dose 
remains at 4 mg. 
For ND, ESA-user subjects and PD subjects, the starting dose of GSK1278863 were not changed and 
remains at 4 mg respectively.
In addition, Week 2 visit for additional Hgb monitoring in Cohort 3 was also included to allow earlier 
safety assessment of Hgb change at early phase of GSK1278863 treatment. (Refer to Section 6.4.1.)
Maintenance dose range and dose adjustment algorithm
Simulation results using the longitudinal model showed that drug response to GSK1278863 greatly 
varied among subjects, indicating that the dose range from 1 to 24 mg may be necessary to achieve 
and maintain target Hgb. Accordingly, a total of 8 dose levels (1, 2, 4, 6, 8, 12, 18, and 24 mg) were 
selected as the maintenance doses, with 4 mg intended for subjects with a standard drug response. 
The dose adjustment algorithm was defined so that target Hgb (11.0-13.0 g/dL) set for the present 
study according to the Guidelines for Renal Anemia [The Japanese Society for Dialysis Therapy,
2008] can be maintained. Since the upper limit of the Hgb target (13.0 g/dL) is equivalent to the 
interruption criterion for ESA, the dose level of GSK1278863 will be reduced by one step when Hgb 
increases to more than 12.5 g/dL, and the dose level will be maintained while Hgb is in the range of 
11.5-<12.5 g/dL. Since the guidelines state that an Hgb increase of 0.5 g/dL or less per week is 
appropriate to prevent adverse reactions, the dose level will be reduced by one step when Hgb 
increases by more than 2 g/dL over 4 weeks (or when Hgb increases by more than 1 g/dL over 2 
weeks at Week 4). For subjects whose anemia needs to be corrected (≥7.5 g/dL and <11.5 g/dL), the 
dose level will be maintained while the Hgb increase per 4 weeks is 0.5-2 g/dL, and the dose level will 
be increased by one step when the Hgb increase per 4 weeks is less than 0.5 g/dL. 


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Starting dose and dose adjustments of control (epoetin beta pegol)
The starting dose and the dose adjustment algorithm for epoetin beta pegol are described in Section 
6.4..
The starting dose of epoetin beta pegol for subjects not using ESA or subjects on epoetin was selected 
based on the Prescribing Information in Japan. For subjects on darbepoetin alfa, darbepoetin alfa will 
be switched to epoetin beta pegol at a dose ratio of 6:5 according to overseas Prescribing Information, 
given no specification for dose conversion from darbepoetin currently approved in Japan to epoetin 
beta pegol. 
The dose adjustment algorithm for epoetin beta pegol was determined based on the product 
information and previous Japanese clinical studies. In Cohort 3, a study visit at Week 2 for Hgb 
monitoring was also added for the control group. (Refer to Section 6.4.2.)
4.6.
Benefit: Risk Assessment
Summaries of findings from clinical and nonclinical studies of GSK1278863 can be found in the IB
and IB supplement. The risk assessment and risk minimization strategies for the present study are 
outlined in the following sections: 
4.6.1.
Risk Assessment
Based on the results of completed clinical and nonclinical studies of GSK1278863, the potential risks 
of clinical significance and the risk minimization strategies for the present study are outlined in 
Section 12.2. Appendix 2.
4.6.2.
Benefit Assessment 
Study PHI201753 is a Phase 3 study in Japanese ND and PD subjects with renal anemia. Previous
clinical studies of GSK1278863 administered for up to 24 weeks in ND or HD subjects have 
demonstrated clinical efficacy (increase in and/or maintenance of Hgb) with serum EPO 
concentrations increased within the normal physiologic range in CKD subjects. Data obtained in 
Study PHI201753 will generate safety and efficacy data in Japanese ND and PD subjects with renal 
anemia for a 52-week treatment period. Study participants who will receive GSK1278863 may benefit 
from the expected clinical efficacy. Participants who will receive the control (epoetin beta pegol 
approved for the treatment of renal anemia in Japan) are also expected to benefit from the clinical 
efficacy. 
GSK1278863 may have important advantages over existing ESAs. GSK1278863, which is orally 
administered and requires no cold chain management unlike ESAs, is more convenient to patients. 
GSK1278863 is shown to increase Hgb at lower EPO concentrations than ESAs. Since increased 
exposure to EPO following administration of ESAs may be associated with an increased 
cardiovascular risk [Szczech, 2008], GSK1278863 may increase Hgb without increasing the 
cardiovascular risk. 
4.6.3.
Overall Benefit: Risk Conclusion
GSK1278863 is shown to have a positive benefit-risk balance based on the following findings: in 
studies of GSK1278863 administered for up to 24 weeks, treatment with GSK1278863 resulted in 


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achievement of target Hgb, and no adverse events have been identified as related to treatment with 
GSK1278863.
The present study is intended to evaluate the efficacy and safety of GSK1278863 administered for 52
weeks in Japanese ND and PD subjects with renal anemia, and designed to administer GSK1278863 
or epoetin beta pegol as control to all enrolled subjects; therefore, subjects randomized in either 
treatment group are expected to benefit from the treatment. 
This protocol employs precautions to mitigate known and potential risks to enrolled subjects (Section 
12.2. Appendix 2). Given these precautions, as well as the potential benefit that GSK1278863 holds 
for the treatment of renal anemia compared with the current standard treatment, the overall benefit risk 
balance is considered to be positive.
5.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, and other 
pertinent information on the GSK investigational product or other study treatment that may impact 
subject eligibility is provided in the IB/IB supplement(s) and/or other pertinent documents.
Deviations from inclusion/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.
5.1.
Inclusion Criteria
Subjects eligible for enrolment in the study must meet all of the inclusion criteria.
Note: Verification at both provisional enrolment (screening) and official enrolment (Day 1) is required, 
unless otherwise specified.
1.
Age (at the time of informed consent): ≥20 years of age
2.
(Screening verification only) Stage of chronic kidney disease (CKD) (ND patients only): CKD 
stages 3, 4, and 5 defined by eGFR using the Japanese Society of Nephrology-Chronic Kidney 
Disease Initiatives (JSN-CKDI) formula
3.
Dialysis: 

Not on dialysis for at least 12 weeks prior to screening (ND patients)

On peritoneal dialysis (PD patients)
4.
Use of erythropoiesis-stimulating agent (ESA): 

ESA non-users: Have not used ESAs for at least 8 weeks prior to screening

ESA users: Have used the same ESA for at least 8 weeks prior to screening. However, in the 
ND patients, the dose of darbepoetin alfa or epoetin beta pegol must be stable (administered 
once every 4 weeks and up to one-step dose change during at least 8 weeks prior to 
screening). 
5.
Hemoglobin (Hgb): Determined at the site using an Hgb analyzer (HemoCue) 

ESA non-users: ≥8.0 g/dL and <11.0 g/dL

ESA users: ≥9.0 g/dL and ≤13.0 g/dL 


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6.
Iron parameters: Ferritin >100 ng/mL or transferrin saturation (TSAT) >20% (screening 
verification only)
7.
Gender (screening verification only): Female or male
Females: Not pregnant [demonstrated to be negative for human chorionic gonadotropin (hCG) in 
urine or serum], not breast-feeding, and meet at least one of the following: 
1)
Females of non-childbearing potential are defined as follows: 

Pre-menopausal with at least one of the following and no plans to utilise assisted 
reproductive techniques (e.g., in vitro fertilisation or donor embryo transfer):

History of bilateral tubal ligation or salpingectomy

History of hysteroscopic tubal occlusion and postoperatively documented bilateral 
tubal obstruction 

History of hysterectomy

History of bilateral oophorectomy

Postmenopausal defined as 1) females 60 years of age or older or 2) In females < 60 years 
of age, 12 months of spontaneous amenorrhea [in questionable cases a blood sample with 
postmenopausal follicle stimulating hormone (FSH) and estradiol concentrations is 
confirmatory (see separately specified reference ranges)]. Females on hormone replacement 
therapy (HRT) whose menopausal status is in doubt will be required to use one of the most 
effective contraception methods 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 enrolment.
2)
Females of childbearing potential must agree to comply with one of the contraception 
methods listed as requirements in “GSK Listing of Most Effective Contraceptive Methods for 
Females of Childbearing Potential (Section 12.3. Appendix 3: Modified List of Highly Effective 
Methods for Avoiding Pregnancy in Females of reproductive potential)” from at least 28 days 
prior to the first dose of study medication until the completion of the follow-up visit (for subjects 
randomized to the GSK1278863 group) or 7 weeks after the last dose of study treatment (for 
subjects randomized to the Epoetin beta pegol group).
8.
Informed consent: Written informed consent, including adherence to the requirements and 
conditions specified in the consent form and the protocol, must be obtained from each subject as 
specified in Section 10.2..
5.2.
Exclusion Criteria
Subjects meeting any of the following criteria must not be enrolled in the study.
Note: Verification at both provisional enrolment (screening) and official enrolment (Day 1) is required, 
unless otherwise specified.
Chronic kidney disease (CKD)-related criteria 
1.
Dialysis

Cohort 1and Cohort 3: Start or plan to initiate dialysis during the study

Cohort 2: Plan to stop peritoneal dialysis or start hemodialysis during the study
2.
Kidney transplant: Planned living-related kidney transplant during the study


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Anemia-related criteria
3.
Aplasia: History of bone-marrow hypoplasia or pure red cell aplasia
4.
Other causes of anemia: pernicious anemia, thalassemia, sickle cell anemia, or myelodysplastic
syndromes
5.
Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal 
ulcer disease OR clinically significant GI bleeding within 8 weeks prior to screening or during a 
period from screening to Day 1.
Cardiovascular disease-related criteria
6.
Myocardial infarction, acute coronary syndrome, stroke, or transient ischemic attack: Diagnosed 
within 8 weeks prior to screening or during a period from screening to Day 1.
7.
Heart failure: Class IV heart failure, as defined by the New York Heart Association (NYHA) 
functional classification system
8.
QTc (screening verification only): QTc >500 msec or QTc >530 msec in subjects with bundle 
branch block 
Note: QT interval corrected using the Bazett’s formula (QTcB) will be used, and ECG can be 
mechanically or manually read. 
Other disease-related criteria
9.
Liver disease (if any of the following occurs): 

(Screening verification only): Alanine transaminase (ALT) >2×upper limit of normal (ULN)

(Screening verification only): Bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is 
acceptable if bilirubin is fractionated and direct bilirubin is <35%)

Current unstable active liver or biliary disease (generally defined by the onset of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, persistent 
jaundice, or cirrhosis)
Note: Stable liver disease (including asymptomatic gallstones, chronic hepatitis B/C, or 
Gilbert’s syndrome) is acceptable if the subject otherwise meets entry criteria.
10. Malignancy: History of malignancy within 2 years prior to screening, or currently receiving 
treatment for cancer, (PD patients only) complex renal cystic >3 cm (II F, III or IV based on the 
Bosniak classification)
Note (ND patients and PD patients): The only exception is squamous cell or basal cell carcinoma 
of the skin that has been definitively treated 8 weeks before screening.
11. In the opinion of the investigator, Hgb increase to the target range (11.0-13.0 g/dL) is medically 
risky.
Concomitant medication and other study treatment-related criteria
12. Iron: Planned use of intravenous iron during the screening phase or during a period from Day 1 
to Week 4
Note: Oral iron is acceptable. However, the same dose regimen must be used throughout the 
screening phase and from Day 1 to Week 4. Antihyperphosphatemic agents containing iron (e.g., 
ferric citrate hydrate) are also acceptable only if used for at least 12 weeks prior to screening. 
However, they must be continued throughout the screening phase and from Day 1 to Week 4. 


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13. Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity 
to excipients in the investigational product [see the GSK1278863 IB (ND and PD patients) or 
epoetin beta pegol Prescribing Information (ND patients)]
14. Drugs and supplements: Use or planned use of any prescription or non-prescription drugs or 
dietary supplements that are prohibited during the study period (prohibited medications: strong 
inducers and inhibitor of CYP2C8, see Section 6.11.2.)
15. Prior investigational product exposure: Use of an investigational agent within 30 days or five half 
lives of the investigational agent (whichever is longer)
16. Prior treatment with GSK1278863: Any prior treatment with GSK1278863 for a treatment 
duration of >30 days
General health-related criteria
17. Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding 
that the investigator (or subinvestigator) considers would put the subject at unacceptable risk, 
which may affect study compliance or prevent understanding of the aims or investigational 
procedures or possible consequences of the study
5.3.
Screening Failures
Screen failures are defined as subjects who consent to participate in the clinical trial, but are not 
subsequently randomized in the study. A minimum set of information is required from screen failure 
subjects including Demography, Screen Failure details, Eligibility Criteria, and SAEs in order to 
report screen failures in a reliable manner, satisfy the requirements for publication defined by the 
Consolidated Standards of Reporting Trials (CONSORT), and respond to requests of the regulatory 
authorities.
Subjects that fail screening are eligible to be rescreened up to 3 times as soon as the investigator (or 
subinvestigator) assesses they may meet study entry criteria. Re-screening subjects are allowed to use 
the results of the latest ophthalmology exam to replace the rescreening ophthalmology exam, at the 
discretion of the investigator (see Table 14).
5.4.
Withdrawal/Dropout Criteria
If subjects meet one of the following criteria, study treatment should be permanently discontinued and 
subjects will be withdrawn from the study. The withdrawal reason should be recorded.

Hgb <7.5 g/dL
Note: HemoCue Hgb values will be employed. If an initial Hgb value meets the Hgb stopping 
criteria, measurement will be repeated at the same study visit (using the same sample) to 
calculate the average. If the average meets the Hgb stopping criteria, study treatment will be 
discontinued.

Subject needs for maintenance dialysis or changes dialysis modality (PD subjects only) during 
the study period.

Kidney transplant

Subject becomes pregnant or intends to become pregnant during the study.

Diagnosis of new or recurrent cancer


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
Liver chemistry abnormalities exceeding the threshold criteria (see Section 5.4.1.)

Need for chronic (more than 14 days) use of prohibited medication (strong inhibitors/ inducers of 
CYP2C8 meet this criteria)

When the investigator (or subinvestigator) considers necessary to withdraw the subject from the 
study for other reasons
Subjects who meet any of the withdrawal criteria or are withdrawn for other reasons during the 
treatment phase should be assessed at withdrawal visit after study treatment is discontinued, and will 
then enter the follow-up phase. 
Should a subject fail to attend a required study visit, the investigator (or subinvestigator) should take 
the following measures: 

The investigator (or subinvestigator) or designee should attempt to contact the subject and re-
schedule the missed visit as soon as possible.

The investigator (or subinvestigator) should counsel the subject on the importance of maintaining 
the assigned visit schedule and determine whether the subject is willing to continue his/her 
participation in the study and/or whether the subject should remain in the study. 

The investigator (or subinvestigator) or designee should make every effort to regain contact with 
a subject who is deemed “Lost to Follow-up”. All efforts to contact the subject should be 
documented in the subject’s clinical charts. 

Should the subject continue to be unreachable, then and only then will he/she be considered 
“Lost to Follow-up.”
A subject may withdraw from the study at any time at his/her own request. The investigator (or 
subinvestigator) may withdraw a subject from the study at any time for safety or compliance reasons 
or study conduct considerations. If a subject withdraws from the study, he/she may request destruction 
of any clinical samples taken, and the investigator (or subinvestigator) must document this in the site 
study records.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure subject 
safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety 
guidance).


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Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Chemistry Increased Monitoring Algorithm with Continued Therapy for ALT 3xULN 
but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in Section 12.5. 
Appendix 5


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5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by any subject 
participating in this study is not allowed.
5.5.
Subject and Study Completion
A completed subject is one who has completed all periods of the study including the follow-up visit.
The study will be completed with the last subject’s last study visit. 
6.
STUDY TREATMENTS
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any products received by the 
subject as per the protocol design. Accordingly, ‘study treatment’ sometimes refers to each product 
and sometimes refers to multiple products. 
GSK1278863 (study drug)
The study drug GSK1278863 will be supplied as fast-release film coated tablets for oral 
administration containing 1 mg, 2 mg, 4 mg, or 6 mg of GSK1278863 (Table 3). There are two sizes 
of GSK1278863 tablets.
Table 3   Description of GSK1278863 Tablets
GSK1278863 tablets of 
specific content
Description
1 mg tablets, 2 mg tablets, 
4 mg tablets
7.0 mm round, standard biconvex, white film coated tablets containing 
1 mg, 2 mg, or 4 mg of GSK1278863 as active ingredient
6 mg tablets
9.0 mm round, standard biconvex, white film coated tablets containing 
6 mg of GSK1278863 as active ingredient
GSK1278863 tablets of specific content are packed in high density polyethylene (HDPE) bottles, with 
35 tablets per bottle. Subjects are to take one to four tablets (Table 4) with water once daily according 
to the dose level indicated at each study visit. Subjects can take GSK1278863 tablets without regard to 
food or peritoneal dialysis. The administration schedule (starting dose and dose adjustment) described 
in Section 6.4.1. should be followed. 
Table 4    Dose Levels of GSK1278863 and Number of Tablets Taken
Dose level of 
GSK1278863
(once daily)
1 mg
2 mg
4 mg
6 mg
8 mg
12 mg
18 mg
24 mg
Number of 
GSK1278863
tablets taken
1 mg 
tablet
×1
2 mg 
tablet
×1
4 mg 
tablet
×1
6 mg 
tablet
×1
4 mg 
tablet
×2
6 mg 
tablet
×2
6 mg 
tablet
×3
6 mg 
tablet
×4
Subjects should be instructed to bring GSK1278863 tablets with bottles at each study visit, and all 
unused GSK1278863 tablets will be collected from subjects at each study visit.


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Epoetin beta pegol (control)
The control epoetin beta pegol (brand name: MirceraPre-filled Syringe) will be supplied by GSK. 
This product is an injectable formulation containing 25 g, 50 g, 75 g, 100 g, 150 g, 200 g, or 
250 g of epoetin beta pegol per syringe (0.3 mL) and is supplied as a glass syringe prefilled with 
epoetin beta pegol solution (clear colorless to pale yellow).
Subjects are to receive epoetin beta pegol subcutaneously once every 2 or 4 weeks at the site (Table 5). 
The administration schedule (starting dose and dose adjustment) described in Section 6.4.2. should be 
followed. 
Table 5    Dose Levels of Epoetin Beta Pegol and Number of Subcutaneous Doses
Dose level of epoetin beta 
pegol
(once every 2 or 4 weeks)
25 g
50 g
75 g
100 g
150 g
200 g
250 g
Number of subcutaneous 
doses of epoetin beta pegol
25 g 
injection
×1
50 g 
injection
×1
75 g
injection
×1
100 g 
injection
×1
150 g 
injection
×1
200 g 
injection
×1
250 g 
injection
×1
6.2.
Medical Devices
The Epoetin beta pegol (Brand name :MIRCERA® Injection Syringe) marketed with the device (kit 
formulation which was filled liquid medication in glass syringe ) provided for use in this study.
Instructions for medical device are described in the Prescribing Infromation of MIRCERA® Injection 
Syringe.
The medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study – see Section 7.4.4.
6.3.
Treatment Assignment
The randomization schedule will be generated by GlaxoSmithKline (GSK) using the randomization 
system (Randall).
In Cohort 1 and Cohort 3 (ND subjects), subjects will be stratified by the current ESA therapy (ESA 
non-user or ESA user) and the Hgb level on Day 1 and randomized in a 1:1 ratio to one of the two 
treatment groups according to the randomization schedule. Randomization should precede the study 
treatment. 

GSK1278863 group

Epoetin beta pegol group
In Cohort 2 (PD subjects), all eligible subjects will start treatment with GSK1278863 on Day 1. 
Subjects will be assigned a randomization number by the Interactive Web Recognition System 
(IWRS). Once a randomization number has been assigned, it must not be re-assigned. Further details 
are provided in the Study Reference Manual (SRM).


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6.4.
Administration Schedule (Starting Dose, Dose Adjustment, and Dosing 
Frequency)
6.4.1.
GSK1278863 (ND and PD Subjects)
6.4.1.1.
Starting Dose
For ND subjects randmized to GSK1278863 group
(Cohort 1)
Both ESA non-users and users will start oral treatment with GSK1278863 at the starting dose of 4 
mg once daily (Day 1) and remain on the same regimen until the day of Week 4.
(Cohort 3)

ESA non-users

Baseline Hgb 8.0 g/dL and <9.0 g/dL: the subjects will start oral treatment with 
GSK1278863 at the starting dose of 4 mg once daily (Day 1) and remain on the same 
regimen until the day of Week 4*.

Baseline Hgb 9.0 g/dL and <11.0 g/dL: the subjects will start oral treatment with 
GSK1278863 at the starting dose of 2 mg once daily (Day 1) and remain on the same 
regimen until the day of Week 4*.

ESA users will start oral treatment with GSK1278863 at the starting dose of 4 mg once daily 
(Day 1) and remain on the same regimen until the day of Week 4*.
*: The HemoCue Hgb value will be measured for safety confirmation at Week 2 in ND subjects. 
When Hgb > 1.0 g/dL increase over 2 weeks, the dose of GSK1278863 is decreased to the next lower 
dose.
For PD subjects randomized to the GSK1278863 group (Cohort 2)

ESA non-users will start oral treatment with GSK1278863 at the starting dose of 4 mg once daily 
(Day 1) and remain on the same regimen until the day of Week 4. 

ESA users will start oral treatment with GSK1278863 at the starting dose of 4 mg once daily 
(Day 1) and remain on the same regimen until the day of Week 4.
ESA users should skip ESA on Day 1 when treatment with GSK1278863 is started. 
6.4.1.2.
Maintenance Dose
From Weeks 4 to 52, interruption of treatment or dose adjustments will be made within the 
maintenance dose range of 1-24 mg (Table 6) according to the dose adjustment algorithm (Table 7) to 
achieve and/or maintain Hgb within the target range (11.0-13.0 g/dL) based on the HemoCue Hgb 
value measured every 4 weeks. Dose changes will be made every 4 weeks. If any of the one-step dose 
reduction criteria is met during treatment at the minimum maintenance dose (1 mg), treatment should 
be interrupted; once the one-step dose increase criteria are met, treatment at 1 mg will be resumed. If 
the one-step dose increase criterion is met during treatment at the maximum maintenance dose 
(24 mg), treatment at 24 mg should be continued. 


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Table 6    Maintenance Dose of GSK1278863
Dose step
1
2
3
4
5
6
7
8
Dose level of 
GSK1278863
(once daily)
1 mg
2 mg
4 mg
6 mg
8 mg
12 mg
18 mg
24 mg
Number of 
GSK1278863
tablets taken
1 mg 
tablet
×1
2 mg 
tablet
×1
4 mg 
tablet
×1
6 mg 
tablet
×1
4 mg 
tablet
×2
6 mg 
tablet
×2
6 mg 
tablet
×3
6 mg 
tablet
×4
Table 7   Dose Adjustment Algorithm (GSK1278863)
Hgb
(g/dL)
Hgb increase over 4 weeks 
(g/dL)
Treatment
>13.0
NA
Interrupt treatment until Hgb decreases to less than 
12.5 g/dL
Resume treatment at the one lower dose level (If 
interrupted at 1 mg: resume treatment at 1 mg once 
the one-step dose increase criteria are met)
12.5-13.0
NA
One-step dose reduction
11.5-<12.5
>2.01)
One-step dose reduction
2.0
Continue treatment at the current dose level
7.5-<11.5
>2.01)
One-step dose reduction
0.5-2.0
Continue treatment at the current dose level
<0.5
One-step dose increase
<7.5
NA
Discontinue treatment permanently 2) and initiate 
another appropriate treatment
1) Cohort 3 only: At Week 4, if an Hgb increase of >1.0 g/dL over 2 weeks is observed, the dose of GSK1278863 will 
be reduced by one step; if an Hgb increase of 1.0 g/dL over 2 weeks is observed, treatment will be continued as 
specified in the dose adjustment algorithm other than one-step dose reduction for an Hgb increase of >2.0 g/dL over 4
weeks.
2): If an initial Hgb value is less than 7.5 g/dL, measurement will be repeated at the same study visit (using the same 
sample) to calculate the average. If the average meets the Hgb stopping criteria, study treatment will be permanently
discontinued.
6.4.2.
Epoetin Beta Pegol (ND Subjects Only)
For ND subjects (Cohort 1 and Cohort 3) randomized to the epoetin beta pegol group, ESA non-users 
and users will receive epoetin beta pegol subcutaneously according to the treatment regimens 
described below.
6.4.2.1.
Starting Dose for ESA Non-users
ESA non-users will start subcutaneous treatment with epoetin beta pegol at a dose of 25 μg once every 
2 weeks (Day 1). Dose adjustments will be made within the initial dose range of 25-150 μg (Table 8)
according to the dose adjustment criteria (Table 9) to increase Hgb to 11.0 g/dL (lower limit of the 
target) or more based on the HemoCue Hgb value measured every 4 weeks. Dose changes will be 
made every 4 weeks. If any of the dose reduction criteria shown in Table 9 is met during treatment 
with epoetin beta pegol at 25 μg, treatment should be interrupted; once the dose reduction criteria are
not met any longer, treatment will be resumed at a dose of 25 μg. 


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At Week 2, HemoCue Hgb value will be measured for subjects' safety confirmation. If the 
measurement shows an Hgb increase of >1.0 g/dL over 2 weeks, the dose of epoetin beta pegol will be 
reduced by one step (or treatment interrupted) (Cohort 3 only).
Table 8    Initial Dose of Epoetin Beta Pegol (ESA Non-users)
Dose step
1
2
3
4
5
Dose level of epoetin beta pegol
(once every 2 weeks)
25 μg
50 μg
75 μg
100 μg
150 μg
Table 9    Initial Dose Adjustment Criteria for Epoetin Beta Pego (ESA Non-users)
Hgb
Treatment
Hgb increase <1.0 g/dL over past 4 weeks, 
OR Hgb <10.0 g/dL and Hgb increase ≤2.0 g/dL over past 4 weeks
One-step dose increase
Hgb increase >2.0 g/dL over past 4 weeks1)
One-step dose reduction
Otherwise
Continue treatment at the 
current dose level
1) Cohort 3 only: Hgb increaseof >1.0 g/dL over past 2 weeks at Week 2.
Once Hgb increases to 11.0 g/dL or more, dose adjustments will be made according to the 
prespecified dose adjustment algorithm (Table 13). The dosing interval should be changed from once 
every 2 weeks to once every 4 weeks with dose conversion for dosing interval change (Table 10) after 
it is confirmed that all of the following criteria are met:

Hgb in the target range (11.0-13.0 g/dL)

Hgb change ≤2.0 g/dL over past 4 weeks

Equivalent dose will be given twice (at least 4 weeks)
Table 10    Dose Conversion of Epoetin Beta Pegol for Dosing Interval Change (ESA 
Non-users)
Initial dose of epoetin beta pegol
(given once every 2 weeks)
Dose conversion of epoetin beta pegol
(given once every 4 weeks)
25 μg
→
50 μg
50 μg
→
100 μg
75 μg
→
150 μg
100 μg
→
200 μg
150 μg
→
250 μg
6.4.2.2.
Dose Conversion for ESA Users
For ESA users, prior ESA will be replaced with epoetin beta pegol at the equivalent dose once every 4 
weeks (Day 1). 
At Week 2, HemoCue Hgb value will be measured for subjects' safety confirmation. If the 
measurement shows an Hgb increase of >1.0 g/dL over 2 weeks, the dose of GSK1278863 will be 
reduced by one step (or treatment interrupted) at Week 4 (Cohort 3 only).


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Table 11    Replacement with Epoetin Beta Pegol-Initial Dose (ESA Users)
Prior ESA
Epoetin beta pegol
Epoetin
<4500 IU per week
100 g once every 4 weeks
4500 IU per week
150 g once every 4 weeks
Darbepoetin alfa
30 g once every 4 weeks *
25 g once every 4 weeks
60 g once every 4 weeks *
50 g once every 4 weeks
90 g once every 4 weeks *
75 g once every 4 weeks
120 g once every 4 weeks *
100 g once every 4 weeks
180 g once every 4 weeks *
150 g once every 4 weeks
Epoetin beta pegol
25, 50, 75, 100, 150, 200, 250 g
once every 4 weeks *
25, 50, 75, 100, 150, 200, 250 g
once every 4 weeks
*: Allowance of ±1 week
Maintenance treatment will be started at Week 4 as described in Section 6.4.2.3. 
6.4.2.3.
Maintenance Dose (ESA Non-users and Users)
Epoetin beta pegol will be administered once every 4 weeks from dosing interval change (once every 
4 weeks) with Hgb ≥11.0 g/dL to Week 52 in ESA non-users and from Weeks 4 to 52 in ESA users. 
Interruption of treatment or dose adjustments will be made within the maintenance dose range of 25-
250 μg (Table 12) according to the dose adjustment algorithm (Table 13) to achieve and/or maintain 
Hgb within the target range (11.0-13.0 g/dL) based on the HemoCue Hgb value measured every 4 
weeks. If any of the one-step dose reduction criteria is met during treatment at the minimum 
maintenance dose (25 μg), treatment should be interrupted; once the one-step dose reduction criteria 
are not met any longer, treatment at 25 μg will be resumed. If the one-step dose increase criterion is 
met during treatment at the maximum maintenance dose (250 μg), treatment at 250 μg should be 
continued.
Table 12    Maintenance Dose of Epoetin Beta Pegol
Dose step
1
2
3
4
5
6
7
Epoetin beta pegol
(once every 4 weeks)
25 g
50 g
75 g
100 g
150 g
200 g
250 g
Table 13  Dose Adjustment Algorithm (Epoetin Beta Pegol)
Hgb
Hgb increase over 4 weeks 
Treatment


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(g/dL)
(g/dL)
>13.0
NA
Interrupt treatment until Hgb decreases to less than 
12.5 g/dL
Resume treatment at the one lower dose level 
(resume treatment at 25 g if interrupted at 25 g)
12.5-13.0
NA
One-step dose reduction
11.5-<12.5
>2.0
One-step dose reduction
2.0
Continue treatment at the current dose level
7.5-<11.5
>2.0
One-step dose reduction
1.0-2.0
Continue treatment at the current dose level
<1.0
One-step dose increase
<7.5
NA
Discontinue treatment permanently * and initiate 
another appropriate treatment
*: If an initial Hgb value is less than 7.5 g/dL, measurement will be repeated at the same study visit (using the same 
sample) to calculate the average. If the average meets the Hgb stopping criteria, study treatment will be permanently 
discontinued.
6.5.
Blinding
This is an open-label study. 
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory requirements.
6.7.
Preparation/Handling/Storage/Accountability

No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study medications must be stored in a secure 
environmentally controlled and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator (or subinvestigator) and 
authorized site staff.

Subjects must bring all of supplied study medication bottles of GSK127886 at each study visit. 
Study staff will collect all of study medication bottles supplied at the previous study visit and 
supply new study medication bottles. 

The investigator (or subinvestigator), institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records). 

Under normal conditions of handling and administration, study medication is not expected to 
pose significant safety risks to site staff. GSK will provide a document describing occupational 
hazards and recommended handling precautions either to the investigator (or subinvestigator) 
when necessary or upon request of the medical institution. 

Further details are provided in the SRM. 


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6.8.
Compliance with Study Treatment Administration
GSK1278863
Since GSK1278863 is self-administered, compliance with GSK1278863 treatment will be assessed 
through an interview with subjects at each study visit and recorded in the source document and eCRF. 
A record of the number of GSK1278863 tablets dispensed to and taken by each subject will be 
maintained and reconciled with study treatment and compliance records. In addition, the number of 
GSK1278863 doses dispensed, used, and unused, as well as study treatment start and stop dates will 
be recorded in the eCRF (the number of doses returned and unreturned will also be recorded 
separately).
Epoetin beta pegol
Epoetin beta pegol will be subcutaneously administered to subjects at the site. Dosing details will be 
recorded in the source document and eCRF. 
6.9.
Treatment of Study Treatment Overdose
For the purposes of this study, an overdose of GSK1278863 is defined as any dose greater than the 
highest daily dose included in the protocol. There is no specific antidote for overdose with 
GSK1278863. 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 hemodialysis or peritoneal dialysis 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 a suspected overdose, 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 cardiovascular events, increased heart rate and 
hematologic abnormalities.
Consult the respective approved Prescribing Information for information on overdose for epoetin beta 
pegol.
6.10.
Treatment after the End of the Study
Since the target disease studied is not life-threatening or severely debilitating and there is the 
alternative therapy, subjects will not receive any additional treatment from GSK after completion of 
the study. Regardless of whether the sponsor provides specific treatments at the completion of the 
study, the investigator (or subinvestigator) is responsible for ensuring that consideration has been 
given to post-study care of the subject’s medical condition. 
6.11.
Concomitant Medications and Non-Drug Therapies
Concomitant medications, including over-the-counter medications and supplements, taken during the 
study will be recorded in the eCRF. Drug names and start/stop dates will be recorded for general 
concomitant medications, while additional details, including dose, route of administration, and dosing 
frequency, will be recorded for certain medications (e.g., ESAs, iron, anti-hypertensive medications).
Further details are provided in the SRM.


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6.11.1.
Permitted Medications and Non-Drug Therapies
Unless specified as a prohibited medication in Section 6.11.2., all concomitant medications should be 
considered permitted provided they are not contraindicated for the individual subject concerned.
Regular multivitamins (at recommended daily allowance) and other supplements such as calcium and 
vitamin D may be used if permitted by the investigator or his/her designee. 
CYP2C8 is involved in the primary route of metabolism of GSK1278863. Accordingly, co-
administration of GSK1278863 with moderate CYP2C8 inhibitors (e.g., clopidogrel, teriflunomide, 
deferasirox) should be performed with caution. If one of these medications is started, stopped or the 
dose is changed, Hgb should be monitored every 4 weeks for 12 weeks using a point-of-care Hgb 
analyzer. 
Antihyperphosphatemic agents containing iron (e.g., ferric citrate hydrate) may be started from 
Week 4 onwards unless any other antihyperphosphatemic agents are appropriate. Once started, iron-
containing antihyperphosphatemic agents must be continued until the end of the study wherever 
possible. 
6.11.2.
Prohibited Medications and Non-Drug Therapies
Use of any of the following drugs from screening until 7 days after the last dose of study treatment is 
prohibited:

Strong inhibitors of CYP2C8 (e.g., gemfibrozil)

Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)
Use of the following drug from 8 weeks prior to screening until the last dose of study treatment in 
ESA non-users and during study treatment in ESA user is prohibited.

Erythropoietin (e.g., epoetin/darbepoetin alfa/ epoetin beta pegol)
Note: excluding epoetin beta pegol (brand name: Mircera® Injection Syringe) supplied by GSK.
6.12.
Supplemental Iron Therapy
Supplemental iron therapy will be administered according to the Guidelines for Renal Anemia [The 
Japanese Society for Dialysis Therapy, 2008] if ferritin is ≤100 ng/mL and TSAT is ≤20%. The 
investigator (or subinvestigator) can choose the route of administration and dose of prescription iron. 
7.
Study Assessments and Procedures
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the Time and 
Events Table, are essential and required for study conduct.
7.1.
Time and Events Table
The time and events tables for the entire study and PK assessment are presented as Table 14 and Table 
15, respectively. To allow scheduling flexibility, study visits may occur within a window of ±7 days
on Day 1 scheduled 4 weeks after screening, within a window of ±3 days at Week 2 (Cohort 3 only)
and Week 4, and within a window of ±5 days for the rest of the study. However, subjects receiving the 
control epoetin beta pegol every 2 weeks should attend study visits, including those only for study 
treatment, within a window of ±3 days. Visit days are counted from Day 1.


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Table 14    Time and Events Table
Phase
Screening9
Treatment
Follow-up
Week
-4
Day 1
210
4
8
12
16
20
24
28
32
36
40
44
48
52
Early 
withdr
awal11
4 weeks 
after 52 or 
withdrawal
Permissible range (days)
±7
-
±3
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
-
±7
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history, demography, 
height, weight
X
Registration with IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study medication dispensing 1,2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study treatment compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
Ophthalmology 3
ECG
X
X
X
HemoCue Hgb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Urinalysis (ND subjects only)
X
X
X
X
X
Pregnancy test (urine or serum 
hCG) 4
X
X
X
X
X
X
X
X
X
Estradiol, FSH 5
X
PK 6
X
X
Ferritin, TSAT
X
X
X
X
X
X
X
X
Serum iron, TIBC, UIBC, serum 
transferrin, hepcidin
X
X
X
X
X
X
X
iPTH
X
X
X
HR-QoL
X
X
X
X
X
Genetics sample 7
X
Adverse event assessment 8
Review Concomitant Medications
1.
In Cohort 1 and Cohort 3, ESA non-users randomized to the epoetin beta pegol group will start treatment with epoetin beta pegol at a dose of 25 μg once every 2 weeks. For these subjects, specified 
examinations will be performed at Week 2 (Cohort 3 only) and every 4 weeks after Week 4, and no study-related assessments will be necessary at study visits only for study treatment [e.g., Week 2 
(Cohort 1 only), Week 6, Week 10) (see Section 6.4.2). It should be noted that subjects receiving epoetin beta pegol once every 2 weeks should attend study visits within a window of ±3 days.
2.
If a subject visit the study site only to receive study medication, only registration with the IWRS, study medication dispensing, and study medication compliance will be required. 
3.
Ophthalmology exams should be conducted at the following time points.


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
Screening: anytime after consenting and prior to first dose of study medication (Day 1)

Week 12: window from weeks 10-14 (inclusive)

End of study: window from weeks 48-52 (inclusive)

Early study medication discontinuation: withdrawal eye exam as close to the last dose as possible (the repeat exams are not required if one has been performed within the 2 prior weeks).
4.
Performed in females of childbearing potential: serum pregnancy test will be performed if urine pregnancy test is not feasible.
5.
Measured in female subjects only to determine the menopausal status (see Section 5.1.)
6.
See Table 15.
7.
Informed consent for optional Genetic research should be obtained before collecting a sample (see Section 7.6.).
8.
See Section 7.4.1.1..
9.
Re-screening subjects who meet all the following conditions are allowed to use the results of the latest ophthalmonogy exam and not required to undergo the rescreening ophthalmonogy exam, at the 
discretion of the investigator. 
   •
Subjects had no findings that deem re-exams within 3 months at the latest screening ophthalmology exam. 
   •
Subjects had no new eye-related symptoms or complaints until the rescreening following the latest screening ophthalmology exam. 
   •
The latest screening ophthalmology exam was performed within 3 months prior to Day 1 scheduled at the rescreening. 
10.
All ND subjects randomized to Cohort 3 will undergo assessment scheduled for Week 2 visit.
11.
For withdrawn subjects, specified assessments should be done wherever possible. 


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Table 15    Blood Sampling Schedule for Pharmacokinetics (Only Subjects in 
GSK1278863 Group)
PK sample
Week 12 2
Week 24 2
Blood sampling timing 1
1, 2, 3, and 4 h after administration of GSK1278863
Subjects must take the study medication with regard to blood sampling time. Subjects will record the date and time of the last two 
study medication doses taken prior to blood sampling in the medication diary. Preferably, there should be an interval of at least 12 h 
between these two doses. 
1.
Blood sampling should be completed within +/- 30 min of the planned collected time.
2.
Blood sampling not performed at this visit may be postponed until the following visits. 
7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors will be assessed (documented in the eCRF) at baseline.
In addition, the following demographic information will be collected:

Year of birth

Gender

Race and ethnic

Medical history/treatment history/family history will be assessed in relation to the 
inclusion/exclusion criteria (Section 5.). 
Full details of baseline assessments are provided in Table 14.
7.3.
Efficacy
Efficacy will be assessed according to the Time and Event Table (Table 14). 
Hgb concentrations measured by the central laboratory will be mainly used for efficacy assessment 
(see Section 7.4.7.). 
GSK will supply a point-of-care Hgb analyzer (HemoCue) to each site for rapid and convenient 
measurement of Hgb and to ensure consistency of Hgb measurements across all sites participating in 
the study. Assessment for Hgb concentrations via HemoCue will be used for eligibility (Section 5.1.), 
withdrawal (Section 5.4.), and dose adjustment criteria (Section 6.4.). 
In addition, assessments of iron metabolism parameters and measures of CKD progression (e.g., 
eGFR) used for efficacy assessment are outlined with specific procedures in Section 7.4.7..
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table (Table 14).  
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.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 12.6. Appendix 6.
The investigator and their designees are responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE.


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7.4.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-up contact 
(see Section 7.4.1.3.), at the timepoints specified in the Time and Events Table (Table 14).

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 section of the CRF.

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 hours, as indicated in Section 12.6.
Appendix 6.

Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 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 must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs plus procedures 
for completing and transmitting SAE reports to GSK are provided in Section 12.6. Appendix 6.
7.4.1.2.
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?”
7.4.1.3.
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 SAEs, and non-serious AEs of special interest (as defined in Section
7.4.2.) will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up (as defined in Section 5.4.). Further information on 
follow-up procedures is given in Section 12.6. Appendix 6..
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 12.6. Appendix 6 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be required to 
be completed.  These sections include questions regarding cardiovascular (including sudden cardiac 
death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA terms.  The 
CV information should be recorded in the specific cardiovascular section of the CRF within one week 
of receipt of a CV Event data query prompting its completion.  


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The Death CRF is provided immediately after the occurrence or outcome of death is reported. Initial 
and follow-up reports regarding death must be completed within one week of when the death is 
reported.
7.4.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to study 
treatment (even for non- interventional post-marketing studies) is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects and the safety of a product under clinical 
investigation 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 the regulatory authority, Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) 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 a 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.
7.4.2.
Adverse Events of Special Interest
The investigator (or subinvestigator) or designee will be responsible for detecting, documenting, and 
reporting any AEs of special interest listed below. These events have been identified based on the 
known safety profiles of ESAs, theoretical or potential risks based on the mechanism of action of 
GSK1278863, and findings from completed nonclinical studies of GSK1278863. 

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 

Death, myocardial infarction, stroke, heart failure, thromboembolic events, thrombosis of 
vascular access

Cardiomyopathy  

Pulmonary artery hypertension

Cancer-related mortality and tumor progression and recurrence 

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization 

Exacerbation of rheumatoid arthritis
Any relevant AE should be recorded in the relevant section of the subject’s eCRF.
7.4.3.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of dosing and until 
the follow-up contact.


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
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of learning of 
the pregnancy and should follow the procedures outlined in Section 12.4.. Appendix 4.
Note: Subjects randomized in the epoetin beta pegol group should be advised to inform the 
investigator if they discover pregnancy in 7 weeks after the last dose of study treatment.
7.4.4.
Medical Device Incidents (Including Malfunctions)
The medical devices are being provided for use in this study. The investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction that occur 
during the study with such devices. 
The definition of a Medical Device Incident can be found in Appendix 8 (Section 12.8.)
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes outlined in 
Section 7.4.1. and Appendix 6 (Section 12.6.) of the Protocol.
7.4.4.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident will be detected, 
documented and reported during all periods of the study in which the medical devices are 
available for use. 

If the investigator learns of any incident at any time after a subject has been discharged from the 
study, and such incident is reasonably related to a medical device provided for the study, the 
investigator will promptly notify GSK.
NOTE: The method of documenting Medical Device Incidents is provided in Appendix 8 (Section 
12.8.).
7.4.4.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE, will be followed until resolution of the event, until 
the condition stabilizes, until the condition is otherwise explained, or until the subject is lost to 
follow-up (as defined in Section 5.4.). This applies to all subjects, including those withdrawn 
prematurely. 

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as practical the nature and/or 
causality of the incident.

New or updated information will be recorded on the originally completed form ”Medical Device 
Incident Report Form” with all changes signed and dated by the investigator.
7.4.4.3.
Prompt Reporting of Medical Device Incidents to GSK

Medical device incidents will be reported to GSK within 24 hours once the investigator 
determines that the event meets the protocol definition of a medical device incident.

Facsimile transmission of the "Medical Device Incident Report Form" is the preferred method to 
transmit this information to the SAE contact information.

The same individual will be the contact for receipt of medical device reports and SAEs.

In the absence of facsimile equipment, notification by telephone is acceptable for incidents, with 
a copy of the "Medical Device Incident Report Form" sent by overnight mail.


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7.4.4.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator, or responsible person will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.
7.4.5.
Vital Signs/Height/Weight
Systolic and diastolic blood pressure and pulse rate will be measured in sitting or semi-supine position 
after at least 5 minutes rest prior to clinical examination at each visit blood pressure and pulse rate. 
One reading of blood pressure and pulse rate will be taken and recorded in the source document and 
the CRF. Height and weight will be measured at screening visit only.
7.4.6.
Electrocardiogram (ECG)
12-lead ECGs will be recorded in supine position. The heart rate, PR, QRS, and QT (pre-corrected)
intervals will be measured. QTcB should be calculated by machine or manually by designated staff at 
each site. The investigator determines whether the ECG data is assessable or not.
At screening, visit when an ECG is performed, two additional ECGs are required if initial ECG 
indicates prolonged QTc using the automated or manually calculated QTcB value. The average QTcB 
value of all three ECGs will be used to determine eligibility.
QTc exclusion criteria can be found in Section 5.2. Refer to SRM for further details.
7.4.7.
Clinical Laboratory Assessments
All study-required laboratory assessments will be performed by a central laboratory with the exception 
of HemoCue Hgb. The results of each HemoCue Hgb must be entered into the subject’s eCRF. Details 
are provided in the SRM. 
All laboratory assessments, as defined in Table 16, must be conducted in accordance with the 
Laboratory Manual and Protocol Time and Events Schedule. Laboratory requisition forms must be 
completed and samples must be clearly labeled with the subject number, protocol number, site/center 
number, and visit date. Details for the preparation and shipment of samples will be provided by the 
central laboratory. Reference ranges for all parameters will be provided to the site by the central 
laboratory. Details of blood sampling (including the volume of blood to be collected) as well as 
procedures for processing, storage, and shipment of samples are provided in the SRM. 
PK assessment of GSK1278863 is outlined in Section 7.5.


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Table 16    Laboratory Assessments
Laboratory 
assessment
Parameter
Hematology
Leukocyte count
RBC indices:
WBC count with Differential
Platelet count
MCV
Neutrophils
RBC count
MCH
Lymphocytes
Reticulocyte count
MCHC
Monocytes
Hemoglobin
RDW
Eosinophils
Hematocrit
Basophils
Clinical chemistry
Sodium
AST
Bicarbonate
Potassium
ALT
Inorganic phosphate
Chloride
Creatinine
Glucose
Calcium (total and albumin-
corrected)
Total bilirubin
Direct/indirect bilirubin 
Albumin
Urea nitrogen
Total cholesterol
HDL cholesterol
LDL cholesterol
Iron parameters
Serum iron
Serum ferritin
Serum transferrin
TIBC
UIBC
TSAT
Hepcidin
Urinalysis
(ND subjects only) Urine albumin
Urine creatinine
Urine albumin/creatinine ratio
Other laboratory 
tests
FSH 1
Estradiol 1
iPTH
eGFR 2
hCG (serum or urine) 3
1.
Measured in female subjects only to determine the menopausal status (see Section 5.1.) 
2.
Calculated from serum creatinine using the Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-CKDI) 
formula
3.
Performed in females of childbearing potential: serum pregnancy test will be performed if urine pregnancy test is not feasible. 
If additional non-protocol specified laboratory assessments are performed at the institution’s local 
laboratory and result in a change in subject management or are considered clinically significant by the 
investigator (or subinvestigator) (e.g., SAE or AE or dose modification), the results must be recorded 
in the eCRF.
Refer to the SPM for appropriate processing and handling of samples to avoid duplicate and/or 
additional blood draws.
All laboratory tests with values that are considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline. If such 
values do not return to normal within a period judged reasonable by the investigator (or 
subinvestigator), the etiology should be identified and the Sponsor notified.
7.4.8.
Ophthalmology
Ophthalmology exams will be performed by a study-designated ophthalmology specialist. Each 
assessment will include a comprehensive eye exam with at least the following components: 
measurement of best corrected visual acuity, intraocular pressure, an anterior aqueous chamber exam, 
and a fundoscopic exam. These exams will be used for assessment of ocular adverse events. 
Assessment results will be captured on worksheets which will be transferred to the eCRF. Additional 
details on the process for completing these assessments are provided in the SRM.


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7.5.
Pharmacokinetics
Blood samples for PK analysis of GSK1278863 will be collected from only subjects in the 
GSK1278863 group as outlined in Table 15, and the date and time of the last two study medication 
doses taken prior to blood sampling as well as the date and time of sampling must be recorded in the 
eCRF.
Blood PK analysis will be performed under the control of GSK Platform Technologies and Science-
Drug Metabolism and Pharmacokinetics (PTS-DMPK)/Scinovo and GSK-Japan Bioanalysis, the 
details of which will be included in the SPM. Concentrations of parent GSK1278863 will be 
determined in blood samples using the currently approved analytical methodology. Raw data will be 
archived at the bioanalytical site.
Procedures for processing, storage, and shipment of samples are provided in the SRM. 
7.6.
Genetics
A blood sample will be collected for genetic analysis from consenting subjects. This sample can be 
collected on Day 1 once written informed consent has been obtained. Information regarding genetic 
research is included in Section 12.7. Appendix 7.
7.7.
Patient Reported Outcome (PRO)
The patient reported outcome (PRO) [e.g., symptoms, severity, health-related QOL (HR-QoL), health 
status] will be assessed using several rating scales. 
All questionnaires used in this study have been translated into Japanese and validated. 
Specific instructions on how the subject is to complete the scales and the process for data entry are 
provided in the SPM.
7.7.1.
SF-36
The SF-36 acute version is a general health status questionnaire designed to elucidate the patient’s 
perception of his/her health on several domains, including physical functioning, role physical, bodily 
pain, vitality, social functioning, role emotional, mental health, and general health over the past seven 
days. The questionnaire contains 36 Likert type questions that ask the patient to recall how he/she felt 
during the past seven days.
7.7.2.
EuroQol Health Utility Index (EQ-5D-5L)/EQ Visual Analogue Scale (EQ-VAS)
The EQ-5D-5L is intended to measure the general health status and health utility. The EQ-5D-5L 
consists of 2 concepts: self-reported health status consisting of five dimensions (mobility, self-care, 
usual activities, pain/discomfort, anxiety/depression) each of which can take one of five responses and 
self-rated health status on a visual analog scale (VAS), a thermometer-like line. 


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8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted electronically to 
GSK or designee 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.  

CRFs (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.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
A detailed description of any planned analyses will be documented in a RAP..Any deviations from the 
analyses described in the protocol will be documented in the RAP or the final study report. 
9.1.
Hypotheses
The primary objective of the study is to demonstrate the non-inferiority of GSK1278863 to epoetin 
beta pegol based on mean Hgb during the primary efficacy evaluation period (Weeks 40 to 52) in ND 
subjects, including Cohort 1 subjects (only ESA users) and Cohort 3 subjects (both ESA users and 
ESA non-users).
As a preliminary assessment, it will be confirmed whether the mean Hgb during the primary efficacy 
evaluation period in GSK1278863 group would be in target range (11.0-13.0 g/dL) at first. And then 
the following non-inferiority statistical hypotheses are to be tested at a one-sided significance level of 
2.5% (i.e. two-sided significance level of 5%):

H0: Treatment difference in mean Hgb during the primary efficacy evaluation period is -1.0 g/dL 
or less.

H1: Treatment difference in mean Hgb during the primary efficacy evaluation period is greater 
than -1.0 g/dL.
Only when the primary endpoint achieves non-inferiority, statistical testing will progress to the 
principal secondary endpoint with a focus on superiority according to the step-down procedure. More 
specifically, the superiority of GSK1278863 to epoetin beta pegol in terms of target Hgb control in 
ND subjects, including Cohort 1 subjects (only ESA users) and Cohort 3 subjects (both ESA users and 
ESA non-users), is to be demonstrated at a two-sided significance level of 5% by testing the following 
statistical hypotheses:

H0: The proportion of subjects whose mean Hgb during the primary efficacy evaluation period is 
within the target range (11.0-13.0 g/dL) is equal between the treatment groups.

H1: The proportion of subjects whose mean Hgb during the primary efficacy evaluation period is 
within the target range (11.0-13.0 g/dL) is different between the treatment groups. 


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No hypothesis will be tested in PD subjects (Cohort 2). 
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Assuming a non-inferiority margin of -1.0 g/dL, a treatment difference of 0.0 g/dL, and a standard 
deviation of 1.5 g/dL for mean Hgb during the primary efficacy evaluation period in ND subjects, 
two-sample t-test has at least 99% power at a one-sided significance level of 2.5% (i.e. two-sided 
significance level of 5%) with a sample size of 100 subjects per group. At planning the study, a 
dropout rate was assumed to be approximately 25%, 135 subjects were going to be randomized to 
each group. Given the results from previous non-inferiority studies of similar drugs (darbepoetin alfa, 
epoetin beta pegol, and peginesatide), the non-inferiority margin of -1.0 g/dL is set. Since an increase 
of 1.0 g/dL indicates improvement in anemia according to the guidelines for renal anemia in Japan, 
the non-inferiority margin of -1.0 g/dL may be the clinically acceptable largest difference in renal 
anemia. 
While the present study is designed to ensure long-term safety data from 100 ND subjects, and the 
primary hypothesis test has at least 99% power to estimate the efficacy very precisely, non-inferiority 
can be statistically demonstrated with a minimum between-group difference of -0.582 g/dL. 
During this study, the protocol has been amended (Amendment No.3) according to the change in
starting dose for ND, ESA non-users. ESA non-users in Cohort 1 will be excluded from primary 
efficacy analysis according to this amendment. Additionally the protocol amendment has been made 
(Amendment No.4), in which the assumption of dropout rate after the start of study treatment was 
changed from 25% to 30% and 143 subjects per group (total 286 subjects) will be randomized. 
Analysis populations for primary efficacy analysis and safety evaluation on ND subjects are illustrated 
below.
Table 17    Primary Efficacy and Safety Analyses Populations for ND Subjects
ND Subjects
Treatment 
Group
Starting 
Dose
Number of Randomized 
Subjects
Analysis Population
Cohort 1
ESA non-
users
GSK1278863
4 mg
82 subjects
169 subjects
286 subjects 
for safety 
analyses
Epoetin beta 
pegol
-
ESA users
GSK1278863
4 mg
87 subjects
204 subjects
for primary 
efficacy 
analyses
Epoetin beta 
pegol
-
Cohort 3
ESA non-
users
GSK1278863
2 mg or 
4 mg
≥80 ESA non-
users will be 
randomized
117 subjects
Epoetin beta 
pegol
-
ESA users
GSK1278863
4 mg
Epoetin beta 
pegol
-
Note: In Cohort 1, 169 ND subjects who met eligibility criteria were stratified by the current ESA therapy and baseline 
Hgb (ESA non-users: 9.5 g/dL, <9.5 g/dL, ESA users: <11.0 g/dL, 11.0 g/dL) and then randomized in a 1:1 ratio to 
GSK1278863 or epoetin beta pegol group. The same randomization strategy is used in Cohort 3.
When non-inferiority is tested in 204 ND subjects, this number of subjects ensures an enough power. 
This is because a power of at least 97% will be achieved in a population consisting of 140 subjects, 


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who will complete study on the condition of a dropout rate of approximately 30%, by the same 
assumptions and non-inferiority margin stated as above. In order to allow a subgroup analysis of the 
primary endpoint by the use of ESA in subgroups the sizes of which are equal as much as possible, at 
least 80 ND, ESA non-users are to be enrolled in Cohort 3.
For PD subjects, the sample size is based on the feasibility. Assuming a sample size of 38 subjects and 
a standard deviation of 1.5 g/dL, the half width of the 95% CI for mean Hgb during the primary 
efficacy evaluation period is 0.493 g/dL. 
9.2.2.
Sample Size Sensitivity
The power for the primary endpoint is shown according to treatment difference and standard deviation 
in Table 18 based on a population consisting of 140 subjects (70 subjects per group) who will 
complete study on the condition of a dropout rate of approximately 30%. This population is derived 
from 204 ND subjects, including Cohort 1 subjects (only ESA users) and Cohort 3 subjects (both ESA 
users and ESA non-users)
Table 18    Power Sensitivity (70 Subjects Evaluated Per Group, Noninferiority 
Margin of -1.0, One-Sided Significance Level of 2.5%)
Treatment Difference
Standard Deviation
1.25
1.5
1.75
0
99.7%
97.5%
91.2%
-0.1
98.8%
94.1%
85.6%
-0.2
96.4%
88.0%
76.6%
-0.3
90.8%
78.3%
65.2%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned for this study.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations

All Screening Population
The All Screening Population consists of all subjects who are given subject number and whose data 
are collected, including demographics at screening.

Intent-to-Treat (ITT) Population
The Intention-To-Treat Population consists of Cohort 1 subjects (only ESA users) and Cohort 3 
subjects (both ESA users and ESA non-users) who are given randomization number with Hgb 
measurement at both baseline and at least one scheduled visits following the baseline. Subjects will be 
analyzed according to randomized treatment. This population will be the primary population for an 
assessment of non-inferiority.

modified ITT (mITT) Population


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The mITT Population consists of all ITT subjects who have at least one Hgb measurement during the 
efficacy evaluation period. Subjects will be analyzed according to randomized treatment. This 
population will be the primary population for an assessment of superiority. 

Per-Protocol (PP) Population
The PP Population consists of all mITT subjects who are not major protocol violators. Details will be 
defined in the RAP. This population will be used for efficacy sensitivity analyses.

Safety Population
The Safety Population consists of all subjects who receive at least one dose of study treatment. 
Subjects will be analyzed according to the treatment received. This population will be used for safety 
analyses. 

PK Population
The PK Population consists of all GSK1278863-treated subjects from whom PK samples are collected 
and analyzed. 
Additional populations may be defined in the RAP.
9.3.2.
Interim Analysis
No interim analysis is planned. 
9.3.3.
Adjustment for Multiplicity
Adjustment for multiplicity will be applied to maintain an overall type I error rate of 5%. After a 
preliminary assessment, the primary endpoint will be evaluated to demonstrate the non-inferiority at a 
one-sided significance level of 2.5% (i.e. two-sided significance level of 5%). Only when the primary 
endpoint achieves non-inferiority, statistical testing will progress to the principal secondary endpoint 
with a focus on superiority. Since the process will follow step-down manner, a multiplicity adjustment 
for a two-sided significance level of 5% will not be needed according to a closed test procedure. 
Other secondary endpoints, which will be evaluated on a complementary or exploratory basis, will be 
compared at a two-sided significance level of 5% without multiplicity adjustment. 
Since Cohort 2 is a single-arm cohort, no testing will be performed to evaluate the efficacy in PD 
subjects. 
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Efficacy Analysis
The primary endpoint, which is the mean Hgb during the primary efficacy evaluation period, will be 
analyzed to demonstrate the non-inferiority of GSK1278863 to epoetin beta pegol in ND subjects. 
MMRM will be used to estimate the mean Hgb during the primary efficacy evaluation period and its 
95% CI by treatment groups. This model includes treatment groups, baseline Hgb, assessment visits, 
interaction terms between treatment groups and assessment visits, as well as interaction terms between 
baseline Hgb and assessment visit. As a preliminary assessment, it will be confirmed if the mean Hgb 
during the primary efficacy evaluation period in GSK1278863 group would be in target range (11.0-


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13.0 g/dL) at first. This confirmation will be established if the lower and upper limit of 95% CI for the 
mean Hgb in GSK1278863 group would lie fully within target range (11.0-13.0 g/dL). In addition, the 
point estimate and 95% CI for the treatment difference (GSK1278863-epoetin beta pegol) in the mean 
Hgb during the primary efficacy evaluation period will be estimated. Non-inferiority will be 
established if the lower limit of the 95% CI is greater than -1.0 g/dL. Even if the 95% CI for the 
difference is completely negative (i.e. lies fully within the range -1.0 to <0 g/dL) non-inferiority 
would still be concluded on condition that the mean Hgb estimated in the GSK1278863 group is 
within the target range.
The primary efficacy population will be the ITT Population, and the analysis will be repeated in the 
mITT and PP Population to evaluate the robustness of the conclusion. The subgroup analysis by the 
current ESA therapy (presence or absence) will also be conducted.
Following sensitivity analyses will be conducted to assess robustness of the study result. 

If ND, ESA users in cohort 3 whose dose level was decreased by one step at Week 2 exist, 
sensitivity analysis excluding these subjects from primary analysis will be conducted.

Sensitivity analysis to primary efficacy analysis for all ND patients in Cohort 1 and Cohort 3 will 
be conducted.

If there are Hgb considered to be impacted by blood transfusion or marketed ESAs, sensitivity 
analysis excluding the Hgb values from the analyses of primary endpoint will be conducted.

Analysis of covariance (ANCOVA) will be conducted as sensitivity analysis to MMRM. This 
model includes treatment group and baseline Hgb. The analysis population will be mITT 
population and the same analysis will be repeated in the PP population.

A tipping point analysis based on multiple imputation will be conducted as sensitivity analysis to 
missing data assumption. This analysis explores a point where non-inferiority is not confirmed 
(tipping point) by changing assumption to missing data and repeating imputation. The analysis 
population will be ITT population and the same analysis will be repeated in the mITT and PP 
population.
Further details of sensitivity analyses will be provided in the RAP.
9.4.2.
Principal Secondary Efficacy Analysis
The principal secondary endpoint, which is the proportion of subjects whose mean Hgb during the 
primary efficacy evaluation period is within the target range will be analyzed to demonstrate the 
superiority of GSK1278863 to epoetin beta pegol in ND subjects. 
In the mITT Population, a logistic regression model including treatment group, baseline Hgb, and 
current ESA therapy (presence or absence) as covariates will be used to estimate the point estimate 
and 95% CI for the odds ratio (GSK1278863/epoetin beta pegol). This analysis will be performed to 
demonstrate the superiority at a two-sided significance level of 5%, conditional on the primary 
endpoint achieving noninferiority. Superiority will be established if the lower limit of the 95% CI 
for odds ratio is greater than 1.0.
9.4.3.
Other Secondary Efficacy Analyses
Among the secondary efficacy endpoints, the time (%) in Hgb target range during the primary efficacy 
evaluation period , proportion of subjects who have an Hgb increase of more than 2 g/dL over any 4 
weeks, and changes in iron metabolism parameters (ferritin, TSAT, hepcidin, serum iron, and TIBC), 


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the point estimates and 95% CIs for the treatment difference (or odds ratio) in ND subjects will be 
calculated. Other secondary efficacy and exploratory endpoints will be summarized by each treatment 
group. 
For PD subjects, the efficacy endpoints will be descriptively summarized. 
9.4.4.
Safety Analyses
In principle, safety data will be summarized by each treatment group in the Safety Population. ND 
subjects and PD subjects will be summarized separately.
9.4.4.1.
Exposure
Exposure information will be listed for all subjects. The duration of treatment (number of days) and 
cumulative dose will be tabulated. In addition, distribution of the dose level at each assessment visit
and final dosing visit will be tabulated. Frequency of dose adjustment and duration of treatment 
interruption due to Hgb >13 g/dL will be summarized.
9.4.4.2.
Adverse Events
All AEs will be categorized by the MedDRA system organ class and preferred term to tabulate the 
number and incidence. All AEs, SAEs, AEs leading to discontinuation of study treatment, and AEs of 
special interest will be summarized separately. Similar summary will be provided for study treatment-
related AEs. 
9.4.4.3.
Other Safety Parameters
For laboratory tests, vital signs and ECG, parameters and/or changes from baseline will be 
summarized using summary statistics at each assessment visit. The number and percentage of subjects 
with values of the potential clinical importance values will be tabulated. The criteria for the potential 
clinical importance will be described in the RAP. For lipid parameters (total cholesterol, LDL 
cholesterol, and HDL cholesterol), percent changes will also be tabulated. The number (%) of subjects 
who have any change in anti-hypertensive medications (type and/or dose) due to increased blood 
pressure will be tabulated.
9.4.5.
Pharmacokinetics Analyses
For plasma concentrations of GSK1278863 over time, individual data will be listed, and summary 
statistics at each time point will be calculated for each dose level. For PK parameters (AUC 0-4 and 
Cmax), summary statistics will be calculated for each dose level, and scatter plots against the dose 
level will be generated. 
9.4.6.
PRO Data Analysis
Details of PRO data tabulation will be described in the RAP.


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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 
enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the Informed Consent 
Process
The study will be conducted in accordance with “the Ministerial Ordinance on the Standards for the 
Conduct of Clinical Trials of Medicinal Products (MHW Notification No.28 dated 27th March, 1997)” 
and the Pharmaceutical Affairs Law.
GSK will submit the CTN to the regulatory authorities in accordance with with Article 80-2 of the 
Pharmaceutical Affairs Law before conclusion of any contract for the conduct of the study with study 
sites.
The study will be conducted in accordance with all applicable regulatory requirements, and with GSK 
policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), all applicable 
subject privacy requirements, and the guiding principles of the current version of the Declaration of 
Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and amendments as 
applicable

Signed informed consent to be obtained for each subject before participation in the study (and for 
amendments as applicable) 

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or both.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical protocol and all 
optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate informed 
consent) and the clinical protocol should be concurrently submitted for approval unless 
regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the clinical protocol 
where required by regulatory authorities.  In this situation, written approval of the clinical 
protocol should state that approval of optional assessments is being deferred and the study, with 
the exception of the optional assessments, can be initiated.
Informed Consent
Prior to participation in the study, the investigator (or subinvestigator) should fully inform the 
potential subject and the subject's legally acceptable representative (as required) of the study including 
the written information. The investigator (or subinvestigator) should provide the subject and the 
subject's legally acceptable representative ample time and opportunity to inquire about details of the 
study. The subject and the subject’s legally acceptable representative should sign and personally date 
the consent form. If the subject wishes to consider the content of the written information at home, 


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he/she may take the consent form home. The person who conducted the informed consent discussion 
and study collaborator giving supplementary explanation, where applicable, should sign and 
personally date the consent form. If an impartial witness is required, the witness should sign and 
personally date the consent form. The investigator (or subinvestigator) should retain this signed and 
dated form (and other written information) together with the source medical records, such as clinical 
charts (in accordance with the rules for records retention, if any, at each medical institution) and give a 
copy to the subject and the subject’s legally acceptable representative.
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 the CRF 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.
10.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, the GSK monitor will conduct site closure
activities with the investigator or site staff, as appropriate, in accordance with applicable regulations
including GCP, and GSK Standard Operating Procedures.
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 the reasons for taking such action with the
investigator or the head of the medical institution (where applicable). When feasible, GSK will
provide advance notification to the investigator or the head of the medical institution, where


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applicable, of the impending action.
If the study is suspended or prematurely discontinued for safety reasons, GSK will promptly inform
all investigators, heads of the medical institutions (where applicable) and/or institution(s) conducting
the study. GSK will also promptly inform the relevant 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 elsewhere), in a safe and secure location.  
The records must be maintained to allow easy and timely retrieval, when needed (e.g., for a GSK audit
or regulatory inspection) and must be available for review in conjunction with assessment of the
facility, supporting systems, and relevant site 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 ensure 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, GSK standards/procedures, and/or institutional requirements.  
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 is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of Information on 
Publically Available Clinical Trials Registers and Publicatio
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.
The procedures and timing for public disclosure of the results summary and for development of a 
manuscript for publication will be in accordance with GSK Policy.


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10.8.
Study Period
See Exhibit 1
10.9.
Study Administrative Structure
Sponsor information is included in Exhibit 2. List of Medical Institutions and Investigators is included 
in Exhibit 3.


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11. REFERENCES
Akizawa Tadao, Makino Hirofumi, Matsuo Seiichi, et al. Management of anemia in chronic kidney 
disease patients: baseline findings from Chronic Kidney Disease Japan Cohort Study. Clin Exp 
Nephrol. 2011;15:248-57.
Szczech Lynda A, Barnhart Huiman X., Inrig Jula K., et al. Secondary analysis of the CHOIR trial 
epoetin-α dose and achieved hemoglobin outcomes. Kidney International. 2008;74:791-8.
Guidelines for Renal Anemia in Chronic Kidney Disease issued by the Japanese Society for Dialysis 
Therapy in 2008. Journal of Japanese Society for Dialysis Therapy. 2008;41(10):661-716


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12. APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under Curve
CKD
Chronic Kidney Disease
Cmax
Maximum concentration
CPK
Creatine Phosphokinase
CYP
Cytochrome P450
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
EPO
Erythropoietin
EQ-5D-5L
EuroQol Health Utility Index
ESA
Erythropoiesis-Stimulating Agent
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
hCG
Human Chorionic Gonadotrophin
HD
Hemodialysis
HDL
High Density Lipoprotein
HDPE
High Density Polyethylene
Hgb
Hemoglobin
HIF
Hypoxia-Inducible Factor
HRT
Hormone Replacement Therapy
ICH
International Conference on Harmonization
INR
International Normalized Ratio
iPTH
Intact Parathyroid Hormone
ITT
Intent-to-Treat
IWRS
Interactive Web Recognition System
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
MCS
Mental Component Summary
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-Treat
ND
Non dialysis
NYHA
New York Heart Association
PCS
Physical Component Summary
PD
Peritoneal Dialysis
PHI
Prolyl Hydroxylase Inhibitor
PK
Pharmacokinetic
PP
Per-Protocol
PRO
Patient Reported Outcome
QT
Q-T Interval
QTc
Q-T Interval Corrected for Heart Rate


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QTcB
Bazett’s Correction of QT Interval
RAP
Reporting and Analysis Plan
RDW
Red Blood Cell Distribution Width
RNA
Ribonucleic Acid
rhEPO
Recombinant human erythropoietin
SAE
Serious Adverse Event
SRM
Study Reference Manual
TIBC
Total Iron Binding Capacity
TSAT
Transferrin Saturation
UIBC
Unsaturated iron Binding Capacity
VAS
Visual Analog Scale
VEGF
Vascular Endothelial Growth Factor
Trademark Information
Trademarks of the GlaxoSmithKline group of 
companies
Trademarks not owned by the GlaxoSmithKline 
group of companies
None
Hemocue
Mircera


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12.2.
Appendix 2: Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
GSK1278863 
Excessive erythropoiesis (polycythemia) leading to 
thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis attributed to GSK1278863 
was associated with vascular congestion, microthrombi, and tissue 
ischemia in a number of organs.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
Phase 2 dose-ranging studies, and associated statistical and exposure 
response modelling has informed Phase 3 dose rationale, starting 
doses, dose levels, and dose adjustment scheme to optimize Hgb 
management.
•
Specific eligibility criteria related to requirements for 
entry Hgb are detailed in Section 5.1.
•
Hgb will be closely monitored throughout the dosing 
period as outlined in the Time and Events Table 
Section 7.1.
•
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of GSK1278863 
based on achieved Hgb is provided in Section 6.4.1.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Risk of death, MI, stroke, heart failure, thromboembolic 
events, thrombosis of vascular access at Hgb levels which 
are within the normal range (i.e. not polycythemic 
conditions)
Marketed rhEPO/ESAs have been associated with an increased risk for 
death and serious cardiovascular events when used in patients with 
anemia of CKD.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
•
Specific eligibility criteria related to CV risk are 
outlined in Section 5.2.
•
Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Esophageal and gastric erosions
In animal studies, undesirable GI effects including emesis, abnormal 
feces and/or decreased food consumption/body weight loss and 
stomach erosions/ ulcers with hemorrhage were observed.  
In rodents stomach erosions observed with intravenous and oral 
administration of GSK1278863.
Gender-averaged systemic exposure (AUC) at the no observed adverse 
•
Suspected GI bleeding or significant symptoms 
consistent with erosion should be investigated 
diagnostically (i.e. endoscopic examination) as 
clinically warranted
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
effect levels (NOAEL) are 3.3 -fold (monkeys) and 737 -fold (rats) 
above human exposure (25 mg).
In clinical trials to date, mild-moderate GI signs and symptoms 
represent the most frequently reported adverse event, however causal 
association has not been established.
Following review of clinical data received to date, GI erosions have 
not been identified as a safety concern for GSK1278863.
period.
Cancer-related mortality, tumor progression and recurrence
In clinical trials, use of rhEPO in patients with cancer has been associated with 
increased risk of cancer related morbidity and mortality.
Administration of 60 mg/kg GSK1278863 to mice caused minimal increases in 
circulating VEGF while significant EPO increases were observed.
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations, an angiogenic factor that has been 
implicated in tumor growth, was observed at doses ranging from 10 to 
150 mg. In clinical studies up to 24 weeks duration at doses up to 
25 mg, changes in VEGF plasma concentrations were variable but 
similar relative to control.
Following review of clinical data received to date, this has not been identified 
as a safety concern for GSK1278863.
•
Specific eligibility criteria related to personal history 
of malignancy are outlined in Section 5.2..
•
Stopping criteria for subjects with treatment 
emergent malignancy are outlined in Section 5.4.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Pulmonary artery hypertension (PAH)
・A role for HIF-regulated pathways in the pathophysiology of PAH 
has been suggested based on well established effects of acute and 
chronic hypoxia in man on the pulmonary vasculature 
(vasoconstriction), and by findings in patients with naturally occurring 
mutations that result in decreased HIF degradation (Smith, 2006; 
Formenti, 2011).
・There have been no histopathologic findings suggestive of PAH in 
pre-clinical safety studies (up to 13-weeks duration in mice and dog, 
up to 26-weeks in rat, and up to 39-weeks in monkeys.
・Acute hypoxic challenge (rats): GSK1278863A produced increases 
in peak right ventricular pressure (PRVP) during acute hypoxia that 
were slightly higher than the vehicle control group. These hypoxia-
induced PRVP changes fall within the range of PRVP differences 
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
noted among non-treated rats.
・Results from a clinical study of acute hypoxic challenge in healthy 
volunteers demonstrated that short-term therapy with GSK1278863 
5 mg or 100 mg has no clinically significant effect on 
echocardiographically estimated pulmonary artery systolic pressure 
(PASP) under either normoxic or hypoxic conditions.
・ECHO assessments performed in Phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes 
in sPAP in subjects not on dialysis. Changes in sPAP from baseline in 
dialysis patients were comparable between GSK1278863 group and 
Control group (median). The numbers of patients who met the 
potentially clinically significant sPAP criteria (increased from baseline 
by >20 mmHg) were disproportionate between the treatment groups [8 
patients (7%) in GSK1278863 group and 0 patient in Control group]. 
This imbalance was associaited with some confounding factors, 
including the randomization scheme of 4.5:1 ratio and inconsistency in 
timings of ECHO assessment related to dialysis. Additionally, 2 of the 
3 patients with sPAP improvement at the follow-up ECHO assessment 
had confounding factors that were potentially attributable for sPAP 
improvement other than study medication discontinuation. No dose 
relationship was seen in patients who met potentially clinically 
significant sPAP criteria. Overall, no sufficient evidence was obtained 
to conclude the relationship with GSK1278863.
・Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.  
Cardiomyopathy
Published data suggest that cardiac effects of HIF stabilization are 
likely a function of the mechanism, extent, and duration of the effects, 
and can range from protective to detrimental depending upon the 
specific model and experimental conditions utilized.
Small increases in cardiac troponin in 6 month rat study were 
consistent with the background finding of spontaneous rodent 
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
cardiomyopathy. There were no elevations observed in cardiac 
troponin in 9 month monkey study.
Cardiomyopathy has not been associated with naturally occurring 
mutation in man which results in increased HIF stabilization.
ECHO assessments performed in phase 2b studies (24 weeks treatment 
duration) did not identify any clinically meaningful changes in LVEF.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
Proliferative retinopathy, macular edema, choroidal 
neovascularization
Increases in local (ocular) VEGF production with retinal 
neovascularization and macular edema observed in diabetic 
retinopathy and to choroidal leakage, edema and neovascularization 
seen in age-related macular degeneration (Campochiaro, 2006).
Administration of 60 mg/kg GSK1278863 to mice caused minimal 
increases in circulating VEGF while significant EPO increases were 
observed.
No ocular abnormalities were seen in non-clinical studies of up to 13 
weeks duration in mice and dogs, 26 weeks in rats, and 39-weeks in 
monkeys.  
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations was observed at doses ranging from 10 
to 150 mg. In studies up to 24 weeks duration at doses up to 25 mg, 
changes in VEGF plasma concentrations were variable but similar 
relative to control.
Ophthalmologic assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes 
in proliferative retinopathy, macular edema, or choroidal 
neovascularization.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
•
Ophthalmology exams will be performed during 
screening, at approximately Week 12 on-study, and 
at the end of treatment.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
•
Ophthalmology exams should be specified in 
Section 7.4.8. and monitored.
•
When proliferative retinopathy, macular edema or 
choroidal neovascularization is suggested, or 
symptoms that are consistent with these AEs are 
reported, patients should consult ophthalmologist as 
clinically necessary.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Exacerbation of rheumatoid arthritis
In inflamed rheumatic joints, activation of HIF- related genes 
secondary to decreased oxygen and pro-inflammatory cytokines has 
been postulated to contribute to the neo-angiogenesis, proliferation and 
infiltration of rheumatoid synovial fibroblasts (Westra, 2010; Muz, 
2009).
No abnormalities seen in non-clinical studies conducted to date.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Drug-drug interactions
Co-administration of GSK1278863 with a strong CYP2C8 inhibitor increased 
the Cmax and AUC of GSK1278863, 4- and 19-fold, respectively, while co-
administration of a weak inhibitor increased the Cmax and AUC of 
GSK1278863 by 1.3- and 1.5-fold, respectively. Population PK analysis from 
completed Phase 2 studies suggests that co-administration of GSK1278863 
with a moderate CYP2C8 inhibitor, leads to a ~ 2-fold increase in AUC, with no 
clinically-significant increase in the measured Hgb response.
GSK1278863 is an inhibitor of CYP2C8 in vitro, with an IC50 value of 
21 µM.
Population PK analysis from completed Phase 2 studies suggests that 
co-administration of GSK1278863 with clopidogrel (a moderate 
CYP2C8 inhibitor) leads to a ~ 2-fold increase in AUC, with no 
clinically-significant increase in the measured Hgb response. Co-
administration of GSK1278863 with moderate CYP2C8 inhibitors (i.e., 
clopidogrel, teriflunomide, deferasirox) should be performed with 
caution.
Co-administration of GSK1278863 with potent BCRP inhibitors has 
the potential to increase exposure of GSK1278863. Use of BCRP 
inhibitors (mostly weak) was found to result in a small change in 
metabolite exposure (20% increase in AUC).
GSK1278863 is an inhibitor of OATP1B1/1B3 in vitro, with IC50
values of 6 µM and 11 µM, respectively. A clinical drug interaction 
•
Co-administration of GSK1278863 with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 
inducers (e.g., rifampin/rifampicin) is not 
permitted as outlined in Section 6.11.2.
•
Co-administration of GSK1278863 with 
moderate CYP2C8 inhibitors (i.e., clopidogrel, 
teriflunomide, deferasirox) should be 
performed with caution. If one of these 
medications is started, stopped or the dose is 
changed, Hgb should be monitored every 4 
weeks for 12 weeks as outlined in Section 
6.11.1.
•
Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in Section 
6.11.
•
Hgb will be closely monitored throughout the dosing 
period as outlined in the Time and Events Table 
Section 7.1.
•
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of 
GSK1278863 based on achieved Hgb is 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
study between 25mg GSK1278863 with either a CYP2C8 substrate or 
an OATP1B1/1B3 substrate showed that there is no PK interaction at 
this dose of GSK1278863.
provided in Section 6.4.1.
•
These risks will be monitored instreamly by the 
internal safety review team throughout the 
study period.
Other
ESA risks (Control)
・See risks outlined in table for GSK1278863 for Excessive 
erythropoiesis (polycythemia) leading to thrombosis and/or tissue 
ischemia; Risk of MI, stroke, thromboembolic events, thrombosis of 
vascular access; and risk of cancer-related mortality and tumor 
progression.
・Non-controllable hypertension 
・Pure red cell aplasia
・Hepatic function disorder with increase of AST, ALT and Gamma-
glutamyltransferase, and jaundice have been reported as adverse drug 
reactions for other ESA according to the prescribing information of 
Epoetin beta pegol.

The same mitigation strategies have been 
indentified in acoordance with the mitigation 
strategies for GSK1278863 

Blood pressure will be monitored throughout 
the dosing period as outlined in the Time and 
Events Table provided in Section 7.1..

A criterion to exclude subjects with history of 
pure red cell aplasia is added to Section 5.2..

Liver function will be monitored throughout 
the dosing period as outlined in the Time and 
Events Table provided in Section 7.1.
References
Campochiaro et al., Ocular versus Extraocular Neovascularization: Mirror Images or Vague Resemblances; Invest Ophthalmol & Vis Sci 2006. 47:462-474.
Formenti et al., Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha 
gain-of-function mutation. FASEB J. 2011, 25(6): 2001-2011.
Muz et al., The role of hypoxia and HIF-dependent signaling events in rheumatoid arthritis, Arthritis Research & Therapy 2009. 11:201-210.
Smith et al., Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology PLOS 2006. 3:1176-1186.


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Westra et al., Hypoxia-Inducible Factor-1 as Regulator of Angiogenesis in Rheumatoid Arthritis - Therapeutic Implications.  Current Medicinal Chemistry 
2010. 17:254-263.


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12.3.
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of reproductive potential
This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle 
or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long 
term and persistent basis.
1.
Contraceptive subdermal implant that meets the Prescribing Information effectiveness criteria 
including a <1% rate of failure per year, as stated in the Prescribing Information
2.
Intrauterine device or intrauterine system that meets the Prescribing Information effectiveness 
criteria including a <1% rate of failure per year, as stated in the Prescribing Information
[Hatcher, 2011]
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female subject's entry 
into the study, and this male is the sole partner for that subject [Hatcher, 2011].  
These allowed methods of contraception are only effective when used consistently, correctly and in 
accordance with the Prescribing Information. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception.
References
Trussell J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, Kowal D, and 
Policar M (editors). Contraceptive Technology: Twentieth Revised Edition. New York: Ardent Media, 
2011.


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12.4.
Appendix 4: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes pregnant 
while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 weeks of 
learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The investigator will collect 
follow up information on mother and infant, which will be forwarded to GSK. Generally, follow-
up will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as such.  

Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related 
to the study treatment by the investigator, will be reported to GSK as described in Section 12.6.
Appendix 6. While the investigator is not obligated to actively seek this information in former 
study participants, he or she may learn of an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating

will discontinue study medication or be withdrawn from the study


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12.5.
Appendix 5: Liver Safety Required Actions and Follow up Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance).
Phase III-IV liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted

If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments 
MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) and 
quantitative hepatitis B DNA 

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 24 hours after last 
dose5

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:


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hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  
24-72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct 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 computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, (for ND patients only) if serum bilirubin fractionation testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if 
INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold 
value stated will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody or Hepatitis E RNA
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
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 in the 
SRM.  
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 


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<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and 
<8xULN to ≥3xULN but <5xULN, continue to 
monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to 
within baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute 
Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, Follow-
Up and Reporting of Adverse Events
12.6.1.
Definition of Adverse Events
Adverse Event Definition:

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 AE definition 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).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE.  However, the signs and symptoms and/or clinical sequelae resulting from lack 
of efficacy will be reported if they fulfil the definition of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the 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.


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12.6.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of 
disease, etc).
Serious Adverse Event (SAE) is defined as 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
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
e.
Is a congenital anomaly/birth defect
f.
Other situations:

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; (for ND patients only) if 


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unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury. 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.
12.6.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF 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
12.6.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in the CRF

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 CRF page.

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.

PRO questionnaires and the collection of AE data are independent components of the study.

Responses to each question in PRO 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.
12.6.5.
Evaluating AEs and SAEs
Assessment of Intensity


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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.
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

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 


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histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated reporting time 
frames.
12.6.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use the paper SAE 
data collection tool and fax it to the SAE contact.

Site will enter the serious adverse event data into the electronic system as soon as it becomes 
available.

The investigator will confirm that causal relationship of SAE has been considered, by ticking the 
'reviewed' box at the bottom of eCRF page within 72 hours following the submission of SAE. 

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 subject 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 the SAE contact by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the Sponsor/Medical 
Monitor Contact Information page.


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12.7.
Appendix 7 - Genetic Research
Background
Naturally occurring genetic variation may contribute to inter-individual variability in response to 
medicines, as well as an individual's risk of developing specific diseases. Genetic factors associated 
with disease characteristics may also be associated with response to therapy, and could help to explain 
some clinical study outcomes. For example, genetic variants associated with age-related macular 
degeneration (AMD) are reported to account for much of the risk for the condition [Gorin, 2012] with 
certain variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the genetic 
etiology of disease may better inform understanding of disease and the development of medicines. 
Additionally, genetic variability may impact the pharmacokinetics (absorption, distribution, 
metabolism, and elimination), or pharmacodynamics (relationship between concentration and 
pharmacologic effects or the time course of pharmacologic effects) of a specific medicine and/or 
clinical outcomes (efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objective of the genetic research is to understand the response to GSK1278863. To achieve this 
objective, the relationship between genetic variants and the followings may be investigated.

Response to medicine, including GSK1278863, ESA, other study medicines or any concomitant 
medicines;

Nephrogenic anemia and related conditions susceptibility, severity, and progression 
Genetic data may be generated while the study is underway or following completion of the study.  
Genetic evaluations may include focused candidate gene approaches and/or examination of a large 
number of genetic variants throughout the genome (whole genome analyses). Genetic analyses which 
will be conducted for this study will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data from multiple 
clinical studies related to GSK1278863 to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed description of any 
planned analyses will be documented in a Reporting and Analysis Plan (RAP) prior to initiation of the 
analysis. Planned analyses and results of genetic investigations will be reported either as part of the 
clinical RAP and study report, or in a separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in the genetic research. Any subject who has 
received an allogeneic bone marrow transplant must be excluded from the genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during clinical studies. 
Collection of samples, even when no a priori hypothesis has been identified, may enable future 
genetic analyses to be conducted, align with the purpose of the genetic research, to help understand 
variability in disease and medicine response.  


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
A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A Blood 
sample is collected at the baseline visit, after the subject has been randomized and provided 
informed consent for genetic research. Instructions for collection and shipping of the genetic 
sample are described in the laboratory manual. The DNA from the blood sample may undergo 
quality control analyses to confirm the integrity of the sample. If there are concerns regarding the 
quality of the sample, then the sample may be destroyed. The blood sample is taken on a single 
occasion unless a duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to label other 
samples and data in the study. This number 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). 
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 only use samples collected from the study for the purpose stated in this protocol and 
in the informed consent form. Samples may be used as part of the development of a companion 
diagnostic to support the GSK medicinal product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the study.  
Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic 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 genetic sample, if already collected:

Continue to participate in the genetic research in which case the genetic DNA sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA sample
If a subject withdraws consent for genetic 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. 
Genotype data may be generated during the study or after completion of the study and may be 
analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been analyzed, it 
will not be analyzed or used for future research.  


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
Genetic data that has been analyzed at the time of withdrawn consent will continue to be stored 
and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject does not meet 
the entry criteria for participation in the study, then the investigator should instruct the subject that 
their genetic 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.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or separately and may 
publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific understanding in 
alignment with the informed consent. GSK does not inform the subject, family members, 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 genetic studies is generally preliminary in nature, and therefore the significance and 
scientific validity of the results are undetermined. Further, data generated in a research laboratory may 
not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular Degeneration 
(AMD) Susceptibility Gene CFH and Treatment Response of AMD: A Meta-Analysis. PloS ONE 
2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies addressing risk, 
causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.


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12.8.
Appendix 8: Definition of and Procedures for Documenting Medical Device 
Incidents
12.8.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all medical devices 
provided for use in the study (see Section 6.2. for the list of the medical devices).
Medical Device Incident Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance of a device, 
as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, 
might lead to or might have led to the death of a patient/user/other persons or to a serious 
deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health. The non-occurrence of such a 
result might have been due to other fortunate circumstances or to the intervention of health care 
personnel.
It is sufficient that:

an incident associated with a device happened and

the incident was such that, if it occurred again, might lead to death or a serious deterioration in 
health.
A serious deterioration in state of health can include:

life-threatening illness

permanent impairment of body function or permanent damage to a body structure

a condition necessitating medical or surgical intervention to prevent one of the above 

fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of a medical device failure or its 
misuse

a patient’s treatment is interrupted or compromised by a medical device failure

misdiagnosis due to medical device failure leads to inappropriate treatment

a patient’s health deteriorates due to medical device failure
12.8.1.1.
Documenting Medical Device Incidents
Medical Device Incident Documenting:

Any medical device incident occurring during the study will be documented in the subject’s 
medical records, in accordance with the investigator’s normal clinical practice, and on the 
appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE CRF page 
will be completed as described in Section 12.6. (Appendix 6). 

The form will be completed as thoroughly as possible and signed by the investigator before 
transmittal to GSK.


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
It is very important that the investigator provides his/her assessment of causality to the medical 
device provided by GSK at the time of the initial report, and describes any corrective or remedial 
actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a device where 
such action is necessary to prevent recurrence of an incident. This includes any amendment to the 
design to prevent recurrence.


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TITLE PAGE
Division：Worldwide Development
Information Type：Clinical Protocol
Title：A 52-week, Phase III, open-label, multi-center study to evaluate efficacy and safety of 
GSK1278863 in Japanese non-dialysis and peritoneal dialysis subjects with anemia associated with 
chronic kidney disease.
Compound Number：
GSK1278863
Development Phase
III
Effective Date：
08-MAR-2017
Protocol Amendment Number: 03
Author(s)：
 
Revision Chronology
GlaxoSmithKline Document Number 
Date
Version
2015N266248_00
2016-02-18
Original
2015N266248_01
2016-04-12
Amendment No. 1
Clarification of the method of administration of control, clarification of the withdrawal/dropout criteria, 
addition of medical devices, clarification of the time and events, clarification of procedures after 
occurrence of liver events
2015N266248_02
2016-08-01
Amendment No. 2
Clarification of exclusion criteria, clarification of the procedure for the ophthalmology exam at the re-
screening, clarification of analysis populations, updates of risk assessment, updates of the procedures for 
SAE reports
2015N266248_03
2017-03-08
Amendment No. 3
Addition of Cohort 3, change of the starting dose for ND subjects, ESA non-users, change of analysis 
population for efficacy analyses, addition of Week 2 visit, clarification of the timing of eligibility 
assessment regarding exclusion criteria, clarification of prohibited medications, correction of adverse 
events of special interest
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
PPD


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Sponsor Signatory:
Kihito Takahashi
Director,
Japan Development and Medical Affairs (JDMA),
GlaxoSmithKline K. K.
Date


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time 
Phone 
Number
Fax Number
Site Address
Medical Monitor
M.D., Ph.D.
GlaxoSmithKline K.K.
6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-8566 
JAPAN
SAE contact 
information
Person in charge 
of GSK1278863
Clinical 
Operations dept. 
GlaxoSmithKline K.K.
6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-8566 
JAPAN
Emergency Contact
Emergency Contact (Mon to Fri 10am to 6pm, except for national holiday and year-end and New Year
holidays)
Person in charge of GSK1278863, Clinical Operations dept. R&D, Glaxo Smith Kline K.K
TEL:
FAX:
Emergency Contact at night and holiday (Mon to Fri 6pm to 10am, Sat, Sun, national holiday and 
year-end and New Year holidays)
BI medical Inc.
Responsible Person: 
TEL:
(toll free)
FAX:
(toll free)
Sponsor Legal Registered Address:
6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566 JAPAN
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol and the rivision.

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 Signature
Date


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TABLE OF CONTENTS
Page
1.
PROTOCOL SYNOPSIS FOR STUDY PHI201753 ........................................................9
2.
INTRODUCTION............................................................................................................15
2.1.
Study Rationale....................................................................................................15
2.2.
Background..........................................................................................................15
3.
OBJECTIVES AND ENDPOINTS..................................................................................15
4.
STUDY DESIGN.............................................................................................................17
4.1.
Overall Design......................................................................................................17
4.2.
Treatment Groups and Study Periods...............................................................19
4.3.
Study Subjects and Number of Subjects..........................................................20
4.4.
Rationale for Study Design.................................................................................20
4.5.
Rationale for Dose Levels...................................................................................21
4.6.
Benefit: Risk Assessment...................................................................................23
4.6.1.
Risk Assessment ........................................................................................23
4.6.2.
Benefit Assessment....................................................................................23
4.6.3.
Overall Benefit: Risk Conclusion..............................................................23
5.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ...........................................24
5.1.
Inclusion Criteria..................................................................................................24
5.2.
Exclusion Criteria ................................................................................................25
5.3.
Screening Failures...............................................................................................27
5.4.
Withdrawal/Dropout Criteria...............................................................................27
5.4.1.
Liver Chemistry Stopping Criteria.............................................................28
5.4.1.1.
Study Treatment Restart or Rechallenge.........................................30
5.5.
Subject and Study Completion ..........................................................................30
6.
STUDY TREATMENTS..................................................................................................30
6.1.
Investigational Product and Other Study Treatment.......................................30
6.2.
Medical Devices ...................................................................................................31
6.3.
Treatment Assignment........................................................................................31
6.4.
Administration Schedule (Starting Dose, Dose Adjustment, and 
Dosing Frequency) ..............................................................................................32
6.4.1.
GSK1278863 (ND and PD Subjects)..........................................................32
6.4.1.1.
Starting Dose ......................................................................................32
6.4.1.2.
Maintenance Dose..............................................................................32
6.4.2.
Epoetin Beta Pegol (ND Subjects Only) ...................................................33
6.4.2.1.
Starting Dose for ESA Non-users.....................................................33
6.4.2.2.
Dose Conversion for ESA Users ......................................................34


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6.4.2.3.
Maintenance Dose (ESA Non-users and Users) .............................35
6.5.
Blinding.................................................................................................................36
6.6.
Packaging and Labeling......................................................................................36
6.7.
Preparation/Handling/Storage/Accountability..................................................36
6.8.
Compliance with Study Treatment Administration..........................................37
6.9.
Treatment of Study Treatment Overdose..........................................................37
6.10.
Treatment after the End of the Study ................................................................37
6.11.
Concomitant Medications and Non-Drug Therapies .......................................37
6.11.1.
Permitted Medications and Non-Drug Therapies ....................................37
6.11.2.
Prohibited Medications and Non-Drug Therapies...................................38
6.12.
Supplemental Iron Therapy ................................................................................38
7.
Study Assessments and Procedures.........................................................................38
7.1.
Time and Events Table........................................................................................38
7.2.
Screening and Critical Baseline Assessments ................................................41
7.3.
Efficacy .................................................................................................................41
7.4.
Safety ....................................................................................................................41
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)....................41
7.4.1.1.
Time period and Frequency for collecting AE and SAE 
information..........................................................................................42
7.4.1.2.
Method of Detecting AEs and SAEs.................................................42
7.4.1.3.
Follow-up of AEs and SAEs ..............................................................42
7.4.1.4.
Cardiovascular and Death Events....................................................42
7.4.1.5.
Regulatory Reporting Requirements for SAEs...............................43
7.4.2.
Adverse Events of Special Interest...........................................................43
7.4.3.
Pregnancy....................................................................................................43
7.4.4.
Medical Device Incidents (Including Malfunctions) ................................44
7.4.4.1.
Time Period for Detecting Medical Device Incidents......................44
7.4.4.2.
Follow-up of Medical Device Incidents ............................................44
7.4.4.3.
Prompt Reporting of Medical Device Incidents to GSK.................44
7.4.4.4.
Regulatory Reporting Requirements for Medical Device 
Incidents..............................................................................................45
7.4.5.
Vital Signs/Height/Weight ..........................................................................45
7.4.6.
Electrocardiogram (ECG) ...........................................................................45
7.4.7.
Clinical Laboratory Assessments.............................................................45
7.4.8.
Ophthalmology............................................................................................46
7.5.
Pharmacokinetics................................................................................................47
7.6.
Genetics................................................................................................................47


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7.7.
Patient Reported Outcome (PRO)......................................................................47
7.7.1.
SF-36.............................................................................................................47
7.7.2.
EuroQol Health Utility Index (EQ-5D-5L)/EQ Visual Analogue 
Scale (EQ-VAS)............................................................................................47
8.
DATA MANAGEMENT ..................................................................................................48
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .....................................48
9.1.
Hypotheses...........................................................................................................48
9.2.
Sample Size Considerations ..............................................................................49
9.2.1.
Sample Size Assumptions .........................................................................49
9.2.2.
Sample Size Sensitivity ..............................................................................50
9.2.3.
Sample Size Re-estimation or Adjustment...............................................50
9.3.
Data Analysis Considerations............................................................................50
9.3.1.
Analysis Populations..................................................................................50
9.3.2.
Interim Analysis ..........................................................................................51
9.3.3.
Adjustment for Multiplicity.........................................................................51
9.4.
Key Elements of Analysis Plan ..........................................................................51
9.4.1.
Primary Efficacy Analysis..........................................................................51
9.4.2.
Principal Secondary Efficacy Analysis.....................................................52
9.4.3.
Other Secondary Efficacy Analyses .........................................................52
9.4.4.
Safety Analyses...........................................................................................52
9.4.4.1.
Exposure .............................................................................................52
9.4.4.2.
Adverse Events...................................................................................53
9.4.4.3.
Other Safety Parameters ...................................................................53
9.4.5.
Pharmacokinetics Analyses ......................................................................53
9.4.6.
PRO Data Analysis......................................................................................53
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
10.3.
Quality Control (Study Monitoring)....................................................................55
10.4.
Quality Assurance ...............................................................................................55
10.5.
Study and Site Closure .......................................................................................55
10.6.
Records Retention...............................................................................................56
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publicatio....................56
10.8.
Study Period.........................................................................................................57
10.9.
Study Administrative Structure..........................................................................57


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11. REFERENCES...............................................................................................................58
12. APPENDICES ................................................................................................................59
12.1.
Appendix 1: Abbreviations and Trademarks....................................................59
12.2.
Appendix 2:  Risk Assessment.........................................................................61
12.3.
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of reproductive potential.............................................68
12.4.
Appendix 4: Collection of Pregnancy Information...........................................69
12.5.
Appendix 5: Liver Safety Required Actions and Follow up 
Assessments........................................................................................................70
12.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events ...................................................73
12.6.1.
Definition of Adverse Events.....................................................................73
12.6.2.
Definition of Serious Adverse Events.......................................................74
12.6.3.
Definition of Cardiovascular Events.........................................................75
12.6.4.
Recording of AEs and SAEs......................................................................75
12.6.5.
Evaluating AEs and SAEs..........................................................................75
12.6.6.
Reporting of SAEs to GSK.........................................................................77
12.7.
Appendix 7 - Genetic Research..........................................................................78
12.8.
Appendix 8: Definition of and Procedures for Documenting Medical 
Device Incidents...................................................................................................81
12.8.1.
Definitions of a Medical Device Incident ..................................................81
12.8.1.1.
Documenting Medical Device Incidents...........................................81


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1.
PROTOCOL SYNOPSIS FOR STUDY PHI201753
Rationale
This is a Phase III study to evaluate the efficacy and safety of GSK1278863 in Japanese non-dialysis 
(ND) and peritoneal dialysis (PD) subjects with renal anemia. The primary objective is to demonstrate
non-inferiority of GSK1278863 to epoetin beta pegol based on hemoglobin (Hgb) in the ND patient 
population included in this study. Study results will be used as pivotal study data for an NDA 
submitted for GSK1278863 for the treatment of renal anemia in Japan. 
Objective(s)/Endpoint(s)
Objective
Endpoint
Primary (efficacy)

To demonstrate non-inferiority of 
GSK1278863 to epoetin beta pegol based 
on hemoglobin (Hgb) in ND subjects 

Mean Hgb during the primary efficacy 
evaluation period (Weeks 40 to 52)
Principal secondary (efficacy)

To demonstrate superiority of 
GSK1278863 to epoetin beta pegol in 
terms of achievement/maintenance of 
target Hgb in ND subjects

Number (%) of subjects with mean Hgb in the 
target range (11.0-13.0 g/dL) during the 
primary efficacy evaluation period (Weeks 40 
to 52)
Other secondary (efficacy, PK)

To evaluate the appropriateness of the 
starting dose of GSK1278863 in ND 
subjects using epoetin beta pegol as 
control

To evaluate the appropriateness of the 
starting dose of GSK1278863 in PD 
subjects

Change from baseline in Hgb at Week 4 (Hgb 
increase rate)

Number (%) of subjects by Hgb change from 
baseline category at Week 4

To evaluate dose adjustment scheme of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate dose adjustment scheme of 
GSK1278863 in PD subjects

Distribution of the dose level

Duration of treatment interruption due to Hgb 
>13 g/dL

Frequency of dose adjustments

To evaluate the overall Hgb control of
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate the overall Hgb control of
GSK1278863 in PD subjects

Hgb and change from baseline at each 
assessment visit

Number (%) of subjects with Hgb within the 
target range (11.0-13.0 g/dL) at each 
assessment visit

Time (%) in Hgb target range (11.0-13.0 g/dL) 
during the primary efficacy evaluation period 
(Weeks 40 to 52)

Time (in days) to reach the lower Hgb target 


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Objective
Endpoint
(11.0 g/dL) 

Number (%) of subjects who have an Hgb 
level of less than 7.5 g/dL

Number (%) of subjects who have an Hgb 
increase of more than 2 g/dL over any 4 weeks 

Number (%) of subjects who have an Hgb 
level of more than 13.0 g/dL and number of 
episodes

To evaluate the effect on iron use of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate effect on iron use of 
GSK1278863 in PD subjects

Dose of oral iron during the study period and 
the primary efficacy evaluation period 
(Weeks 40 to 52) 

Number (%) of subjects who use oral iron 
during the study period and the primary 
efficacy evaluation period (Weeks 40 to 52)

To evaluate the effect on iron metabolism
of GSK1278863 in ND subjects using
epoetin beta pegol as control

To evaluate the effect on iron metabolism 
of GSK1278863 in PD subjects

Change from baseline in ferritin

Change from baseline in transferrin saturation 
(TSAT)

Changes from baseline in hepcidin, serum iron, 
and total iron binding capacity (TIBC) 

To evaluate the PK of GSK1278863

AUC and Cmax of plasma GSK1278863
Exploratory (efficacy)

To evaluate the effect on progression of 
Chronic Kidney Disease (CKD) of 
GSK1278863 in ND subjects using
epoetin beta pegol as control

Estimated glomerular filtration rate (eGFR) 
and change from baseline

Serum creatinine and change from baseline

Urine creatinine and urine albumin, and 
changes from baseline

Urine albumin/creatinine ratio and change 
from baseline
Patient reported outcome

To evaluate the effect on health-related 
QoL (HR-QoL) of GSK1278863 in ND 
subjects using epoetin beta pegol as 
control

To evaluate the effect on HR-QoL of 
GSK1278863 in PD subjects
SF-36

Changes from baseline in SF-36 HR-QoL 
scores [Physical Component Summary (PCS), 
Mental Component Summary (MCS), and 8 
subscales]
EuroQol Health Utility Index (EQ-5D-5L)

Change from baseline in EQ-5D-5L score 

Change from baseline in EQ-5D-5L Visual 
Analog Scale (VAS) 
Safety

To evaluate the safety and tolerability of 
GSK1278863 in ND and PD subjects

Incidence and severity of AEs and SAEs, 
including AEs of special interest


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Objective
Endpoint

Reasons for discontinuation of study 
medication

Laboratory tests, ECG, vital signs, and 
ophthalmology assessments
Study Design
This is a Phase III, open-label, active-controlled, parallel-group, multi-center study to compare the efficacy 
(demonstration of non-inferiority) and safety of GSK1278863 administered for 52 weeks versus epoetin 
beta pegol in approximately 270 Japanese ND subjects with renal anemia. This study also includes an open-
label, uncontrolled part to evaluate the efficacy and safety of GSK1278863 in approximately 50 Japanese 
PD subjects. Cohort 1 (ND subjects) and Cohort 2 (PD subjects) were set for target population of this study
when the study was planned. Cohort 3 is newly added in Protocol amendment (Amendment No.3). ND 
subjects will be randomized not to Cohort 1 but to Cohort 3 after Protocol amendment:
Patient 
population
Cohort
Treatment group
Target number of subjects
(randomized)
ND patient
Cohort 11
GSK1278863 group (starting dose: 4 mg)
169 subjects4)
270 subjects5)
Epoetin beta pegol group
Cohort 32)
GSK1278863 group (starting dose: 2 mg or 4
mg3))
101 subjects
Epoetin beta pegol group
PD patient
Cohort 2
GSK1278863 group (starting dose: 4 mg)
50 subjects
1) At least 50 ESA users and at least 50 ESA non-users will be randomized to Cohort 1. 
2) ND patients will be randomized to Cohort 3 and at least 80 ESA non-user will be randomized after Protocol Amendment No.3.
3) GSK 1278863 starting dose in Cohort 3 as below

ESA non-user (baseline Hgb 8.0-<9.0 g/dL):4 mg

ESA non-user (baseline Hgb 9.0-<11.0 g/dL):2 mg

ESA user: 4 mg
4) The exact number of ND subjects randomized to Cohort 1 
5) Subjects will be randomized in a 1:1 ratio to one of the two treatment groups
ESA: erythropoiesis-stimulating agent
For the patient populations in either cohort, the Hgb criteria are specified according to the presence or 
absence of prior ESA: ESA non-users with an Hgb level of ≥8.0 to <11.0 g/dL and ESA users with an 
Hgb level of 9.0 to 13.0 g/dL will be included in the study.
In Cohort 1 and Cohort 3, eligible ND subjects [total of 270 subjects (169 subjects in Cohort 1, 101
subjects in Cohort 3)] will be stratified by the current ESA therapy and baseline Hgb (ESA non-users: 
9.5 g/dL, >9.5 g/dL, ESA users: <11.0 g/dL, 11.0 g/dL) and then randomized in a 1:1 ratio to 
GSK1278863 or epoetin beta pegol group. 
In Cohort 2, 50 eligible PD subjects will be included in the GSK1278863 group. 
This study consists of a 4-week screening phase, a 52-week treatment phase [including the primary 
efficacy evaluation period (Weeks 40 to 52)], and a 4-week follow-up phase following the treatment 
phase. The study design is shown below. 


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Screening phase
(4 weeks)
Treatment phase (52 weeks)
Follow-up phase
(4 weeks)
Primary efficacy 
evaluation period
Cohort 1
GSK1278863 group
Non-dialysis (ND)
subjects
Epoetin beta pegol group
Cohort 2
Peritoneal dialysis 
(PD) subjects
GSK1278863 group
Cohort 3
GSK1278863 group
Non-dialysis (ND)
subjects
Epoetin beta pegol group
Week -4                Day 1                            Week 40          Week 52          Week 56
Method of Administration of Study Medication in Each Treatment Group
In each treatment group, study medication will be administered as follows: 
GSK1278863 group:

Cohort 1 (ND subjects) and Cohort 2 (PD subjects)
Treatment with GSK1278863 will be started at a dose of 4 mg once daily on Day 1. 

Cohort 3 (ND subjects)

For ESA non-user with Baseline Hgb 8.0 and <9.0 g/dL, Treatment with 
GSK1278863 will be started at a dose of 4 mg once daily on Day 1.

For ESA non-user with Baseline Hgb 9.0 and <11.0 g/dL, Treatment with 
GSK1278863 will be started at a dose of 2 mg once daily on Day 1.

For ESA users, Treatment with GSK1278863 will be started at a dose of 4 mg once 
daily on Day 1.
After Week 4, dose adjustments will be made within the dose range of 1-24 mg every 4 weeks 
according to the prespecified dose adjustment algorithm to achieve and/or maintain Hgb within the 
target range (11.0-13 0 g/dL).

Epoetin beta pegol group (ND subjects): 

ESA non-users: Subcutaneous treatment with epoetin beta pegol will be started at a dose of 
25 g once every 2 weeks on Day 1. Subsequently, dose adjustments will be made within 
the dose range of 25-150 g every 4 weeks according to the prespecified initial dose 
adjustment criteria to achieve the lower limit of the Hgb target (11.0 g/dL). Once Hgb 
increases to 11.0 g/dL or more, dose adjustments will be made according to the prespecified 
dose adjustment algorithm. After it is confirmed that all of the criteria for dosing interval 


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change are met, dosing frequency will be changed to once every 4 weeks, and dose 
adjustments will be made within the dose range of 25-250 g every 4 weeks according to 
the prespecified dose adjustment algorithm to achieve and/or maintain Hgb within the target 
Hgb range (11.0-13.0 g/dL). 

ESA users: Prior ESA therapy will be replaced with subcutaneous treatment with epoetin 
beta pegol at the equivalent dose once every 4 weeks according to prespecified dose 
conversion. Subsequently, dose adjustments will be made within the dose range of 25-
250 g every 4 weeks according to the prespecified dose adjustment algorithm to achieve 
and/or maintain Hgb within the target range (11.0-13.0 g/dL).
Analysis
Assuming a non-inferiority margin of -1.0 g/dL, a treatment difference of 0.0 g/dL, and a standard 
deviation of 1.5 g/dL for mean Hgb during in the primary efficacy evaluation period in ND subjects, 
two-sample t-test has at least 99% power at a two-sided significance level of 5% with a sample size of 
100 subjects per group. Assuming a dropout rate of approximately 25%, 135 subjects will be 
randomized to each group. For PD subjects, the sample size is based on the feasibility. Assuming a 
sample size of 38 subjects and a standard deviation of 1.5 g/dL, the half the width of the 95% CI for 
mean Hgb during in the primary efficacy evaluation period is 0.493 g/dL. During this study, the 
protocol has been amended according to the change in starting dose for ND, ESA non-users in the 
GSK1278863 group; however, this amendment will need no change for the overall target sample size
(see Section 9.2.).
The primary endpoint, which is the mean Hgb during the primary efficacy evaluation period, will be 
analyzed to demonstrate the non-inferiority of GSK1278863 to epoetin beta pegol in ND subjects,
including Cohort 1 subjects (only ESA users) and Cohort 3 subjects. A mixed model for repeated 
measurements (MMRM) will be used to estimate the mean Hgb during the primary efficacy 
evaluation period and its 95% CI by treatment groups. As a preliminary assessment, it will be 
confirmed if the lower and upper limit of 95% CI for mean Hgb in GSK1278863 group would lie fully 
within target range (11.0-13.0 g/dL) In addition, the point estimate and 95% CI for the treatment 
difference (GSK1278863-epoetin beta pegol) in mean Hgb during the primary efficacy evaluation 
period will be estimated. Non-inferiority will be established if the lower limit of the 95% CI is greater 
than -1.0 g/dL. Even if the 95% CI for the difference is completely negative (i.e. lies fully within the 
range -1.0 to 0 g/dL) non-inferiority would still be concluded on condition that the mean Hgb estimate 
in the GSK1278863 group is within the target range.
The primary efficacy population will be the ITT Population (excluding non-ESA users from Cohort 1),
and the analysis will be repeated in the mITT and PP Population to evaluate the robustness of the 
conclusion. The subgroup analysis by the current ESA therapy (presence or absence) will also be 
conducted. Further details of sensitivity analyses will be provided in the Reporting and Analysis Plan
(RAP).
The principal secondary endpoint, which is the proportion of subjects whose mean Hgb during the 
primary efficacy evaluation period is within the target range will be analyzed to demonstrate the 
superiority of GSK1278863 to epoetin beta pegol in ND subjects. 


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In the mITT Population, a logistic regression model including treatment group, baseline Hgb, and the 
current ESA therapy (presence or absence) as covariates will be used to estimate the point estimate 
and 95% CI for the odds ratio (GSK1278863/epoetin beta pegol). This analysis will be performed to 
demonstrate the superiority at a two-sided significance level of 5%, conditional on the primary 
endpoint achieving noninferiority. Superiority will be established if the lower limit of the 95% CI for 
the odds ratio is greater than 1.0.


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2.
INTRODUCTION
GSK1278863 is a hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (PHI) that stimulates 
erythropoiesis in the same manner as innate response to hypoxia and is currently being developed as a 
new treatment for renal anemia.
2.1.
Study Rationale
This is a Phase III study to evaluate the efficacy and safety of GSK1278863 in Japanese non-dialysis 
(ND) and peritoneal dialysis (PD) subjects with renal anemia. The primary objective is to demonstrate 
non-inferiority of GSK1278863 to epoetin beta pegol based on hemoglobin (Hgb) in the ND patient 
population included in this study. Study results will be used as pivotal study data for an NDA 
submitted for GSK1278863 for the treatment of renal anemia in Japan. 
2.2.
Background
Renal anemia is diagnosed in many patients with CKD, and the prevalence of renal anemia increases 
with progression of CKD [Akizawa, 2011]. Causes of anemia in CKD patients include absolute or 
relative deficiency of erythropoietin (EPO), shortened erythrocyte survival, and reduced iron 
availability. Anemia is further exacerbated by chronic blood loss associated with hemodialysis 
procedure, infection, and functional hemolysis [Japanese Society for Dialysis Therapy, 2008]. 
GSK1278863 is a hypoxia-inducible factor-prolyl hydroxylase inhibitor that is currently being 
developed as a treatment for renal anemia. Data in Japanese patients have been collected from a 
Japanese Phase II 4-week treatment study in Japanese hemodialysis (HD) subjects (PHI116099: 97 
Japanese subjects), an international multi-center Phase II 24-week treatment study in HD subjects 
(PHI113633: including 24 Japanese subjects), and an international multi-center Phase II 24-week 
treatment study in ND subjects (PHI113747: including 42 Japanese subjects). In these clinical studies, 
GSK1278863 increased endogenous EPO, reduced hepcidin, and increased Hgb in HD and ND 
subjects including Japanese subjects. In addition, GSK1278863 increased Hgb at lower blood EPO 
concentrations than existing erythropoiesis-stimulating agents (ESAs). 
Data from completed clinical and clinical pharmacology studies and the preclinical data safety 
package are provided in the Development Core Safety Information found in the current GSK1278863 
Investigator Brochure (IB). A benefit: risk assessment, including risk mitigation strategies, is outlined 
in Section 4.6.
3.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary (efficacy)

To demonstrate non-inferiority of 
GSK1278863 to epoetin beta pegol based 
on hemoglobin (Hgb) in ND subjects 

Mean Hgb during the primary efficacy 
evaluation period (Weeks 40 to 52)
Principal secondary (efficacy)

To demonstrate superiority of 

Number (%) of subjects with mean Hgb in the 


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Objective
Endpoint
GSK1278863 to epoetin beta pegol in 
terms of achievement/maintenance of 
target Hgb in ND subjects
target range (11.0-13.0 g/dL) during the 
primary efficacy evaluation period (Weeks 40 
to 52)
Other secondary (efficacy, PK)

To evaluate the appropriateness of the 
starting dose of GSK1278863 in ND 
subjects using epoetin beta pegol as 
control

To evaluate the appropriateness of the 
starting dose of GSK1278863 in PD 
subjects

Change in Hgb from baseline to Week 4 (Hgb 
increase rate)

Number (%) of subjects by Hgb change from 
baseline category to Week 4

To evaluate dose adjustments of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate dose adjustments of 
GSK1278863 in PD subjects

Distribution of the dose level

Duration of treatment interruption due to Hgb 
>13 g/dL

Frequency of dose adjustments

To evaluate the overall Hgb control by 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate the overall Hgb control by 
GSK1278863 in PD subjects

Hgb at each assessment time point and change 
in Hgb from baseline to each assessment time 
point

Number (%) of subjects with Hgb within the 
target range (11.0-13.0 g/dL) at each 
assessment time point

Proportion (%) of time with Hgb within the 
target range (11.0-13.0 g/dL) in the primary 
efficacy evaluation period (Weeks 40 to 52)

Time (number of days) to the lower Hgb target 
(11.0 g/dL) 

Number (%) of subjects who have an Hgb 
level of less than 7.5 g/dL

Number (%) of subjects who have an Hgb 
increase of more than 2 g/dL over any 4 weeks 
before Week 52

Number (%) of subjects who achieve an Hgb 
level of more than 13.0 g/dL and number of 
episodes

To compare the effect of GSK1278863 
versus epoetin beta pegol on iron use in 
ND subjects

To evaluate the effect of GSK1278863 on 
iron use in PD subjects

Dose of oral iron in the study period and the 
primary efficacy evaluation period (Weeks 40 
to 52) 

Number (%) of subjects who use oral iron 
during the study period and the primary 
efficacy evaluation period (Weeks 40 to 52)

To compare the effect of GSK1278863 

Change in ferritin from baseline


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Objective
Endpoint
versus epoetin beta pegol on iron 
metabolism in ND subjects

To evaluate the effect of GSK1278863 on 
iron metabolism in PD subjects

Change in transferrin saturation (TSAT) from 
baseline

Changes in hepcidin, serum iron, and total iron 
binding capacity (TIBC) from baseline

To evaluate the PK of GSK1278863

AUC and Cmax of plasma GSK1278863
Exploratory (efficacy)

To compare the effect of GSK1278863 
versus epoetin beta pegol on progression 
of CKD in ND subjects

Estimated glomerular filtration rate (eGFR) 
and change from baseline

Serum creatinine and change from baseline

Urine creatinine and urine albumin, and 
changes from baseline

Urine albumin/creatinine ratio and change 
from baseline
Patient reported outcome

To compare the effect of GSK1278863 
versus epoetin beta pegol on health-
related QoL (HR-QoL) in ND subjects

To evaluate the effect of GSK1278863 on 
H-RQoL in PD subjects
SF-36

Changes in SF-36 HR-QoL scores (PCS, MCS, 
and 8 subscales) from baseline
EuroQol Health Utility Index (EQ-5D-5L)

Change in EQ-5D-5L score from baseline

Change in EQ-5D-5L Visual Analog Scale 
(VAS) from baseline
Safety

To evaluate the safety and tolerability of 
GSK1278863 in ND and PD subjects

Incidence and severity of AEs and SAEs, 
including AEs of special interest

Reasons for discontinuation of study 
medication

Laboratory tests, ECG, vital signs, and 
ophthalmology assessments
4.
STUDY DESIGN
4.1.
Overall Design 
This is a Phase III, open-label, active-controlled, parallel-group, multi-center study to compare the 
efficacy (verification of noninferiority) and safety of GSK1278863 administered for 52 weeks versus 
epoetin beta pegol in approximately 270 Japanese ND subjects with renal anemia. This study also 
includes an open-label, uncontrolled part to evaluate the efficacy and safety of GSK1278863 in 
approximately 50 Japanese PD subjects. Cohort 1 (ND subjects) and Cohort 2 (PD subjects) were set 
for target population of this study when the study was planned. Cohort 3 is newly added in 
amendment (Amendment No.3). ND subjects will be randomized not to Cohort 1 but to Cohort 3 after 
amendment No.3:


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Table 1    Composition of each cohort 
[Including target number of subjects (randomized)]
Patient 
population
Cohort
Treatment group
Target number of subjects
(randomized)
ND patient
Cohort 11)
GSK1278863 group (starting dose: 4 mg)
169 subjects4)
270 subjects5)
Epoetin beta pegol group
Cohort 32)
GSK1278863 group (starting dose: 2 mg or 4
mg3))
101 subjects
Epoetin beta pegol group
PD patient
Cohort 2
GSK1278863 group (starting dose: 4 mg)
50 subjects
1) At least 50 ESA users and at least 50 ESA non-users will be randomized to Cohort 1. 
2) ND patients will be randomized to cohort 3 and at least 80 ESA non-user will be randomized after Protocol amendment 
(Amendment No.3).
3) GSK 1278863 starting dose in Cohort 3 as below

ESA non-user (baseline Hgb 8.0-<9.0 g/dL):4 mg

ESA non-user (baseline Hgb 9.0-<11.0 g/dL):2 mg

ESA user: 4 mg
4) The exact number of ND subjects randomized to cohort 1 
5) Subjects will be randomized in a 1:1 ratio to one of the two treatment groups
ESA: erythropoiesis-stimulating agent
For the patient populations in either cohort, the Hgb criteria are specified according to the presence or 
absence of prior ESA: ESA non-users with an Hgb level of ≥8.0 to <11.0 g/dL and ESA users with an 
Hgb level of 9.0 to 13.0 g/dL will be included in the study.
In Cohort 1and Cohort 3, eligible ND subjects [total of 270 subjects (169 subjects in Cohort 1, 101
subjects in Cohort 3)] will be stratified by the current ESA therapy (ESA non-user or ESA user) and 
baseline Hgb (ESA non-users: 9.5 g/dL, >9.5 g/dL, ESA users: <11.0 g/dL, 11.0 g/dL) and then 
randomized in a 1:1 ratio to GSK1278863 or epoetin beta pegol group. 
In Cohort 2, 50 eligible PD subjects will be included in the GSK1278863 group. 
This study consists of a 4-week screening phase, a 52-week treatment phase [including the primary 
efficacy evaluation period (Weeks 40 to 52)], and a 4-week follow-up phase following the treatment 
phase. The study design is shown in Figure 1.


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Screening phase
(4 weeks)
Treatment phase (52 weeks)
Follow-up phase
(4 weeks)
Primary efficacy 
evaluation period
Cohort 1
GSK1278863 group
Non-dialysis (ND)
subjects
Epoetin beta pegol group
Cohort 2
Peritoneal dialysis 
(PD) subjects
GSK1278863 group
Cohort 3
GSK1278863 group
Non-dialysis (ND)
subjects
Epoetin beta pegol group
Week -4                Day 1                            Week 40          Week 52          Week 56
Figure 1 Study Design
4.2.
Treatment Groups and Study Periods
Details for each study period and treatments are described below. In this study, a point-of-care Hgb 
analyzer (HemoCue®) will consistently be utilized for confirmation of subjects’ eligibility, withdrawal 
criteria and dose adjustments of study medication.
Screening phase
Subjects who have provided informed consent and meet all of the eligibility criteria at screening 
(Week -4) (Sections 5.1 and 5.2) will be provisionally enrolled in the study. Subjects who have used 
ESA and/or oral iron since before the start of the study must remain on the same regimen throughout 
the screening phase (intravenous iron will not be allowed). 
Treatment phase
Subjects who meet all of the eligibility criteria at the start of the treatment phase (Day 1) will be 
enrolled in the study. Study medication (either GSK1278863 or epoetin beta pegol group) will be 
administered for 52 weeks according to randomization in Cohort 1and Cohort 3. GSK1278863 will be 
administered in Cohort 2 for 52 weeks. For ESA users, prior ESA will be replaced with study 
medication on Day 1. GSK1278863 will be orally administered once daily, and epoetin beta pegol will 
be subcutaneously administered once every 2 or 4 weeks. In both groups, dose adjustments for study 
medication during the treatment phase will be made according to the administration schedule specified 
in Section 6.4. to achieve and/or maintain Hgb within the target range (11.0-13.0 g/dL). In addition, 


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supplemental iron therapy will be administered according to the standard initiation criteria as 
described in Section 6.12.. It should be noted that intravenous iron or dose change for oral iron will 
not be allowed from Day 1 to Week 4. 
Follow-up phase
Subjects will visit the site for follow-up assessments and observations 4 weeks after the 
completion/discontinuation of study treatment. During the follow-up phase, treatment of renal anemia 
will be allowed as necessary at the discretion of the investigator (or subinvestigator). 
4.3.
Study Subjects and Number of Subjects
For ND subjects, a total of 270 subjects will be randomized (135 subjects in GSK1278863 group,135 
subjects in epoetin beta pegol group). The minimum target number of subjects is 50 ESA non-users 
and 50 ESA users to allow for evaluations by the current ESA therapy (ESA non-user or ESA user) in 
Cohort 1. At least 80 ESA non-user will be randomized to Cohort 3 defined in Protocol (Amendment 
No.3). In protocol amendment No.3, each target number subjects are amended as Table 2, but total of 
target number of subjects is not changed.
Assuming a dropout rate of 35% during the screening phase, approximately 416 ND subjects need to 
be screened. Assuming a dropout rate of 25% after the start of study treatment, a total of 202 subjects 
are expected to complete the 52-week treatment. 
In Cohort 2 involving PD subjects, 50 subjects will be enrolled (GSK1278863 group only). Since the 
number of PD patients is very limited in Japan, the target number of subjects is not set for either ESA 
non-users or users. Assuming a dropout rate of 35% during the screening phase, approximately 77 
subjects need to be screened. Assuming a dropout rate of 25% after the start of study treatment, 38 
subjects are expected to complete the 52-week treatment. 
Table 2    Target Number of Subjects
ND subjects
PD subjects 
Cohort 1
Cohort 3
Cohort 2
Screened
416
77
Randomized/enrolled
270 
50
169*1
101*2
Completed 52-week treatment
202
38
*1: In Cohort 1, at least 50 ESA non-users and at least 50 ESA users will be randomized.
*2: In Cohort 3, at least 80 ESA non-user will be randomized 
4.4.
Rationale for Study Design
Objectives and evaluations
This is a Phase III study to evaluate the efficacy and safety of GSK1278863 in Japanese ND and PD 
subjects with renal anemia. For Cohort 1 and Cohort 3, the study is designed as an active-controlled, 
parallel-group comparative study to meet the primary objective, that is, to demonstrate non-inferiority 
of GSK1278863 to the existing drug in ND, ESA user subjects in Cohort 1 or ND subjects in Cohort 3, 
depending on a change of the starting dose for ND, ESA non-users. For Cohort 2, the study is 
designed as an uncontrolled study because there are not many PD patients. The target Hgb range was 
set for study treatment in line with the Guidelines for Renal Anemia in Chronic Kidney Disease issued 


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by the Japanese Society for Dialysis Therapy in 2008 [The Japanese Society for Dialysis Therapy, 
2008] to demonstrate that treatment with GSK1278863 can result in achievement and/or maintenance 
of target Hgb in ND and PD subjects, and evaluate the appropriateness of the starting dose of 
GSK1278863. 
Control
For the ND patient population (Cohort 1 and Cohort 3), epoetin beta pegol, which has been widely 
used in Japanese patients with renal anemia, primarily ND patients, since its approval in Japan in 2011, 
was selected as control. 
Open-label
If the study is conducted as a double-blind study, it is necessary to not only administer GSK1278863 
orally (once daily) or epoetin beta pegol subcutaneously (once every 2 or 4 weeks), but also 
administer the matching placebo subcutaneously or orally. It will be more stressful for subjects and 
complicate treatment procedures to use both active drug and matching placebo for two drugs with 
different routes and intervals of administration for the purpose of maintaining the blind, and make 
dose adjustments for individual subjects according to the change in Hgb over time. Accordingly, this 
study is designed as an open-label study rather than a double-blind study, which seems infeasible. 
Since Hgb used for efficacy evaluation is an objective measure, and dose adjustments for study 
medication will be made according to the prespecified Hgb-based dose adjustment method in both 
GSK1278863 and epoetin beta pegol groups, it is unlikely that the open-label design will create any 
bias in the primary evaluation. 
4.5.
Rationale for Dose Levels
Starting dose and dose adjustments of GSK1278863
The starting dose and the dose adjustment method (maintenance dose range: 1-24 mg) for 
GSK1278863 are described in Section 6.4..
The starting dose and the dose adjustment algorithm selected for Japanese ND subjects in the present 
study are based on the results from a review of the longitudinal model constructed using Hgb data 
from six Japanese or overseas Phase II studies (PHI112844, PHI116581, PHI116582, PHI113633, 
PHI113747, and PHI116099) as well as the results from clinical studies. The data set used in the 
model analyses was based on the data of GSK1278863 administered in a wide dose range (0-25 mg) 
and included a Japanese Phase II 4-week treatment study (PHI116099) and international multi-center 
late Phase II 24-week treatment studies (PHI113633 and PHI113747) in which subjects in Japan 
participated. For PD subjects, the starting dose and the dose adjustment algorithm for ND subjects will 
be applied based on the PK/PD profiles in PD subjects determined from an interim analysis in an 
overseas 14-day treatment clinical pharmacology study (PHI200942). 
Starting dose
Simulation results using the longitudinal model in ND subjects as well as the results from clinical 
studies indicated that GSK1278863 given at a dose of 4 mg may slowly increase Hgb (0.5-1.0 g/dL on 
average) without a rapid increase greater than 2 g/dL after 4 weeks of treatment in ESA non-users. 
4 mg GSK1278863 may also maintain Hgb without a rapid increase greater than 2 g/dL for 4 weeks 


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after switching from prior ESA in ESA users. Therefore, 4 mg was set as starting dose of 
GSK1278863 when study was planned.
As of Dec 2016 during this study, from the result of a review of blinded data, it was determined that 
the percentage of ND, ESA-non-user subjects with an Hgb increases of >2.0 g/dL from baseline to 
Week 4 was higher than expectaion dedscribed above. This finding was not observed in ND, ESA-
user subjects and PD subjects.
Therefore, in the protocol amendment No 3, 

For ND, ESA non-user subjects with baseline Hgb ≥9.0 g/dL and <11.0 g/dL, the starting dose of 
GSK1278863 is changed from 4 mg to 2 mg.

For ND, ESA non-user subjects with baseline Hgb ≥8.0 g/dL and <9.0 g/dL, the starting dose 
remains at 4 mg. 
For ND, ESA-user subjects and PD subjects, the starting dose of GSK1278863 were not changed and 
remains at 4 mg respectively.
In addition, Week 2 visit for additional Hgb monitoring in Cohort 3 was also included to allow earlier 
safety assessment of Hgb change at early phase of GSK1278863 treatment. (Refer to Section 6.4.1.)
Maintenance dose range and dose adjustment algorithm
Simulation results using the longitudinal model showed that drug response to GSK1278863 greatly 
varied among subjects, indicating that the dose range from 1 to 24 mg may be necessary to achieve 
and maintain target Hgb. Accordingly, a total of 8 dose levels (1, 2, 4, 6, 8, 12, 18, and 24 mg) were 
selected as the maintenance doses, with 4 mg intended for subjects with a standard drug response. 
The dose adjustment algorithm was defined so that target Hgb (11.0-13.0 g/dL) set for the present 
study according to the Guidelines for Renal Anemia [The Japanese Society for Dialysis Therapy,
2008] can be maintained. Since the upper limit of the Hgb target (13.0 g/dL) is equivalent to the 
interruption criterion for ESA, the dose level of GSK1278863 will be reduced by one step when Hgb 
increases to more than 12.5 g/dL, and the dose level will be maintained while Hgb is in the range of 
11.5-<12.5 g/dL. Since the guidelines state that an Hgb increase of 0.5 g/dL or less per week is 
appropriate to prevent adverse reactions, the dose level will be reduced by one step when Hgb 
increases by more than 2 g/dL over 4 weeks (or when Hgb increases by more than 1 g/dL over 2 
weeks at Week 4). For subjects whose anemia needs to be corrected (≥7.5 g/dL and <11.5 g/dL), the 
dose level will be maintained while the Hgb increase per 4 weeks is 0.5-2 g/dL, and the dose level will 
be increased by one step when the Hgb increase per 4 weeks is less than 0.5 g/dL. 
Starting dose and dose adjustments of control (epoetin beta pegol)
The starting dose and the dose adjustment algorithm for epoetin beta pegol are described in Section 
6.4..
The starting dose of epoetin beta pegol for subjects not using ESA or subjects on epoetin was selected 
based on the Prescribing Information in Japan. For subjects on darbepoetin alfa, darbepoetin alfa will 
be switched to epoetin beta pegol at a dose ratio of 6:5 according to overseas Prescribing Information, 
given no specification for dose conversion from darbepoetin currently approved in Japan to epoetin 
beta pegol. 


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The dose adjustment algorithm for epoetin beta pegol was determined based on the product 
information and previous Japanese clinical studies. In Cohort 3, a study visit at Week 2 for Hgb 
monitoring was also added for the control group. (Refer to Section 6.4.2.)
4.6.
Benefit: Risk Assessment
Summaries of findings from clinical and nonclinical studies of GSK1278863 can be found in the IB
and IB supplement. The risk assessment and risk minimization strategies for the present study are 
outlined in the following sections: 
4.6.1.
Risk Assessment
Based on the results of completed clinical and nonclinical studies of GSK1278863, the potential risks 
of clinical significance and the risk minimization strategies for the present study are outlined in 
Section 12.2. Appendix 2.
4.6.2.
Benefit Assessment 
Study PHI201753 is a Phase 3 study in Japanese ND and PD subjects with renal anemia. Previous
clinical studies of GSK1278863 administered for up to 24 weeks in ND or HD subjects have 
demonstrated clinical efficacy (increase in and/or maintenance of Hgb) with serum EPO 
concentrations increased within the normal physiologic range in CKD subjects. Data obtained in 
Study PHI201753 will generate safety and efficacy data in Japanese ND and PD subjects with renal 
anemia for a 52-week treatment period. Study participants who will receive GSK1278863 may benefit 
from the expected clinical efficacy. Participants who will receive the control (epoetin beta pegol 
approved for the treatment of renal anemia in Japan) are also expected to benefit from the clinical 
efficacy. 
GSK1278863 may have important advantages over existing ESAs. GSK1278863, which is orally 
administered and requires no cold chain management unlike ESAs, is more convenient to patients. 
GSK1278863 is shown to increase Hgb at lower EPO concentrations than ESAs. Since increased 
exposure to EPO following administration of ESAs may be associated with an increased 
cardiovascular risk [Szczech, 2008], GSK1278863 may increase Hgb without increasing the 
cardiovascular risk. 
4.6.3.
Overall Benefit: Risk Conclusion
GSK1278863 is shown to have a positive benefit-risk balance based on the following findings: in 
studies of GSK1278863 administered for up to 24 weeks, treatment with GSK1278863 resulted in 
achievement of target Hgb, and no adverse events have been identified as related to treatment with 
GSK1278863.
The present study is intended to evaluate the efficacy and safety of GSK1278863 administered for 52
weeks in Japanese ND and PD subjects with renal anemia, and designed to administer GSK1278863 
or epoetin beta pegol as control to all enrolled subjects; therefore, subjects randomized in either 
treatment group are expected to benefit from the treatment. 


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This protocol employs precautions to mitigate known and potential risks to enrolled subjects (Section 
12.2. Appendix 2). Given these precautions, as well as the potential benefit that GSK1278863 holds 
for the treatment of renal anemia compared with the current standard treatment, the overall benefit risk 
balance is considered to be positive.
5.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, and other 
pertinent information on the GSK investigational product or other study treatment that may impact 
subject eligibility is provided in the IB/IB supplement(s) and/or other pertinent documents.
Deviations from inclusion/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.
5.1.
Inclusion Criteria
Subjects eligible for enrolment in the study must meet all of the inclusion criteria.
Note: Verification at both provisional enrolment (screening) and official enrolment (Day 1) is required, 
unless otherwise specified.
1.
Age (at the time of informed consent): ≥20 years of age
2.
(Screening verification only) Stage of chronic kidney disease (CKD) (ND patients only): CKD 
stages 3, 4, and 5 defined by eGFR using the Japanese Society of Nephrology-Chronic Kidney 
Disease Initiatives (JSN-CKDI) formula
3.
Dialysis: 

Not on dialysis for at least 12 weeks prior to screening (ND patients)

On peritoneal dialysis (PD patients)
4.
Use of erythropoiesis-stimulating agent (ESA): 

ESA non-users: Have not used ESAs for at least 8 weeks prior to screening

ESA users: Have used the same ESA for at least 8 weeks prior to screening. However, in the 
ND patients, the dose of darbepoetin alfa or epoetin beta pegol must be stable (administered 
once every 4 weeks and up to one-step dose change during at least 8 weeks prior to 
screening). 
5.
Hemoglobin (Hgb): Determined at the site using an Hgb analyzer (HemoCue) 

ESA non-users: ≥8.0 g/dL and <11.0 g/dL

ESA users: ≥9.0 g/dL and ≤13.0 g/dL 
6.
Iron parameters: Ferritin >100 ng/mL or transferrin saturation (TSAT) >20% (screening 
verification only)
7.
Gender (screening verification only): Female or male
Females: Not pregnant [demonstrated to be negative for human chorionic gonadotropin (hCG) in 
urine or serum], not breast-feeding, and meet at least one of the following: 
1)
Females of non-childbearing potential are defined as follows: 

Pre-menopausal with at least one of the following and no plans to utilise assisted 
reproductive techniques (e.g., in vitro fertilisation or donor embryo transfer):


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
History of bilateral tubal ligation or salpingectomy

History of hysteroscopic tubal occlusion and postoperatively documented bilateral 
tubal obstruction 

History of hysterectomy

History of bilateral oophorectomy

Postmenopausal defined as 1) females 60 years of age or older or 2) In females < 60 years 
of age, 12 months of spontaneous amenorrhea [in questionable cases a blood sample with 
postmenopausal follicle stimulating hormone (FSH) and estradiol concentrations is 
confirmatory (see separately specified reference ranges)]. Females on hormone replacement 
therapy (HRT) whose menopausal status is in doubt will be required to use one of the most 
effective contraception methods 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 enrolment.
2)
Females of childbearing potential must agree to comply with one of the contraception 
methods listed as requirements in “GSK Listing of Most Effective Contraceptive Methods for 
Females of Childbearing Potential (Section 12.3. Appendix 3: Modified List of Highly Effective 
Methods for Avoiding Pregnancy in Females of reproductive potential)” from at least 28 days 
prior to the first dose of study medication until the completion of the follow-up visit (for subjects 
randomized to the GSK1278863 group) or 7 weeks after the last dose of study treatment (for 
subjects randomized to the Epoetin beta pegol group).
8.
Informed consent: Written informed consent, including adherence to the requirements and 
conditions specified in the consent form and the protocol, must be obtained from each subject as 
specified in Section 10.2..
5.2.
Exclusion Criteria
Subjects meeting any of the following criteria must not be enrolled in the study.
Note: Verification at both provisional enrolment (screening) and official enrolment (Day 1) is required, 
unless otherwise specified.
Chronic kidney disease (CKD)-related criteria 
1.
Dialysis

Cohort 1and Cohort 3: Start or plan to initiate dialysis during the study

Cohort 2: Plan to stop peritoneal dialysis or start hemodialysis during the study
2.
Kidney transplant: Planned living-related kidney transplant during the study
Anemia-related criteria
3.
Aplasia: History of bone-marrow hypoplasia or pure red cell aplasia
4.
Other causes of anemia: pernicious anemia, thalassemia, sickle cell anemia, or myelodysplastic
syndromes
5.
Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal 
ulcer disease OR clinically significant GI bleeding within 8 weeks prior to screening or during a 
period from screening to Day 1.


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Cardiovascular disease-related criteria
6.
Myocardial infarction, acute coronary syndrome, stroke, or transient ischemic attack: Diagnosed 
within 8 weeks prior to screening or during a period from screening to Day 1.
7.
Heart failure: Class IV heart failure, as defined by the New York Heart Association (NYHA) 
functional classification system
8.
QTc (screening verification only): QTc >500 msec or QTc >530 msec in subjects with bundle 
branch block 
Note: QT interval corrected using the Bazett’s formula (QTcB) will be used, and ECG can be 
mechanically or manually read. 
Other disease-related criteria
9.
Liver disease (if any of the following occurs): 

(Screening verification only): Alanine transaminase (ALT) >2×upper limit of normal (ULN)

(Screening verification only): Bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is 
acceptable if bilirubin is fractionated and direct bilirubin is <35%)

Current unstable active liver or biliary disease (generally defined by the onset of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, persistent 
jaundice, or cirrhosis)
Note: Stable liver disease (including asymptomatic gallstones, chronic hepatitis B/C, or 
Gilbert’s syndrome) is acceptable if the subject otherwise meets entry criteria.
10. Malignancy: History of malignancy within 2 years prior to screening, or currently receiving 
treatment for cancer, (PD patients only) complex renal cystic >3 cm (II F, III or IV based on the 
Bosniak classification)
Note (ND patients and PD patients): The only exception is squamous cell or basal cell carcinoma 
of the skin that has been definitively treated 8 weeks before screening.
11. In the opinion of the investigator, Hgb increase to the target range (11.0-13.0 g/dL) is medically 
risky.
Concomitant medication and other study treatment-related criteria
12. Iron: Planned use of intravenous iron during the screening phase or during a period from Day 1 
to Week 4
Note: Oral iron is acceptable. However, the same dose regimen must be used throughout the 
screening phase and from Day 1 to Week 4. Antihyperphosphatemic agents containing iron (e.g., 
ferric citrate hydrate) are also acceptable only if used for at least 12 weeks prior to screening. 
However, they must be continued throughout the screening phase and from Day 1 to Week 4. 
13. Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity 
to excipients in the investigational product [see the GSK1278863 IB (ND and PD patients) or 
epoetin beta pegol Prescribing Information (ND patients)]
14. Drugs and supplements: Use or planned use of any prescription or non-prescription drugs or 
dietary supplements that are prohibited during the study period (prohibited medications: strong 
inducers and inhibitor of CYP2C8, see Section 6.11.2.)
15. Prior investigational product exposure: Use of an investigational agent within 30 days or five half 
lives of the investigational agent (whichever is longer)


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16. Prior treatment with GSK1278863: Any prior treatment with GSK1278863 for a treatment 
duration of >30 days
General health-related criteria
17. Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding 
that the investigator (or subinvestigator) considers would put the subject at unacceptable risk, 
which may affect study compliance or prevent understanding of the aims or investigational 
procedures or possible consequences of the study
5.3.
Screening Failures
Screen failures are defined as subjects who consent to participate in the clinical trial and are screened, 
but are not subsequently randomized in the study. A minimum set of information is required from 
screen failure subjects including Demography, Screen Failure details, Eligibility Criteria, and SAEs in 
order to report screen failures in a reliable manner, satisfy the requirements for publication defined by 
the Consolidated Standards of Reporting Trials (CONSORT), and respond to requests of the 
regulatory authorities.
Subjects that fail screening are eligible to be rescreened up to 3 times as soon as the investigator (or 
subinvestigator) assesses they may meet study entry criteria. Re-screening subjects are allowed to use 
the results of the latest ophthalmology exam to replace the rescreening ophthalmology exam, at the 
discretion of the investigator (see Table 14).
5.4.
Withdrawal/Dropout Criteria
If subjects meet one of the following criteria, study treatment should be permanently discontinued and 
subjects will be withdrawn from the study. The withdrawal reason should be recorded.

Hgb <7.5 g/dL
Note: HemoCue Hgb values will be employed. If an initial Hgb value meets the Hgb stopping 
criteria, measurement will be repeated at the same study visit (using the same sample) to 
calculate the average. If the average meets the Hgb stopping criteria, study treatment will be 
discontinued.

Subject needs for maintenance dialysis or changes dialysis modality (PD subjects only) during 
the study period.

Kidney transplant

Subject becomes pregnant or intends to become pregnant during the study.

Diagnosis of new or recurrent cancer

Liver chemistry abnormalities exceeding the threshold criteria (see Section 5.4.1.)

Need for chronic (more than 14 days) use of prohibited medication

When the investigator (or subinvestigator) considers necessary to withdraw the subject from the 
study for other reasons
Subjects who meet any of the withdrawal criteria or are withdrawn for other reasons during the 
treatment phase should be assessed at withdrawal visit after study treatment is discontinued, and will 
then enter the follow-up phase. 


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Should a subject fail to attend a required study visit, the investigator (or subinvestigator) should take 
the following measures: 

The investigator (or subinvestigator) or designee should attempt to contact the subject and re-
schedule the missed visit as soon as possible.

The investigator (or subinvestigator) should counsel the subject on the importance of maintaining 
the assigned visit schedule and determine whether the subject is willing to continue his/her 
participation in the study and/or whether the subject should remain in the study. 

The investigator (or subinvestigator) or designee should make every effort to regain contact with 
a subject who is deemed “Lost to Follow-up”. All efforts to contact the subject should be 
documented in the subject’s clinical charts. 

Should the subject continue to be unreachable, then and only then will he/she be considered 
“Lost to Follow-up.”
A subject may withdraw from the study at any time at his/her own request. The investigator (or 
subinvestigator) may withdraw a subject from the study at any time for safety or compliance reasons 
or study conduct considerations. If a subject withdraws from the study, he/she may request destruction 
of any clinical samples taken, and the investigator (or subinvestigator) must document this in the site 
study records.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure subject 
safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety 
guidance).


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Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Chemistry Increased Monitoring Algorithm with Continued Therapy for ALT 3xULN 
but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in Section 12.5. 
Appendix 5


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5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by any subject 
participating in this study is not allowed.
5.5.
Subject and Study Completion
A completed subject is one who has completed all periods of the study including the follow-up visit.
The study will be completed with the last subject’s last study visit. 
6.
STUDY TREATMENTS
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any products received by the 
subject as per the protocol design. Accordingly, ‘study treatment’ sometimes refers to each product 
and sometimes refers to multiple products. 
GSK1278863 (study drug)
The study drug GSK1278863 will be supplied as fast-release film coated tablets for oral 
administration containing 1 mg, 2 mg, 4 mg, or 6 mg of GSK1278863 (Table 3). There are two sizes 
of GSK1278863 tablets.
Table 3   Description of GSK1278863 Tablets
GSK1278863 tablets of 
specific content
Description
1 mg tablets, 2 mg tablets, 
4 mg tablets
7.0 mm round, standard biconvex, white film coated tablets containing 
1 mg, 2 mg, or 4 mg of GSK1278863 as active ingredient
6 mg tablets
9.0 mm round, standard biconvex, white film coated tablets containing 
6 mg of GSK1278863 as active ingredient
GSK1278863 tablets of specific content are packed in high density polyethylene (HDPE) bottles, with 
35 tablets per bottle. Subjects are to take one to four tablets (Table 4) with water once daily according 
to the dose level indicated at each study visit. Subjects can take GSK1278863 tablets without regard to 
food or peritoneal dialysis. The administration schedule (starting dose and dose adjustment) described 
in Section 6.4.1. should be followed. 
Table 4    Dose Levels of GSK1278863 and Number of Tablets Taken
Dose level of 
GSK1278863
(once daily)
1 mg
2 mg
4 mg
6 mg
8 mg
12 mg
18 mg
24 mg
Number of 
GSK1278863
tablets taken
1 mg 
tablet
×1
2 mg 
tablet
×1
4 mg 
tablet
×1
6 mg 
tablet
×1
4 mg 
tablet
×2
6 mg 
tablet
×2
6 mg 
tablet
×3
6 mg 
tablet
×4
Subjects should be instructed to bring GSK1278863 tablets with bottles at each study visit, and all 
unused GSK1278863 tablets will be collected from subjects at each study visit.


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Epoetin beta pegol (control)
The control epoetin beta pegol (brand name: MirceraPre-filled Syringe) will be supplied by GSK. 
This product is an injectable formulation containing 25 g, 50 g, 75 g, 100 g, 150 g, 200 g, or 
250 g of epoetin beta pegol per syringe (0.3 mL) and is supplied as a glass syringe prefilled with 
epoetin beta pegol solution (clear colorless to pale yellow). 
Subjects are to receive epoetin beta pegol subcutaneously once every 2 or 4 weeks at the site (Table 5). 
The administration schedule (starting dose and dose adjustment) described in Section 6.4.2. should be 
followed. 
Table 5    Dose Levels of Epoetin Beta Pegol and Number of Subcutaneous Doses
Dose level of epoetin beta 
pegol
(once every 2 or 4 weeks)
25 g
50 g
75 g
100 g
150 g
200 g
250 g
Number of subcutaneous 
doses of epoetin beta pegol
25 g 
injection
×1
50 g 
injection
×1
75 g
injection
×1
100 g 
injection
×1
150 g 
injection
×1
200 g 
injection
×1
250 g 
injection
×1
6.2.
Medical Devices
The Epoetin beta pegol (Brand name :MIRCERA® Injection Syringe) marketed with the device (kit 
formulation which was filled liquid medication in glass syringe ) provided for use in this study.
Instructions for medical device are described in the Prescribing Infromation of MIRCERA® Injection 
Syringe.
The medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study – see Section 7.4.4.
6.3.
Treatment Assignment
The randomization schedule will be generated by GlaxoSmithKline (GSK) using the randomization 
system (Randall).
In Cohort 1 and Cohort 3 (ND subjects), subjects will be stratified by the current ESA therapy (ESA 
non-user or ESA user) and the Hgb level on Day 1 and randomized in a 1:1 ratio to one of the two 
treatment groups according to the randomization schedule. Randomization should precede the study 
treatment. 

GSK1278863 group

Epoetin beta pegol group
In Cohort 2 (PD subjects), all eligible subjects will start treatment with GSK1278863 on Day 1. 
Subjects will be assigned a randomization number by the Interactive Web Recognition System 
(IWRS). Once a randomization number has been assigned, it must not be re-assigned. Further details 
are provided in the Study Reference Manual (SRM).


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6.4.
Administration Schedule (Starting Dose, Dose Adjustment, and Dosing 
Frequency)
6.4.1.
GSK1278863 (ND and PD Subjects)
6.4.1.1.
Starting Dose
For ND subjects randmized to GSK1278863 group
(Cohort 1)
Both ESA non-users and users will start oral treatment with GSK1278863 at the starting dose of 4 
mg once daily (Day 1) and remain on the same regimen until the day of Week 4.
(Cohort 3)

ESA non-users

Baseline Hgb 8.0 g/dL and <9.0 g/dL: the subjects will start oral treatment with 
GSK1278863 at the starting dose of 4 mg once daily (Day 1) and remain on the same 
regimen until the day of Week 4*.

Baseline Hgb 9.0 g/dL and <11.0 g/dL: the subjects will start oral treatment with 
GSK1278863 at the starting dose of 2 mg once daily (Day 1) and remain on the same 
regimen until the day of Week 4*.

ESA users will start oral treatment with GSK1278863 at the starting dose of 4 mg once daily
(Day 1) and remain on the same regimen until the day of Week 4*.
*: The HemoCue Hgb value will be measured for safety confirmation at Week 2 in ND subjects. 
When Hgb > 1.0 g/dL increase over 2 weeks, the dose of GSK1278863 is decreased to the next lower 
dose.
For PD subjects randomized to the GSK1278863 group (Cohort 2)

ESA non-users will start oral treatment with GSK1278863 at the starting dose of 4 mg once daily 
(Day 1) and remain on the same regimen until the day of Week 4. 

ESA users will start oral treatment with GSK1278863 at the starting dose of 4 mg once daily 
(Day 1) and remain on the same regimen until the day of Week 4.
ESA users should skip ESA on Day 1 when treatment with GSK1278863 is started. 
6.4.1.2.
Maintenance Dose
From Weeks 4 to 52, interruption of treatment or dose adjustments will be made within the 
maintenance dose range of 1-24 mg (Table 6) according to the dose adjustment algorithm (Table 7) to 
achieve and/or maintain Hgb within the target range (11.0-13.0 g/dL) based on the HemoCue Hgb 
value measured every 4 weeks. Dose changes will be made every 4 weeks. If any of the one-step dose 
reduction criteria is met during treatment at the minimum maintenance dose (1 mg), treatment should 
be interrupted; once the one-step dose increase criteria are met, treatment at 1 mg will be resumed. If 
the one-step dose increase criterion is met during treatment at the maximum maintenance dose 
(24 mg), treatment at 24 mg should be continued. 


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Table 6    Maintenance Dose of GSK1278863
Dose step
1
2
3
4
5
6
7
8
Dose level of 
GSK1278863
(once daily)
1 mg
2 mg
4 mg
6 mg
8 mg
12 mg
18 mg
24 mg
Number of 
GSK1278863
tablets taken
1 mg 
tablet
×1
2 mg 
tablet
×1
4 mg 
tablet
×1
6 mg 
tablet
×1
4 mg 
tablet
×2
6 mg 
tablet
×2
6 mg 
tablet
×3
6 mg 
tablet
×4
Table 7   Dose Adjustment Algorithm (GSK1278863)
Hgb
(g/dL)
Hgb increase over 4 weeks 
(g/dL)
Treatment
>13.0
NA
Interrupt treatment until Hgb decreases to less than 
12.5 g/dL
Resume treatment at the one lower dose level (If 
interrupted at 1 mg: resume treatment at 1 mg once 
the one-step dose increase criteria are met)
12.5-13.0
NA
One-step dose reduction
11.5-<12.5
>2.01)
One-step dose reduction
2.0
Continue treatment at the current dose level
7.5-<11.5
>2.01)
One-step dose reduction
0.5-2.0
Continue treatment at the current dose level
<0.5
One-step dose increase
<7.5
NA
Discontinue treatment permanently 2) and initiate 
another appropriate treatment
1) Cohort 3 only: At Week 4, if an Hgb increase of >1.0 g/dL over 2 weeks is observed, the dose of GSK1278863 will 
be reduced by one step; if an Hgb increase of 1.0 g/dL over 2 weeks is observed, treatment will be continued as 
specified in the dose adjustment algorithm other than one-step dose reduction for an Hgb increase of >2.0 g/dL over 4
weeks.
2): If an initial Hgb value is less than 7.5 g/dL, measurement will be repeated at the same study visit (using the same 
sample) to calculate the average. If the average meets the Hgb stopping criteria, study treatment will be permanently
discontinued.
6.4.2.
Epoetin Beta Pegol (ND Subjects Only)
For ND subjects (Cohort 1 and Cohort 3) randomized to the epoetin beta pegol group, ESA non-users 
and users will receive epoetin beta pegol subcutaneously according to the treatment regimens 
described below.
6.4.2.1.
Starting Dose for ESA Non-users
ESA non-users will start subcutaneous treatment with epoetin beta pegol at a dose of 25 μg once every 
2 weeks (Day 1). Dose adjustments will be made within the initial dose range of 25-150 μg (Table 8)
according to the dose adjustment criteria (Table 9) to increase Hgb to 11.0 g/dL (lower limit of the 
target) or more based on the HemoCue Hgb value measured every 4 weeks. Dose changes will be 
made every 4 weeks. If any of the dose reduction criteria shown in Table 9 is met during treatment 
with epoetin beta pegol at 25 μg, treatment should be interrupted; once the dose reduction criteria are
not met any longer, treatment will be resumed at a dose of 25 μg. 


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At Week 2, HemoCue Hgb value will be measured for subjects' safety confirmation. If the 
measurement shows an Hgb increase of >1.0 g/dL over 2 weeks, the dose of epoetin beta pegol will be 
reduced by one step (or treatment interrupted) (Cohort 3 only).
Table 8    Initial Dose of Epoetin Beta Pegol (ESA Non-users)
Dose step
1
2
3
4
5
Dose level of epoetin beta pegol
(once every 2 weeks)
25 μg
50 μg
75 μg
100 μg
150 μg
Table 9    Initial Dose Adjustment Criteria for Epoetin Beta Pego (ESA Non-users)
Hgb
Treatment
Hgb increase <1.0 g/dL over past 4 weeks, 
OR Hgb <10.0 g/dL and Hgb increase ≤2.0 g/dL over past 4 weeks
One-step dose increase
Hgb increase >2.0 g/dL over past 4 weeks1)
One-step dose reduction
Otherwise
Continue treatment at the 
current dose level
1) Cohort 3 only: Hgb increase of >1.0 g/dL over past 2 weeks at Week 2.
Once Hgb increases to 11.0 g/dL or more, dose adjustments will be made according to the 
prespecified dose adjustment algorithm (Table 13). The dosing interval should be changed from once 
every 2 weeks to once every 4 weeks with dose conversion for dosing interval change (Table 10) after 
it is confirmed that all of the following criteria are met:

Hgb in the target range (11.0-13.0 g/dL)

Hgb change ≤2.0 g/dL over past 4 weeks

Equivalent dose will be given twice (at least 4 weeks)
Table 10    Dose Conversion of Epoetin Beta Pegol for Dosing Interval Change (ESA 
Non-users)
Initial dose of epoetin beta pegol
(given once every 2 weeks)
Dose conversion of epoetin beta pegol
(given once every 4 weeks)
25 μg
→
50 μg
50 μg
→
100 μg
75 μg
→
150 μg
100 μg
→
200 μg
150 μg
→
250 μg
6.4.2.2.
Dose Conversion for ESA Users
For ESA users, prior ESA will be replaced with epoetin beta pegol at the equivalent dose once every 4 
weeks (Day 1). 
At Week 2, HemoCue Hgb value will be measured for subjects' safety confirmation. If the 
measurement shows an Hgb increase of >1.0 g/dL over 2 weeks, the dose of GSK1278863 will be 
reduced by one step (or treatment interrupted) at Week 4 (Cohort 3 only).


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Table 11    Replacement with Epoetin Beta Pegol-Initial Dose (ESA Users)
Prior ESA
Epoetin beta pegol
Epoetin
<4500 IU per week
100 g once every 4 weeks
4500 IU per week
150 g once every 4 weeks
Darbepoetin alfa
30 g once every 4 weeks *
25 g once every 4 weeks
60 g once every 4 weeks *
50 g once every 4 weeks
90 g once every 4 weeks *
75 g once every 4 weeks
120 g once every 4 weeks *
100 g once every 4 weeks
180 g once every 4 weeks *
150 g once every 4 weeks
Epoetin beta pegol
25, 50, 75, 100, 150, 200, 250 g
once every 4 weeks *
25, 50, 75, 100, 150, 200, 250 g
once every 4 weeks
*: Allowance of ±1 week
Maintenance treatment will be started at Week 4 as described in Section 6.4.2.3. 
6.4.2.3.
Maintenance Dose (ESA Non-users and Users)
Epoetin beta pegol will be administered once every 4 weeks from dosing interval change (once every 
4 weeks) with Hgb ≥11.0 g/dL to Week 52 in ESA non-users and from Weeks 4 to 52 in ESA users. 
Interruption of treatment or dose adjustments will be made within the maintenance dose range of 25-
250 μg (Table 12) according to the dose adjustment algorithm (Table 13) to achieve and/or maintain 
Hgb within the target range (11.0-13.0 g/dL) based on the HemoCue Hgb value measured every 4 
weeks. If any of the one-step dose reduction criteria is met during treatment at the minimum 
maintenance dose (25 μg), treatment should be interrupted; once the one-step dose reduction criteria 
are not met any longer, treatment at 25 μg will be resumed. If the one-step dose increase criterion is 
met during treatment at the maximum maintenance dose (250 μg), treatment at 250 μg should be 
continued.
Table 12    Maintenance Dose of Epoetin Beta Pegol
Dose step
1
2
3
4
5
6
7
Epoetin beta pegol
(once every 4 weeks)
25 g
50 g
75 g
100 g
150 g
200 g
250 g


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Table 13  Dose Adjustment Algorithm (Epoetin Beta Pegol)
Hgb
(g/dL)
Hgb increase over 4 weeks 
(g/dL)
Treatment
>13.0
NA
Interrupt treatment until Hgb decreases to less than 
12.5 g/dL
Resume treatment at the one lower dose level 
(resume treatment at 25 g if interrupted at 25 g)
12.5-13.0
NA
One-step dose reduction
11.5-<12.5
>2.0
One-step dose reduction
2.0
Continue treatment at the current dose level
7.5-<11.5
>2.0
One-step dose reduction
1.0-2.0
Continue treatment at the current dose level
<1.0
One-step dose increase
<7.5
NA
Discontinue treatment permanently * and initiate 
another appropriate treatment
*: If an initial Hgb value is less than 7.5 g/dL, measurement will be repeated at the same study visit (using the same 
sample) to calculate the average. If the average meets the Hgb stopping criteria, study treatment will be permanently 
discontinued.
6.5.
Blinding
This is an open-label study. 
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory requirements.
6.7.
Preparation/Handling/Storage/Accountability

No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study medications must be stored in a secure 
environmentally controlled and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator (or subinvestigator) and 
authorized site staff.

Subjects must bring all of supplied study medication bottles of GSK127886 at each study visit. 
Study staff will collect all of study medication bottles supplied at the previous study visit and 
supply new study medication bottles. 

The investigator (or subinvestigator), institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records). 

Under normal conditions of handling and administration, study medication is not expected to 
pose significant safety risks to site staff. GSK will provide a document describing occupational 
hazards and recommended handling precautions either to the investigator (or subinvestigator) 
when necessary or upon request of the medical institution. 

Further details are provided in the SRM. 


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6.8.
Compliance with Study Treatment Administration
GSK1278863
Since GSK1278863 is self-administered, compliance with GSK1278863 treatment will be assessed 
through an interview with subjects at each study visit and recorded in the source document and eCRF. 
A record of the number of GSK1278863 tablets dispensed to and taken by each subject will be 
maintained and reconciled with study treatment and compliance records. In addition, the number of 
GSK1278863 doses dispensed, used, and unused, as well as study treatment start and stop dates will 
be recorded in the eCRF (the number of doses returned and unreturned will also be recorded 
separately).
Epoetin beta pegol
Epoetin beta pegol will be subcutaneously administered to subjects at the site. Dosing details will be 
recorded in the source document and eCRF. 
6.9.
Treatment of Study Treatment Overdose
There is no specific antidote for overdose with GSK1278863. 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 hemodialysis or peritoneal dialysis 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 a suspected overdose, 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 cardiovascular events, increased heart rate and hematologic abnormalities.
Consult the respective approved Prescribing Information for information on overdose for epoetin beta 
pegol.
6.10.
Treatment after the End of the Study
Since the target disease studied is not life-threatening or severely debilitating and there is the 
alternative therapy, subjects will not receive any additional treatment from GSK after completion of 
the study. Regardless of whether the sponsor provides specific treatments at the completion of the 
study, the investigator (or subinvestigator) is responsible for ensuring that consideration has been 
given to post-study care of the subject’s medical condition. 
6.11.
Concomitant Medications and Non-Drug Therapies
Concomitant medications, including over-the-counter medications and supplements, taken during the 
study will be recorded in the eCRF. Drug names and start/stop dates will be recorded for general 
concomitant medications, while additional details, including dose, route of administration, and dosing 
frequency, will be recorded for certain medications (e.g., ESAs, iron, anti-hypertensive medications).
Further details are provided in the SRM.
6.11.1.
Permitted Medications and Non-Drug Therapies
Unless specified as a prohibited medication in Section 6.11.2., all concomitant medications should be 
considered permitted provided they are not contraindicated for the individual subject concerned.


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Regular multivitamins (at recommended daily allowance) and other supplements such as calcium and 
vitamin D may be used if permitted by the investigator or his/her designee. 
CYP2C8 is involved in the primary route of metabolism of GSK1278863. Accordingly, co-
administration of GSK1278863 with moderate CYP2C8 inhibitors (e.g., clopidogrel, teriflunomide, 
deferasirox) should be performed with caution. If one of these medications is started, stopped or the 
dose is changed, Hgb should be monitored every 4 weeks for 12 weeks using a point-of-care Hgb 
analyzer. 
Antihyperphosphatemic agents containing iron (e.g., ferric citrate hydrate) may be started from 
Week 4 onwards unless any other antihyperphosphatemic agents are appropriate. Once started, iron-
containing antihyperphosphatemic agents must be continued until the end of the study wherever 
possible. 
6.11.2.
Prohibited Medications and Non-Drug Therapies
Use of any of the following drugs from screening until 7 days after the last dose of study treatment is 
prohibited:

Strong inhibitors of CYP2C8 (e.g., gemfibrozil)

Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)
Use of the following drug from 8 weeks prior to screening until the last dose of study treatment in 
ESA non-users and during study treatment in ESA user is prohibited.

Erythropoietin (e.g., epoetin/darbepoetin alfa/ epoetin beta pegol)
Note: excluding epoetin beta pegol (brand name: Mircera® Injection Syringe) supplied by GSK.
6.12.
Supplemental Iron Therapy
Supplemental iron therapy will be administered according to the Guidelines for Renal Anemia [The 
Japanese Society for Dialysis Therapy, 2008] if ferritin is ≤100 ng/mL and TSAT is ≤20%. The 
investigator (or subinvestigator) can choose the route of administration and dose of prescription iron. 
7.
Study Assessments and Procedures
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the Time and 
Events Table, are essential and required for study conduct.
7.1.
Time and Events Table
The time and events tables for the entire study and PK assessment are presented as Table 14 and Table 
15, respectively. To allow scheduling flexibility, study visits may occur within a window of ±7 days
on Day 1 scheduled 4 weeks after screening, within a window of ±3 days at Week 2 (Cohort 3 only)
and Week 4, and within a window of ±5 days for the rest of the study. However, subjects receiving the 
control epoetin beta pegol every 2 weeks should attend study visits, including those only for study 
treatment, within a window of ±3 days. Visit days are counted from Day 1.


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Table 14    Time and Events Table
Phase
Screening9
Treatment
Follow-up
Week
-4
Day 1
210
4
8
12
16
20
24
28
32
36
40
44
48
52
Early 
withdr
awal11
4 weeks 
after 52 or 
withdrawal
Permissible range (days)
±7
-
±3
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
-
±7
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history, demography, 
height, weight
X
Registration with IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study medication dispensing 1,2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study treatment compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
Ophthalmology 3
ECG
X
X
X
HemoCue Hgb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Urinalysis (ND subjects only)
X
X
X
X
X
Pregnancy test (urine or serum 
hCG) 4
X
X
X
X
X
X
X
X
X
Estradiol, FSH 5
X
PK 6
X
X
Ferritin, TSAT
X
X
X
X
X
X
X
X
Serum iron, TIBC, UIBC, serum 
transferrin, hepcidin
X
X
X
X
X
X
X
iPTH
X
X
X
HR-QoL
X
X
X
X
X
Genetics sample 7
X
Adverse event assessment 8
Review Concomitant Medications
1.
In Cohort 1 and Cohort 3, ESA non-users randomized to the epoetin beta pegol group will start treatment with epoetin beta pegol at a dose of 25 μg once every 2 weeks. For these subjects, specified 
examinations will be performed at Week 2 (Cohort 3 only) and every 4 weeks after Week 4, and no study-related assessments will be necessary at study visits only for study treatment [e.g., Week 2 
(Cohort 1 only), Week 6, Week 10) (see Section 6.4.2). It should be noted that subjects receiving epoetin beta pegol once every 2 weeks should attend study visits within a window of ±3 days.
2.
If a subject visit the study site only to receive study medication, only registration with the IWRS, study medication dispensing, and study medication compliance will be required. 
3.
Ophthalmology exams should be conducted at the following time points.


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
Screening: anytime after consenting and prior to first dose of study medication (Day 1)

Week 12: window from weeks 10-14 (inclusive)

End of study: window from weeks 48-52 (inclusive)

Early study medication discontinuation: withdrawal eye exam as close to the last dose as possible (the repeat exams are not required if one has been performed within the 2 prior weeks).
4.
Performed in females of childbearing potential: serum pregnancy test will be performed if urine pregnancy test is not feasible.
5.
Measured in female subjects only to determine the menopausal status (see Section 5.1.)
6.
See Table 15.
7.
Informed consent for optional Genetic research should be obtained before collecting a sample (see Section 7.6.).
8.
See Section 7.4.1.1..
9.
Re-screening subjects who meet all the following conditions are allowed to use the results of the latest ophthalmonogy exam and not required to undergo the rescreening ophthalmonogy exam, at the 
discretion of the investigator. 
   •
Subjects had no findings that deem re-exams within 3 months at the latest screening ophthalmology exam. 
   •
Subjects had no new eye-related symptoms or complaints until the rescreening following the latest screening ophthalmology exam. 
   •
The latest screening ophthalmology exam was performed within 3 months prior to Day 1 scheduled at the rescreening. 
10.
All ND subjects randomized to Cohort 3 will undergo assessment scheduled for Week 2 visit.
11.
For withdrawn subjects, specified assessments should be done wherever possible. 


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Table 15    Blood Sampling Schedule for Pharmacokinetics (Only Subjects in 
GSK1278863 Group)
PK sample
Week 12 2
Week 24 2
Blood sampling timing 1
1, 2, 3, and 4 h after administration of GSK1278863
Subjects must take the study medication with regard to blood sampling time. Subjects will record the date and time of the last two 
study medication doses taken prior to blood sampling in the medication diary. Preferably, there should be an interval of at least 12 h 
between these two doses. 
1.
Blood sampling should be completed within +/- 30 min of the planned collected time.
2.
Blood sampling not performed at this visit may be postponed until the following visits. 
7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors will be assessed (documented in the eCRF) at baseline.
In addition, the following demographic information will be collected:

Year of birth

Gender

Race and ethnic

Medical history/treatment history/family history will be assessed in relation to the 
inclusion/exclusion criteria (Section 5.). 
Full details of baseline assessments are provided in Table 14.
7.3.
Efficacy
Efficacy will be assessed according to the Time and Event Table (Table 14). 
Hgb concentrations measured by the central laboratory will be mainly used for efficacy assessment 
(see Section 7.4.7.). 
GSK will supply a point-of-care Hgb analyzer (HemoCue) to each site for rapid and convenient 
measurement of Hgb and to ensure consistency of Hgb measurements across all sites participating in 
the study. Assessment for Hgb concentrations via HemoCue will be used for eligibility (Section 5.1.), 
withdrawal (Section 5.4.), and dose adjustment criteria (Section 6.4.). 
In addition, assessments of iron metabolism parameters and measures of CKD progression (e.g., 
eGFR) used for efficacy assessment are outlined with specific procedures in Section 7.4.7..
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table (Table 14).  
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.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 12.6. Appendix 6.
The investigator and their designees are responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE.


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7.4.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-up contact 
(see Section 7.4.1.3.), at the timepoints specified in the Time and Events Table (Table 14).

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 section of the CRF.

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 hours, as indicated in Section 12.6.
Appendix 6.

Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 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 must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs plus procedures 
for completing and transmitting SAE reports to GSK are provided in Section 12.6. Appendix 6.
7.4.1.2.
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?”
7.4.1.3.
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 SAEs, and non-serious AEs of special interest (as defined in Section
7.4.2.) will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up (as defined in Section 5.4.). Further information on 
follow-up procedures is given in Section 12.6. Appendix 6..
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 12.6. Appendix 6 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be required to 
be completed.  These sections include questions regarding cardiovascular (including sudden cardiac 
death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA terms.  The 
CV information should be recorded in the specific cardiovascular section of the CRF within one week 
of receipt of a CV Event data query prompting its completion.  


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The Death CRF is provided immediately after the occurrence or outcome of death is reported. Initial 
and follow-up reports regarding death must be completed within one week of when the death is 
reported.
7.4.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to study 
treatment (even for non- interventional post-marketing studies) is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects and the safety of a product under clinical 
investigation 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 the regulatory authority, Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) 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 a 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.
7.4.2.
Adverse Events of Special Interest
The investigator (or subinvestigator) or designee will be responsible for detecting, documenting, and 
reporting any AEs of special interest listed below. These events have been identified based on the 
known safety profiles of ESAs, theoretical or potential risks based on the mechanism of action of 
GSK1278863, and findings from completed nonclinical studies of GSK1278863. 

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 

Death, myocardial infarction, stroke, congestive heart failure, venous thromboembolism, 
thrombosis of vascular access

Cardiomyopathy  

Pulmonary artery hypertension

Cancer-related mortality and tumor progression and recurrence 

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization 

Exacerbation of rheumatoid arthritis
Any relevant AE should be recorded in the relevant section of the subject’s eCRF.
7.4.3.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of dosing and until 
the follow-up contact.


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
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of learning of 
the pregnancy and should follow the procedures outlined in Section 12.4.. Appendix 4.
Note: Subjects randomized in the epoetin beta pegol group should be advised to inform the 
investigator if they discover pregnancy in 7 weeks after the last dose of study treatment.
7.4.4.
Medical Device Incidents (Including Malfunctions)
The medical devices are being provided for use in this study. The investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction that occur 
during the study with such devices. 
The definition of a Medical Device Incident can be found in Appendix 8 (Section 12.8.)
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes outlined in 
Section 7.4.1. and Appendix 6 (Section 12.6.) of the Protocol.
7.4.4.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident will be detected, 
documented and reported during all periods of the study in which the medical devices are 
available for use. 

If the investigator learns of any incident at any time after a subject has been discharged from the 
study, and such incident is reasonably related to a medical device provided for the study, the 
investigator will promptly notify GSK.
NOTE: The method of documenting Medical Device Incidents is provided in Appendix 8 (Section 
12.8.).
7.4.4.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE, will be followed until resolution of the event, until 
the condition stabilizes, until the condition is otherwise explained, or until the subject is lost to 
follow-up (as defined in Section 5.4.). This applies to all subjects, including those withdrawn 
prematurely. 

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as practical the nature and/or 
causality of the incident.

New or updated information will be recorded on the originally completed form ”Medical Device 
Incident Report Form” with all changes signed and dated by the investigator.
7.4.4.3.
Prompt Reporting of Medical Device Incidents to GSK

Medical device incidents will be reported to GSK within 24 hours once the investigator 
determines that the event meets the protocol definition of a medical device incident.

Facsimile transmission of the "Medical Device Incident Report Form" is the preferred method to 
transmit this information to the SAE contact information.

The same individual will be the contact for receipt of medical device reports and SAEs.

In the absence of facsimile equipment, notification by telephone is acceptable for incidents, with 
a copy of the "Medical Device Incident Report Form" sent by overnight mail.


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7.4.4.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator, or responsible person will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.
7.4.5.
Vital Signs/Height/Weight
Systolic and diastolic blood pressure and pulse rate will be measured in sitting or semi-supine position 
after at least 5 minutes rest prior to clinical examination at each visit blood pressure and pulse rate. 
One reading of blood pressure and pulse rate will be taken and recorded in the source document and 
the CRF. Height and weight will be measured at screening visit only.
7.4.6.
Electrocardiogram (ECG)
12-lead ECGs will be recorded in supine position. The heart rate, PR, QRS, and QT (pre-corrected)
intervals will be measured. QTcB should be calculated by machine or manually by designated staff at 
each site. The investigator determines whether the ECG data is assessable or not.
At screening, visit when an ECG is performed, two additional ECGs are required if initial ECG 
indicates prolonged QTc using the automated or manually calculated QTcB value. The average QTcB 
value of all three ECGs will be used to determine eligibility.
QTc exclusion criteria can be found in Section 5.2. Refer to SRM for further details.
7.4.7.
Clinical Laboratory Assessments
All study-required laboratory assessments will be performed by a central laboratory with the exception 
of HemoCue Hgb. The results of each HemoCue Hgb must be entered into the subject’s eCRF. Details 
are provided in the SRM. 
All laboratory assessments, as defined in Table 16, must be conducted in accordance with the 
Laboratory Manual and Protocol Time and Events Schedule. Laboratory requisition forms must be 
completed and samples must be clearly labeled with the subject number, protocol number, site/center 
number, and visit date. Details for the preparation and shipment of samples will be provided by the 
central laboratory. Reference ranges for all parameters will be provided to the site by the central 
laboratory. Details of blood sampling (including the volume of blood to be collected) as well as 
procedures for processing, storage, and shipment of samples are provided in the SRM. 
PK assessment of GSK1278863 is outlined in Section 7.5.


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Table 16    Laboratory Assessments
Laboratory 
assessment
Parameter
Hematology
Leukocyte count
RBC indices:
WBC count with Differential
Platelet count
MCV
Neutrophils
RBC count
MCH
Lymphocytes
Reticulocyte count
MCHC
Monocytes
Hemoglobin
RDW
Eosinophils
Hematocrit
Basophils
Clinical chemistry
Sodium
AST
Bicarbonate
Potassium
ALT
Inorganic phosphate
Chloride
Creatinine
Glucose
Calcium (total and albumin-
corrected)
Total bilirubin
Direct/indirect bilirubin 
Albumin
Urea nitrogen
Total cholesterol
HDL cholesterol
LDL cholesterol
Iron parameters
Serum iron
Serum ferritin
Serum transferrin
TIBC
UIBC
TSAT
Hepcidin
Urinalysis
(ND subjects only) Urine albumin
Urine creatinine
Urine albumin/creatinine ratio
Other laboratory 
tests
FSH 1
Estradiol 1
iPTH
eGFR 2
hCG (serum or urine) 3
1.
Measured in female subjects only to determine the menopausal status (see Section 5.1.) 
2.
Calculated from serum creatinine using the Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-CKDI) 
formula
3.
Performed in females of childbearing potential: serum pregnancy test will be performed if urine pregnancy test is not feasible. 
If additional non-protocol specified laboratory assessments are performed at the institution’s local 
laboratory and result in a change in subject management or are considered clinically significant by the 
investigator (or subinvestigator) (e.g., SAE or AE or dose modification), the results must be recorded 
in the eCRF.
Refer to the SPM for appropriate processing and handling of samples to avoid duplicate and/or 
additional blood draws.
All laboratory tests with values that are considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline. If such 
values do not return to normal within a period judged reasonable by the investigator (or 
subinvestigator), the etiology should be identified and the Sponsor notified.
7.4.8.
Ophthalmology
Ophthalmology exams will be performed by a study-designated ophthalmology specialist. Each 
assessment will include a comprehensive eye exam with at least the following components: 
measurement of best corrected visual acuity, intraocular pressure, an anterior aqueous chamber exam, 
and a fundoscopic exam. These exams will be used for assessment of ocular adverse events. 
Assessment results will be captured on worksheets which will be transferred to the eCRF. Additional 
details on the process for completing these assessments are provided in the SRM.


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7.5.
Pharmacokinetics
Blood samples for PK analysis of GSK1278863 will be collected from only subjects in the 
GSK1278863 group as outlined in Table 15, and the date and time of the last two study medication 
doses taken prior to blood sampling as well as the date and time of sampling must be recorded in the 
eCRF.
Blood PK analysis will be performed under the control of GSK Platform Technologies and Science-
Drug Metabolism and Pharmacokinetics (PTS-DMPK)/Scinovo and GSK-Japan Bioanalysis, the 
details of which will be included in the SPM. Concentrations of parent GSK1278863 will be 
determined in blood samples using the currently approved analytical methodology. Raw data will be 
archived at the bioanalytical site.
Procedures for processing, storage, and shipment of samples are provided in the SRM. 
7.6.
Genetics
A blood sample will be collected for genetic analysis from consenting subjects. This sample can be 
collected on Day 1 once written informed consent has been obtained. Information regarding genetic 
research is included in Section 12.7. Appendix 7.
7.7.
Patient Reported Outcome (PRO)
The patient reported outcome (PRO) [e.g., symptoms, severity, health-related QOL (HR-QoL), health 
status] will be assessed using several rating scales. 
All questionnaires used in this study have been translated into Japanese and validated. 
Specific instructions on how the subject is to complete the scales and the process for data entry are 
provided in the SPM.
7.7.1.
SF-36
The SF-36 acute version is a general health status questionnaire designed to elucidate the patient’s 
perception of his/her health on several domains, including physical functioning, role physical, bodily 
pain, vitality, social functioning, role emotional, mental health, and general health over the past seven 
days. The questionnaire contains 36 Likert type questions that ask the patient to recall how he/she felt 
during the past seven days.
7.7.2.
EuroQol Health Utility Index (EQ-5D-5L)/EQ Visual Analogue Scale (EQ-VAS)
The EQ-5D-5L is intended to measure the general health status and health utility. The EQ-5D-5L 
consists of 2 concepts: self-reported health status consisting of five dimensions (mobility, self-care, 
usual activities, pain/discomfort, anxiety/depression) each of which can take one of five responses and 
self-rated health status on a visual analog scale (VAS), a thermometer-like line. 


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8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted electronically to 
GSK or designee 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.  

CRFs (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.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
A detailed description of any planned analyses will be documented in a RAP..Any deviations from the 
analyses described in the protocol will be documented in the RAP or the final study report. 
9.1.
Hypotheses
The primary objective of the study is to demonstrate the non-inferiority of GSK1278863 to epoetin 
beta pegol based on mean Hgb during the primary efficacy evaluation period (Weeks 40 to 52) in ND 
subjects, including Cohort 1 subjects (only ESA users) and Cohort 3 subjects (both ESA users and 
ESA non-users).
As a preliminary assessment, it will be confirmed whether the mean Hgb during the primary efficacy 
evaluation period in GSK1278863 group would be in target range (11.0-13.0 g/dL) at first. And then 
the following non-inferiority statistical hypotheses are to be tested at a one-sided significance level of 
2.5% (i.e. two-sided significance level of 5%):

H0: Treatment difference in mean Hgb during the primary efficacy evaluation period is -1.0 g/dL 
or less.

H1: Treatment difference in mean Hgb during the primary efficacy evaluation period is greater 
than -1.0 g/dL.
Only when the primary endpoint achieves non-inferiority, statistical testing will progress to the 
principal secondary endpoint with a focus on superiority according to the step-down procedure. More 
specifically, the superiority of GSK1278863 to epoetin beta pegol in terms of target Hgb control in 
ND subjects, including Cohort 1 subjects (only ESA users) and Cohort 3 subjects (both ESA users and 
ESA non-users), is to be demonstrated at a two-sided significance level of 5% by testing the following 
statistical hypotheses:

H0: The proportion of subjects whose mean Hgb during the primary efficacy evaluation period is 
within the target range (11.0-13.0 g/dL) is equal between the treatment groups.

H1: The proportion of subjects whose mean Hgb during the primary efficacy evaluation period is 
within the target range (11.0-13.0 g/dL) is different between the treatment groups. 


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No hypothesis will be tested in PD subjects (Cohort 2). 
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Assuming a non-inferiority margin of -1.0 g/dL, a treatment difference of 0.0 g/dL, and a standard 
deviation of 1.5 g/dL for mean Hgb during the primary efficacy evaluation period in ND subjects, 
two-sample t-test has at least 99% power at a one-sided significance level of 2.5% (i.e. two-sided 
significance level of 5%) with a sample size of 100 subjects per group. Assuming a dropout rate of 
approximately 25%, 135 subjects will be randomized to each group. Given the results from previous 
non-inferiority studies of similar drugs (darbepoetin alfa, epoetin beta pegol, and peginesatide), the 
non-inferiority margin of -1.0 g/dL is set. Since an increase of 1.0 g/dL indicates improvement in 
anemia according to the guidelines for renal anemia in Japan, the non-inferiority margin of -1.0 g/dL
may be the clinically acceptable largest difference in renal anemia. 
While the present study is designed to ensure long-term safety data from 100 ND subjects, and the 
primary hypothesis test has at least 99% power to estimate the efficacy very precisely, non-inferiority 
can be statistically demonstrated with a minimum between-group difference of -0.582 g/dL. 
During this study, the protocol has been amended (Amendment No.3) according to the change in 
starting dose for ND, ESA non-users, however, this amendment will need no change for the overall
target sample size. Analysis populations for non-inferiority assessment and safety evaluation on ND 
subjects are amended as illustrated below.
GSK1278863
Starting Dose
Number of Randomized Subjects
Analysis Population
(based on number of randomized 
subjects)
Cohort 1
169 subjects
Cohort 3
101 subjects
GSK1278863 Epoetin beta 
pegol
GSK1278863
Epoetin beta 
pegol
ND
subjects
ESA
non-
users
4 mg
82 subjects
270 
subjects 
for safety 
analyses
2 mg or 4 mg
80 subjects
188 subjects 
for primary 
efficacy 
analyses
ESA
users
4 mg
87 subjects
21 subjects
Note: In Cohort 1, 169 ND subjects who met eligibility criteria were stratified by the current ESA therapy and baseline Hgb (ESA 
non-users: 9.5 g/dL, <9.5 g/dL, ESA users: <11.0 g/dL, 11.0 g/dL) and then randomized in a 1:1 ratio to GSK1278863 or epoetin 
beta pegol group. The same randomization strategy is used in Cohort 3.
Figure 2    Primary Efficacy and Safety Analyses Populations for ND Subjects
When non-inferiority is tested, as shown in Figure 2, in 188 ND subjects, this number of subjects 
ensures an enough power. This is because a power of at least 97% will be achieved in a population 
consisting of 140 subjects, who will complete study on the condition of a dropout rate of 
approximately 25%, by the same assumptions and non-inferiority margin stated as above. In order to 
After Amendment
Before Amendment


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allow a subgroup analysis of the primary endpoint by the use of ESA in subgroups the sizes of which 
are equal as much as possible, at least 80 ND, ESA non-users are to be enrolled in Cohort 3.
For PD subjects, the sample size is based on the feasibility. Assuming a sample size of 38 subjects and 
a standard deviation of 1.5 g/dL, the half width of the 95% CI for mean Hgb during the primary 
efficacy evaluation period is 0.493 g/dL. 
9.2.2.
Sample Size Sensitivity
The power for the primary endpoint is shown according to treatment difference and standard deviation 
in Table 17 based on a population consisting of 140 subjects (70 subjects per group) who will 
complete study on the condition of a dropout rate of approximately 25%. This population is derived 
from 188 ND subjects, including Cohort 1 subjects (only ESA users) and Cohort 3 subjects (both ESA 
users and ESA non-users)
Table 17    Power Sensitivity (70 Subjects Evaluated Per Group, Noninferiority 
Margin of -1.0, One-Sided Significance Level of 2.5%)
Treatment Difference
Standard Deviation
1.25
1.5
1.75
0
99.7%
97.5%
91.2%
-0.1
98.8%
94.1%
85.6%
-0.2
96.4%
88.0%
76.6%
-0.3
90.8%
78.3%
65.2%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned for this study.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations

All Screening Population
The All Screening Population consists of all subjects who are given subject number and whose data 
are collected, including demographics at screening.

Intent-to-Treat (ITT) Population
The Intention-To-Treat Population consists of Cohort 1 subjects (only ESA users) and Cohort 3 
subjects (both ESA users and ESA non-users) who are given randomization number with Hgb 
measurement at both baseline and at least one scheduled visits following the baseline. Subjects will be 
analyzed according to randomized treatment. This population will be the primary population for an 
assessment of non-inferiority.

modified ITT (mITT) Population
The mITT Population consists of all ITT subjects who have at least one Hgb measurement during the 
efficacy evaluation period. Subjects will be analyzed according to randomized treatment. This 
population will be the primary population for an assessment of superiority. 


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
Per-Protocol (PP) Population
The PP Population consists of all mITT subjects who are not major protocol violators. Details will be 
defined in the RAP. This population will be used for efficacy sensitivity analyses.

Safety Population
The Safety Population consists of all subjects who receive at least one dose of study treatment. 
Subjects will be analyzed according to the treatment received. This population will be used for safety 
analyses. 

PK Population
The PK Population consists of all GSK1278863-treated subjects from whom PK samples are collected 
and analyzed. 
Additional populations may be defined in the RAP.
9.3.2.
Interim Analysis
No interim analysis is planned. 
9.3.3.
Adjustment for Multiplicity
Adjustment for multiplicity will be applied to maintain an overall type I error rate of 5%. After a 
preliminary assessment, the primary endpoint will be evaluated to demonstrate the non-inferiority at a 
one-sided significance level of 2.5% (i.e. two-sided significance level of 5%). Only when the primary 
endpoint achieves non-inferiority, statistical testing will progress to the principal secondary endpoint 
with a focus on superiority. Since the process will follow step-down manner, a multiplicity adjustment 
for a two-sided significance level of 5% will not be needed according to a closed test procedure. 
Other secondary endpoints, which will be evaluated on a complementary or exploratory basis, will be 
compared at a two-sided significance level of 5% without multiplicity adjustment. 
Since Cohort 2 is a single-arm cohort, no testing will be performed to evaluate the efficacy in PD 
subjects. 
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Efficacy Analysis
The primary endpoint, which is the mean Hgb during the primary efficacy evaluation period, will be 
analyzed to demonstrate the non-inferiority of GSK1278863 to epoetin beta pegol in ND subjects. 
MMRM will be used to estimate the mean Hgb during the primary efficacy evaluation period and its 
95% CI by treatment groups. This model includes treatment groups, baseline Hgb, assessment visits, 
interaction terms between treatment groups and assessment visits, as well as interaction terms between 
baseline Hgb and assessment visit. As a preliminary assessment, it will be confirmed if the mean Hgb 
during the primary efficacy evaluation period in GSK1278863 group would be in target range (11.0-
13.0 g/dL) at first. This confirmation will be established if the lower and upper limit of 95% CI for the 
mean Hgb in GSK1278863 group would lie fully within target range (11.0-13.0 g/dL). In addition, the 
point estimate and 95% CI for the treatment difference (GSK1278863-epoetin beta pegol) in the mean 


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Hgb during the primary efficacy evaluation period will be estimated. Non-inferiority will be 
established if the lower limit of the 95% CI is greater than -1.0 g/dL. Even if the 95% CI for the 
difference is completely negative (i.e. lies fully within the range -1.0 to <0 g/dL) non-inferiority 
would still be concluded on condition that the mean Hgb estimated in the GSK1278863 group is 
within the target range.
The primary efficacy population will be the ITT Population, and the analysis will be repeated in the 
mITT and PP Population to evaluate the robustness of the conclusion. The subgroup analysis by the 
current ESA therapy (presence or absence) will also be conducted. If ND, ESA users in cohort 3 
whose dose level was decreased by one step at Week 2 exist, sensitivity analysis excluding the 
subjects from primary analysis will be conducted. In addition, sensitivity analysis to primary efficacy 
analysis for all ND patients in Cohort 1 and Cohort 3 will be conducted. Further details of sensitivity 
analyses will be provided in the RAP.
9.4.2.
Principal Secondary Efficacy Analysis
The principal secondary endpoint, which is the proportion of subjects whose mean Hgb during the 
primary efficacy evaluation period is within the target range will be analyzed to demonstrate the 
superiority of GSK1278863 to epoetin beta pegol in ND subjects. 
In the mITT Population, a logistic regression model including treatment group, baseline Hgb, and 
current ESA therapy (presence or absence) as covariates will be used to estimate the point estimate 
and 95% CI for the odds ratio (GSK1278863/epoetin beta pegol). This analysis will be performed to 
demonstrate the superiority at a two-sided significance level of 5%, conditional on the primary 
endpoint achieving noninferiority. Superiority will be established if the lower limit of the 95% CI 
for odds ratio is greater than 1.0.
9.4.3.
Other Secondary Efficacy Analyses
Among the secondary efficacy endpoints, the time (%) in Hgb target range during the primary efficacy 
evaluation period , proportion of subjects who have an Hgb increase of more than 2 g/dL over any 4 
weeks, and changes in iron metabolism parameters (ferritin, TSAT, hepcidin, serum iron, and TIBC), 
the point estimates and 95% CIs for the treatment difference (or odds ratio) in ND subjects will be 
calculated. Other secondary efficacy and exploratory endpoints will be summarized by each treatment 
group. 
For PD subjects, the efficacy endpoints will be descriptively summarized. 
9.4.4.
Safety Analyses
In principle, safety data will be summarized by each treatment group in the Safety Population. ND 
subjects and PD subjects will be summarized separately.
9.4.4.1.
Exposure
Exposure information will be listed for all subjects. The duration of treatment (number of days) and 
cumulative dose will be tabulated. In addition, distribution of the dose level at each assessment visit
and final dosing visit will be tabulated. Frequency of dose adjustment and duration of treatment 
interruption due to Hgb >13 g/dL will be summarized.


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9.4.4.2.
Adverse Events
All AEs will be categorized by the MedDRA system organ class and preferred term to tabulate the 
number and incidence. All AEs, SAEs, AEs leading to discontinuation of study treatment, and AEs of 
special interest will be summarized separately. Similar summary will be provided for study treatment-
related AEs. 
9.4.4.3.
Other Safety Parameters
For laboratory tests, vital signs and ECG, parameters and/or changes from baseline will be 
summarized using summary statistics at each assessment visit. The number and percentage of subjects 
with values of the potential clinical importance values will be tabulated. The criteria for the potential 
clinical importance will be described in the RAP. For lipid parameters (total cholesterol, LDL 
cholesterol, and HDL cholesterol), percent changes will also be tabulated. The number (%) of subjects 
who have any change in anti-hypertensive medications (type and/or dose) due to increased blood 
pressure will be tabulated.
9.4.5.
Pharmacokinetics Analyses
For plasma concentrations of GSK1278863 over time, individual data will be listed, and summary 
statistics at each time point will be calculated for each dose level. For PK parameters (AUC 0-4 and 
Cmax), summary statistics will be calculated for each dose level, and scatter plots against the dose 
level will be generated. 
9.4.6.
PRO Data Analysis
Details of PRO data tabulation will be described in the RAP.


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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 
enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the Informed Consent 
Process
The study will be conducted in accordance with “the Ministerial Ordinance on the Standards for the 
Conduct of Clinical Trials of Medicinal Products (MHW Notification No.28 dated 27th March, 1997)” 
and the Pharmaceutical Affairs Law.
GSK will submit the CTN to the regulatory authorities in accordance with with Article 80-2 of the 
Pharmaceutical Affairs Law before conclusion of any contract for the conduct of the study with study 
sites.
The study will be conducted in accordance with all applicable regulatory requirements, and with GSK 
policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), all applicable 
subject privacy requirements, and the guiding principles of the current version of the Declaration of 
Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and amendments as 
applicable

Signed informed consent to be obtained for each subject before participation in the study (and for 
amendments as applicable) 

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or both.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical protocol and all 
optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate informed 
consent) and the clinical protocol should be concurrently submitted for approval unless 
regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the clinical protocol 
where required by regulatory authorities.  In this situation, written approval of the clinical 
protocol should state that approval of optional assessments is being deferred and the study, with 
the exception of the optional assessments, can be initiated.
Informed Consent
Prior to participation in the study, the investigator (or subinvestigator) should fully inform the 
potential subject and the subject's legally acceptable representative (as required) of the study including 
the written information. The investigator (or subinvestigator) should provide the subject and the 
subject's legally acceptable representative ample time and opportunity to inquire about details of the 
study. The subject and the subject’s legally acceptable representative should sign and personally date 
the consent form. If the subject wishes to consider the content of the written information at home, 


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he/she may take the consent form home. The person who conducted the informed consent discussion 
and study collaborator giving supplementary explanation, where applicable, should sign and 
personally date the consent form. If an impartial witness is required, the witness should sign and 
personally date the consent form. The investigator (or subinvestigator) should retain this signed and 
dated form (and other written information) together with the source medical records, such as clinical 
charts (in accordance with the rules for records retention, if any, at each medical institution) and give a 
copy to the subject and the subject’s legally acceptable representative.
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 the CRF 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.
10.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, the GSK monitor will conduct site closure
activities with the investigator or site staff, as appropriate, in accordance with applicable regulations
including GCP, and GSK Standard Operating Procedures.
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 the reasons for taking such action with the
investigator or the head of the medical institution (where applicable). When feasible, GSK will
provide advance notification to the investigator or the head of the medical institution, where


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applicable, of the impending action.
If the study is suspended or prematurely discontinued for safety reasons, GSK will promptly inform
all investigators, heads of the medical institutions (where applicable) and/or institution(s) conducting
the study. GSK will also promptly inform the relevant 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 elsewhere), in a safe and secure location.  
The records must be maintained to allow easy and timely retrieval, when needed (e.g., for a GSK audit
or regulatory inspection) and must be available for review in conjunction with assessment of the
facility, supporting systems, and relevant site 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 ensure 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, GSK standards/procedures, and/or institutional requirements.  
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 is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of Information on 
Publically Available Clinical Trials Registers and Publicatio
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.
The procedures and timing for public disclosure of the results summary and for development of a 
manuscript for publication will be in accordance with GSK Policy.


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10.8.
Study Period
See Exhibit 1
10.9.
Study Administrative Structure
Sponsor information is included in Exhibit 2. List of Medical Institutions and Investigators is included 
in Exhibit 3.


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11. REFERENCES
Akizawa Tadao, Makino Hirofumi, Matsuo Seiichi, et al. Management of anemia in chronic kidney 
disease patients: baseline findings from Chronic Kidney Disease Japan Cohort Study. Clin Exp 
Nephrol. 2011;15:248-57.
Szczech Lynda A, Barnhart Huiman X., Inrig Jula K., et al. Secondary analysis of the CHOIR trial 
epoetin-α dose and achieved hemoglobin outcomes. Kidney International. 2008;74:791-8.
Guidelines for Renal Anemia in Chronic Kidney Disease issued by the Japanese Society for Dialysis 
Therapy in 2008. Journal of Japanese Society for Dialysis Therapy. 2008;41(10):661-716


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12. APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under Curve
CKD
Chronic Kidney Disease
Cmax
Maximum concentration
CPK
Creatine Phosphokinase
CYP
Cytochrome P450
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
EPO
Erythropoietin
EQ-5D-5L
EuroQol Health Utility Index
ESA
Erythropoiesis-Stimulating Agent
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
hCG
Human Chorionic Gonadotrophin
HD
Hemodialysis
HDL
High Density Lipoprotein
HDPE
High Density Polyethylene
Hgb
Hemoglobin
HIF
Hypoxia-Inducible Factor
HRT
Hormone Replacement Therapy
ICH
International Conference on Harmonization
INR
International Normalized Ratio
iPTH
Intact Parathyroid Hormone
ITT
Intent-to-Treat
IWRS
Interactive Web Recognition System
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
MCS
Mental Component Summary
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-Treat
ND
Non dialysis
NYHA
New York Heart Association
PCS
Physical Component Summary
PD
Peritoneal Dialysis
PHI
Prolyl Hydroxylase Inhibitor
PK
Pharmacokinetic
PP
Per-Protocol
PRO
Patient Reported Outcome
QT
Q-T Interval
QTc
Q-T Interval Corrected for Heart Rate


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QTcB
Bazett’s Correction of QT Interval
RAP
Reporting and Analysis Plan
RDW
Red Blood Cell Distribution Width
RNA
Ribonucleic Acid
rhEPO
Recombinant human erythropoietin
SAE
Serious Adverse Event
SRM
Study Reference Manual
TIBC
Total Iron Binding Capacity
TSAT
Transferrin Saturation
UIBC
Unsaturated iron Binding Capacity
VAS
Visual Analog Scale
VEGF
Vascular Endothelial Growth Factor
Trademark Information
Trademarks of the GlaxoSmithKline group of 
companies
Trademarks not owned by the GlaxoSmithKline 
group of companies
None
Hemocue
Mircera


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12.2.
Appendix 2: Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
GSK1278863 
Excessive erythropoiesis (polycythemia) leading to 
thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis attributed to GSK1278863 
was associated with vascular congestion, microthrombi, and tissue 
ischemia in a number of organs.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
Phase 2 dose-ranging studies, and associated statistical and exposure 
response modelling has informed Phase 3 dose rationale, starting 
doses, dose levels, and dose adjustment scheme to optimize Hgb 
management.
•
Specific eligibility criteria related to requirements for 
entry Hgb are detailed in Section 5.1.
•
Hgb will be closely monitored throughout the dosing 
period as outlined in the Time and Events Table 
Section 7.1.
•
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of GSK1278863 
based on achieved Hgb is provided in Section 6.4.1.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Risk of death, MI, stroke, heart failure, venous 
thromboembolism, thrombosis of vascular access at Hgb 
levels which are within the normal range (i.e. not 
polycythemic conditions)
Marketed rhEPO/ESAs have been associated with an increased risk for 
death and serious cardiovascular events when used in patients with 
anemia of CKD.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
•
Specific eligibility criteria related to CV risk are 
outlined in Section 5.2.
•
Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Esophageal and gastric erosions
In animal studies, undesirable GI effects including emesis, abnormal 
feces and/or decreased food consumption/body weight loss and 
stomach erosions/ ulcers with hemorrhage were observed.  
In rodents stomach erosions observed with intravenous and oral 
administration of GSK1278863.
Gender-averaged systemic exposure (AUC) at the no observed adverse 
•
Suspected GI bleeding or significant symptoms 
consistent with erosion should be investigated 
diagnostically (i.e. endoscopic examination) as 
clinically warranted
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
effect levels (NOAEL) are 3.3 -fold (monkeys) and 737 -fold (rats) 
above human exposure (25 mg).
In clinical trials to date, mild-moderate GI signs and symptoms 
represent the most frequently reported adverse event, however causal 
association has not been established.
Following review of clinical data received to date, GI erosions have 
not been identified as a safety concern for GSK1278863.
period.
Cancer-related mortality, tumor progression and recurrence
In clinical trials, use of rhEPO in patients with cancer has been associated with 
increased risk of cancer related morbidity and mortality.
Administration of 60 mg/kg GSK1278863 to mice caused minimal increases in 
circulating VEGF while significant EPO increases were observed.
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations, an angiogenic factor that has been 
implicated in tumor growth, was observed at doses ranging from 10 to 
150 mg. In clinical studies up to 24 weeks duration at doses up to 
25 mg, changes in VEGF plasma concentrations were variable but 
similar relative to control.
Following review of clinical data received to date, this has not been identified 
as a safety concern for GSK1278863.
•
Specific eligibility criteria related to personal history 
of malignancy are outlined in Section 5.2..
•
Stopping criteria for subjects with treatment 
emergent malignancy are outlined in Section 5.4.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Pulmonary artery hypertension (PAH)
・A role for HIF-regulated pathways in the pathophysiology of PAH 
has been suggested based on well established effects of acute and 
chronic hypoxia in man on the pulmonary vasculature 
(vasoconstriction), and by findings in patients with naturally occurring 
mutations that result in decreased HIF degradation (Smith, 2006; 
Formenti, 2011).
・There have been no histopathologic findings suggestive of PAH in 
pre-clinical safety studies (up to 13-weeks duration in mice and dog, 
up to 26-weeks in rat, and up to 39-weeks in monkeys.
・Acute hypoxic challenge (rats): GSK1278863A produced increases 
in peak right ventricular pressure (PRVP) during acute hypoxia that 
were slightly higher than the vehicle control group. These hypoxia-
induced PRVP changes fall within the range of PRVP differences 
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
noted among non-treated rats.
・Results from a clinical study of acute hypoxic challenge in healthy 
volunteers demonstrated that short-term therapy with GSK1278863 
5 mg or 10 mg has no clinically significant effect on 
echocardiographically estimated pulmonary artery systolic pressure 
(PASP) under either normoxic or hypoxic conditions.
・ECHO assessments performed in Phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes 
in sPAP in subjects not on dialysis. Changes in sPAP from baseline in 
dialysis patients were comparable between GSK1278863 group and 
Control group (median). The numbers of patients who met the 
potentially clinically significant sPAP criteria (increased from baseline 
by >20 mmHg) were disproportionate between the treatment groups [8 
patients (7%) in GSK1278863 group and 0 patient in Control group]. 
This imbalance was associaited with some confounding factors, 
including the randomization scheme of 4.5:1 ratio and inconsistency in 
timings of ECHO assessment related to dialysis. Additionally, 2 of the 
3 patients with sPAP improvement at the follow-up ECHO assessment 
had confounding factors that were potentially attributable for sPAP 
improvement other than study medication discontinuation. No dose 
relationship was seen in patients who met potentially clinically 
significant sPAP criteria. Overall, no sufficient evidence was obtained 
to conclude the relationship with GSK1278863.
・Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.  
Cardiomyopathy
Published data suggest that cardiac effects of HIF stabilization are 
likely a function of the mechanism, extent, and duration of the effects, 
and can range from protective to detrimental depending upon the 
specific model and experimental conditions utilized.
Small increases in cardiac troponin in 6 month rat study were 
consistent with the background finding of spontaneous rodent 
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
cardiomyopathy. There were no elevations observed in cardiac 
troponin in 9 month monkey study.
Cardiomyopathy has not been associated with naturally occurring 
mutation in man which results in increased HIF stabilization.
ECHO assessments performed in phase 2b studies (24 weeks treatment 
duration) did not identify any clinically meaningful changes in LVEF.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
Proliferative retinopathy, macular edema, choroidal 
neovascularization
Increases in local (ocular) VEGF production with retinal 
neovascularization and macular edema observed in diabetic 
retinopathy and to choroidal leakage, edema and neovascularization 
seen in age-related macular degeneration (Campochiaro, 2006).
Administration of 60 mg/kg GSK1278863 to mice caused minimal 
increases in circulating VEGF while significant EPO increases were 
observed.
No ocular abnormalities were seen in non-clinical studies of up to 13 
weeks duration in mice and dogs, 26 weeks in rats, and 39-weeks in 
monkeys.  
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations was observed at doses ranging from 10 
to 150 mg. In studies up to 24 weeks duration at doses up to 25 mg, 
changes in VEGF plasma concentrations were variable but similar 
relative to control.
Ophthalmologic assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes 
in proliferative retinopathy, macular edema, or choroidal 
neovascularization.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
•
Ophthalmology exams will be performed during 
screening, at approximately Week 12 on-study, and 
at the end of treatment.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
•
Ophthalmology exams should be specified in 
Section 7.4.8. and monitored.
•
When proliferative retinopathy, macular edema or 
choroidal neovascularization is suggested, or 
symptoms that are consistent with these AEs are 
reported, patients should consult ophthalmologist as 
clinically necessary.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Exacerbation of rheumatoid arthritis
In inflamed rheumatic joints, activation of HIF- related genes 
secondary to decreased oxygen and pro-inflammatory cytokines has 
been postulated to contribute to the neo-angiogenesis, proliferation and 
infiltration of rheumatoid synovial fibroblasts (Westra, 2010; Muz, 
2009).
No abnormalities seen in non-clinical studies conducted to date.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Drug-drug interactions
Co-administration of GSK1278863 with a strong CYP2C8 inhibitor increased 
the Cmax and AUC of GSK1278863, 4- and 19-fold, respectively, while co-
administration of a weak inhibitor increased the Cmax and AUC of 
GSK1278863 by 1.3- and 1.5-fold, respectively. Population PK analysis from 
completed Phase 2 studies suggests that co-administration of GSK1278863 
with a moderate CYP2C8 inhibitor, leads to a ~ 2-fold increase in AUC, with no 
clinically-significant increase in the measured Hgb response.
GSK1278863 is an inhibitor of CYP2C8 in vitro, with an IC50 value of 
21 µM.
Population PK analysis from completed Phase 2 studies suggests that 
co-administration of GSK1278863 with clopidogrel (a moderate 
CYP2C8 inhibitor) leads to a ~ 2-fold increase in AUC, with no 
clinically-significant increase in the measured Hgb response. Co-
administration of GSK1278863 with moderate CYP2C8 inhibitors (i.e., 
clopidogrel, teriflunomide, deferasirox) should be performed with 
caution.
Co-administration of GSK1278863 with potent BCRP inhibitors has 
the potential to increase exposure of GSK1278863. Use of BCRP 
inhibitors (mostly weak) was found to result in a small change in 
metabolite exposure (20% increase in AUC).
GSK1278863 is an inhibitor of OATP1B1/1B3 in vitro, with IC50
values of 6 µM and 11 µM, respectively. A clinical drug interaction 
•
Co-administration of GSK1278863 with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 
inducers (e.g., rifampin/rifampicin) is not 
permitted as outlined in Section 6.11.2.
•
Co-administration of GSK1278863 with 
moderate CYP2C8 inhibitors (i.e., clopidogrel, 
teriflunomide, deferasirox) should be 
performed with caution. If one of these 
medications is started, stopped or the dose is 
changed, Hgb should be monitored every 4 
weeks for 12 weeks as outlined in Section 
6.11.1.
•
Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in Section 
6.11.
•
Hgb will be closely monitored throughout the dosing 
period as outlined in the Time and Events Table 
Section 7.1.
•
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of 
GSK1278863 based on achieved Hgb is 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
study between 25mg GSK1278863 with either a CYP2C8 substrate or 
an OATP1B1/1B3 substrate showed that there is no PK interaction at 
this dose of GSK1278863.
provided in Section 6.4.1.
•
These risks will be monitored instreamly by the 
internal safety review team throughout the 
study period.
Other
ESA risks (Control)
・See risks outlined in table for GSK1278863 for Excessive 
erythropoiesis (polycythemia) leading to thrombosis and/or tissue 
ischemia; Risk of MI, stroke, venous thromboembolism, thrombosis of 
vascular access; and risk of cancer-related mortality and tumor 
progression.
・Non-controllable hypertension 
・Pure red cell aplasia
・Hepatic function disorder with increase of AST, ALT and Gamma-
glutamyltransferase, and jaundice have been reported as adverse drug 
reactions for other ESA according to the prescribing information of 
Epoetin beta pegol.

The same mitigation strategies have been 
indentified in acoordance with the mitigation 
strategies for GSK1278863 

Blood pressure will be monitored throughout 
the dosing period as outlined in the Time and 
Events Table provided in Section 7.1..

A criterion to exclude subjects with history of 
pure red cell aplasia is added to Section 5.2..

Liver function will be monitored throughout 
the dosing period as outlined in the Time and 
Events Table provided in Section 7.1.
References
Campochiaro et al., Ocular versus Extraocular Neovascularization: Mirror Images or Vague Resemblances; Invest Ophthalmol & Vis Sci 2006. 47:462-474.
Formenti et al., Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha 
gain-of-function mutation. FASEB J. 2011, 25(6): 2001-2011.
Muz et al., The role of hypoxia and HIF-dependent signaling events in rheumatoid arthritis, Arthritis Research & Therapy 2009. 11:201-210.
Smith et al., Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology PLOS 2006. 3:1176-1186.


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Westra et al., Hypoxia-Inducible Factor-1 as Regulator of Angiogenesis in Rheumatoid Arthritis - Therapeutic Implications.  Current Medicinal Chemistry 
2010. 17:254-263.


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12.3.
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of reproductive potential
This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle 
or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long 
term and persistent basis.
1.
Contraceptive subdermal implant that meets the Prescribing Information effectiveness criteria 
including a <1% rate of failure per year, as stated in the Prescribing Information
2.
Intrauterine device or intrauterine system that meets the Prescribing Information effectiveness 
criteria including a <1% rate of failure per year, as stated in the Prescribing Information
[Hatcher, 2011]
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female subject's entry 
into the study, and this male is the sole partner for that subject [Hatcher, 2011].  
These allowed methods of contraception are only effective when used consistently, correctly and in 
accordance with the Prescribing Information. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception.
References
Trussell J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, Kowal D, and 
Policar M (editors). Contraceptive Technology: Twentieth Revised Edition. New York: Ardent Media, 
2011.


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12.4.
Appendix 4: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes pregnant 
while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 weeks of 
learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The investigator will collect 
follow up information on mother and infant, which will be forwarded to GSK. Generally, follow-
up will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as such.  

Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related 
to the study treatment by the investigator, will be reported to GSK as described in Section 12.6.
Appendix 6. While the investigator is not obligated to actively seek this information in former 
study participants, he or she may learn of an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating

will discontinue study medication or be withdrawn from the study


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12.5.
Appendix 5: Liver Safety Required Actions and Follow up Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance).
Phase III-IV liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted

If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments 
MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) and 
quantitative hepatitis B DNA 

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 24 hours after last 
dose5

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:


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hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  
24-72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct 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 computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, (for ND patients only) if serum bilirubin fractionation testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if 
INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold 
value stated will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody or Hepatitis E RNA
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
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 in the 
SRM.  
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 


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<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and 
<8xULN to ≥3xULN but <5xULN, continue to 
monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to 
within baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute 
Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, Follow-
Up and Reporting of Adverse Events
12.6.1.
Definition of Adverse Events
Adverse Event Definition:

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 AE definition 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).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE.  However, the signs and symptoms and/or clinical sequelae resulting from lack 
of efficacy will be reported if they fulfil the definition of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the 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.


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12.6.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of 
disease, etc).
Serious Adverse Event (SAE) is defined as 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
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
e.
Is a congenital anomaly/birth defect
f.
Other situations:

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; (for ND patients only) if 


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unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury. 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.
12.6.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF 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
12.6.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in the CRF

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 CRF page.

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.

PRO questionnaires and the collection of AE data are independent components of the study.

Responses to each question in PRO 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.
12.6.5.
Evaluating AEs and SAEs
Assessment of Intensity


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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.
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

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 


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histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated reporting time 
frames.
12.6.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use the paper SAE 
data collection tool and fax it to the SAE contact.

Site will enter the serious adverse event data into the electronic system as soon as it becomes 
available.

The investigator will confirm that causal relationship of SAE has been considered, by ticking the 
'reviewed' box at the bottom of eCRF page within 72 hours following the submission of SAE. 

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 subject 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 the SAE contact by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the Sponsor/Medical 
Monitor Contact Information page.


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12.7.
Appendix 7 - Genetic Research
Background
Naturally occurring genetic variation may contribute to inter-individual variability in response to 
medicines, as well as an individual's risk of developing specific diseases. Genetic factors associated 
with disease characteristics may also be associated with response to therapy, and could help to explain 
some clinical study outcomes. For example, genetic variants associated with age-related macular 
degeneration (AMD) are reported to account for much of the risk for the condition [Gorin, 2012] with 
certain variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the genetic 
etiology of disease may better inform understanding of disease and the development of medicines. 
Additionally, genetic variability may impact the pharmacokinetics (absorption, distribution, 
metabolism, and elimination), or pharmacodynamics (relationship between concentration and 
pharmacologic effects or the time course of pharmacologic effects) of a specific medicine and/or 
clinical outcomes (efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objective of the genetic research is to understand the response to GSK1278863. To achieve this 
objective, the relationship between genetic variants and the followings may be investigated.

Response to medicine, including GSK1278863, ESA, other study medicines or any concomitant 
medicines;

Nephrogenic anemia and related conditions susceptibility, severity, and progression 
Genetic data may be generated while the study is underway or following completion of the study.  
Genetic evaluations may include focused candidate gene approaches and/or examination of a large 
number of genetic variants throughout the genome (whole genome analyses). Genetic analyses which 
will be conducted for this study will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data from multiple 
clinical studies related to GSK1278863 to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed description of any 
planned analyses will be documented in a Reporting and Analysis Plan (RAP) prior to initiation of the 
analysis. Planned analyses and results of genetic investigations will be reported either as part of the 
clinical RAP and study report, or in a separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in the genetic research. Any subject who has 
received an allogeneic bone marrow transplant must be excluded from the genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during clinical studies. 
Collection of samples, even when no a priori hypothesis has been identified, may enable future 
genetic analyses to be conducted, align with the purpose of the genetic research, to help understand 
variability in disease and medicine response.  


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
A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A Blood 
sample is collected at the baseline visit, after the subject has been randomized and provided 
informed consent for genetic research. Instructions for collection and shipping of the genetic 
sample are described in the laboratory manual. The DNA from the blood sample may undergo 
quality control analyses to confirm the integrity of the sample. If there are concerns regarding the 
quality of the sample, then the sample may be destroyed. The blood sample is taken on a single 
occasion unless a duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to label other 
samples and data in the study. This number 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). 
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 only use samples collected from the study for the purpose stated in this protocol and 
in the informed consent form. Samples may be used as part of the development of a companion 
diagnostic to support the GSK medicinal product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the study.  
Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic 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 genetic sample, if already collected:

Continue to participate in the genetic research in which case the genetic DNA sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA sample
If a subject withdraws consent for genetic 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. 
Genotype data may be generated during the study or after completion of the study and may be 
analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been analyzed, it 
will not be analyzed or used for future research.  


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
Genetic data that has been analyzed at the time of withdrawn consent will continue to be stored 
and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject does not meet 
the entry criteria for participation in the study, then the investigator should instruct the subject that 
their genetic 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.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or separately and may 
publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific understanding in 
alignment with the informed consent. GSK does not inform the subject, family members, 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 genetic studies is generally preliminary in nature, and therefore the significance and 
scientific validity of the results are undetermined. Further, data generated in a research laboratory may 
not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular Degeneration 
(AMD) Susceptibility Gene CFH and Treatment Response of AMD: A Meta-Analysis. PloS ONE 
2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies addressing risk, 
causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.


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12.8.
Appendix 8: Definition of and Procedures for Documenting Medical Device 
Incidents
12.8.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all medical devices 
provided for use in the study (see Section 6.2. for the list of the medical devices).
Medical Device Incident Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance of a device, 
as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, 
might lead to or might have led to the death of a patient/user/other persons or to a serious 
deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health. The non-occurrence of such a 
result might have been due to other fortunate circumstances or to the intervention of health care 
personnel.
It is sufficient that:

an incident associated with a device happened and

the incident was such that, if it occurred again, might lead to death or a serious deterioration in 
health.
A serious deterioration in state of health can include:

life-threatening illness

permanent impairment of body function or permanent damage to a body structure

a condition necessitating medical or surgical intervention to prevent one of the above 

fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of a medical device failure or its 
misuse

a patient’s treatment is interrupted or compromised by a medical device failure

misdiagnosis due to medical device failure leads to inappropriate treatment

a patient’s health deteriorates due to medical device failure
12.8.1.1.
Documenting Medical Device Incidents
Medical Device Incident Documenting:

Any medical device incident occurring during the study will be documented in the subject’s 
medical records, in accordance with the investigator’s normal clinical practice, and on the 
appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE CRF page 
will be completed as described in Section 12.6. (Appendix 6). 

The form will be completed as thoroughly as possible and signed by the investigator before 
transmittal to GSK.


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
It is very important that the investigator provides his/her assessment of causality to the medical 
device provided by GSK at the time of the initial report, and describes any corrective or remedial 
actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a device where 
such action is necessary to prevent recurrence of an incident. This includes any amendment to the 
design to prevent recurrence.


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TITLE PAGE
Division：Worldwide Development
Information Type：Clinical Protocol
Title：A 52-week, Phase III, open-label, multi-center study to evaluate efficacy and safety of 
GSK1278863 in Japanese non-dialysis and peritoneal dialysis subjects with anemia associated with 
chronic kidney disease.
Compound Number：
GSK1278863
Development Phase
III
Effective Date：
12-APR-2016
Protocol Amendment Number: 01
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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Sponsor Signatory:
Hiromu Nakajima
Head,
Medicines Development,
Japan Development and Medical Affairs (JDMA),
GlaxoSmithKline K. K.
Date


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time 
Phone 
Number
Fax Number
Site Address
Medical Monitor
M.D., Ph.D.
GlaxoSmithKline K.K.
6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-8566 
JAPAN
SAE contact  
information
Person in charge 
of GSK1278863
Clinical 
Operations dept. 
GlaxoSmithKline K.K.
6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-8566 
JAPAN
Emergency Contact
Emergency Contact (Mon to Fri 10am to 6pm, except for national holiday and year-end and New Year
holidays)
Person in charge of GSK1278863, Clinical Operations dept. R&D, Glaxo Smith Kline K.K
TEL:
FAX:
Emergency Contact at night and holiday (Mon to Fri 6pm to 10am, Sat, Sun, national holiday and 
year-end and New Year holidays)
Bell Medical Solutions Inc.
Responsible Person: 
TEL:
(toll free)
FAX:
(toll free)
Sponsor Legal Registered Address:
6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566 JAPAN
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

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 Signature
Date


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TABLE OF CONTENTS
Page
1.
PROTOCOL SYNOPSIS FOR STUDY PHI201753 ........................................................9
2.
INTRODUCTION............................................................................................................14
2.1.
Study Rationale....................................................................................................14
2.2.
Background..........................................................................................................14
3.
OBJECTIVES AND ENDPOINTS..................................................................................14
4.
STUDY DESIGN.............................................................................................................16
4.1.
Overall Design......................................................................................................16
4.2.
Treatment Groups and Study Periods...............................................................17
4.3.
Study Subjects and Number of Subjects..........................................................18
4.4.
Rationale for Study Design.................................................................................18
4.5.
Rationale for Dose Levels...................................................................................19
4.6.
Benefit: Risk Assessment...................................................................................20
4.6.1.
Risk Assessment ........................................................................................20
4.6.2.
Benefit Assessment....................................................................................21
4.6.3.
Overall Benefit: Risk Conclusion..............................................................21
5.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ...........................................21
5.1.
Inclusion Criteria..................................................................................................22
5.2.
Exclusion Criteria ................................................................................................23
5.3.
Screening Failures...............................................................................................24
5.4.
Withdrawal/Dropout Criteria...............................................................................25
5.4.1.
Liver Chemistry Stopping Criteria.............................................................26
5.4.1.1.
Study Treatment Restart or Rechallenge.........................................28
5.5.
Subject and Study Completion ..........................................................................28
6.
STUDY TREATMENTS..................................................................................................28
6.1.
Investigational Product and Other Study Treatment.......................................28
6.2.
Medical Devices ...................................................................................................29
6.3.
Treatment Assignment........................................................................................29
6.4.
Administration Schedule (Starting Dose, Dose Adjustment, and 
Dosing Frequency) ..............................................................................................30
6.4.1.
GSK1278863 (ND and PD Subjects)..........................................................30
6.4.1.1.
Starting Dose ......................................................................................30
6.4.1.2.
Maintenance Dose..............................................................................30
6.4.2.
Epoetin Beta Pegol (ND Subjects Only) ...................................................31
6.4.2.1.
Starting Dose for ESA Non-users.....................................................31
6.4.2.2.
Dose Conversion for ESA Users ......................................................32


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6.4.2.3.
Maintenance Dose (ESA Non-users and Users) .............................32
6.5.
Blinding.................................................................................................................33
6.6.
Packaging and Labeling......................................................................................33
6.7.
Preparation/Handling/Storage/Accountability..................................................33
6.8.
Compliance with Study Treatment Administration..........................................34
6.9.
Treatment of Study Treatment Overdose..........................................................34
6.10.
Treatment after the End of the Study ................................................................34
6.11.
Concomitant Medications and Non-Drug Therapies .......................................35
6.11.1.
Permitted Medications and Non-Drug Therapies ....................................35
6.11.2.
Prohibited Medications and Non-Drug Therapies...................................35
6.12.
Supplemental Iron Therapy ................................................................................35
7.
Study Assessments and Procedures.........................................................................35
7.1.
Time and Events Table........................................................................................35
7.2.
Screening and Critical Baseline Assessments ................................................39
7.3.
Efficacy .................................................................................................................39
7.4.
Safety ....................................................................................................................39
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)....................39
7.4.1.1.
Time period and Frequency for collecting AE and SAE 
information..........................................................................................40
7.4.1.2.
Method of Detecting AEs and SAEs.................................................40
7.4.1.3.
Follow-up of AEs and SAEs ..............................................................40
7.4.1.4.
Cardiovascular and Death Events....................................................40
7.4.1.5.
Regulatory Reporting Requirements for SAEs...............................41
7.4.2.
Adverse Events of Special Interest...........................................................41
7.4.3.
Pregnancy....................................................................................................41
7.4.4.
Medical Device Incidents (Including Malfunctions) ................................42
7.4.4.1.
Time Period for Detecting Medical Device Incidents......................42
7.4.4.2.
Follow-up of Medical Device Incidents ............................................42
7.4.4.3.
Prompt Reporting of Medical Device Incidents to GSK.................42
7.4.4.4.
Regulatory Reporting Requirements for Medical Device 
Incidents..............................................................................................43
7.4.5.
Vital Signs/Height/Weight ..........................................................................43
7.4.6.
Electrocardiogram (ECG) ...........................................................................43
7.4.7.
Clinical Laboratory Assessments.............................................................43
7.4.8.
Ophthalmology............................................................................................44
7.5.
Pharmacokinetics................................................................................................45
7.6.
Genetics................................................................................................................45


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7.7.
Patient Reported Outcome (PRO)......................................................................45
7.7.1.
SF-36.............................................................................................................45
7.7.2.
EuroQol Health Utility Index (EQ-5D-5L)/EQ Visual Analogue 
Scale (EQ-VAS)............................................................................................45
8.
DATA MANAGEMENT ..................................................................................................46
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .....................................46
9.1.
Hypotheses...........................................................................................................46
9.2.
Sample Size Considerations ..............................................................................47
9.2.1.
Sample Size Assumptions .........................................................................47
9.2.2.
Sample Size Sensitivity ..............................................................................47
9.2.3.
Sample Size Re-estimation or Adjustment...............................................47
9.3.
Data Analysis Considerations............................................................................47
9.3.1.
Analysis Populations..................................................................................47
9.3.2.
Interim Analysis ..........................................................................................48
9.3.3.
Adjustment for Multiplicity.........................................................................48
9.4.
Key Elements of Analysis Plan ..........................................................................49
9.4.1.
Primary Efficacy Analysis..........................................................................49
9.4.2.
Principal Secondary Efficacy Analysis.....................................................49
9.4.3.
Other Secondary Efficacy Analyses .........................................................49
9.4.4.
Safety Analyses...........................................................................................50
9.4.4.1.
Exposure .............................................................................................50
9.4.4.2.
Adverse Events...................................................................................50
9.4.4.3.
Other Safety Parameters ...................................................................50
9.4.5.
Pharmacokinetics Analyses ......................................................................50
9.4.6.
PRO Data Analysis......................................................................................50
10. STUDY GOVERNANCE CONSIDERATIONS ..............................................................51
10.1.
Posting of Information on Publicly Available Clinical Trial Registers...........51
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process..................................................................................................51
10.3.
Quality Control (Study Monitoring)....................................................................52
10.4.
Quality Assurance ...............................................................................................52
10.5.
Study and Site Closure .......................................................................................52
10.6.
Records Retention...............................................................................................53
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publicatio....................53
10.8.
Study Period.........................................................................................................54
10.9.
Study Administrative Structure..........................................................................54


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11. REFERENCES...............................................................................................................55
12. APPENDICES ................................................................................................................56
12.1.
Appendix 1: Abbreviations and Trademarks....................................................56
12.2.
Appendix 2:  Risk Assessment.........................................................................58
12.3.
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of reproductive potential.............................................64
12.4.
Appendix 4: Collection of Pregnancy Information...........................................65
12.5.
Appendix 5: Liver Safety Required Actions and Follow up 
Assessments........................................................................................................66
12.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events ...................................................69
12.6.1.
Definition of Adverse Events.....................................................................69
12.6.2.
Definition of Serious Adverse Events.......................................................70
12.6.3.
Definition of Cardiovascular Events.........................................................71
12.6.4.
Recording of AEs and SAEs......................................................................71
12.6.5.
Evaluating AEs and SAEs..........................................................................71
12.6.6.
Reporting of SAEs to GSK.........................................................................73
12.7.
Appendix 7 - Genetic Research..........................................................................74
12.8.
Appendix 8: Definition of and Procedures for Documenting Medical 
Device Incidents...................................................................................................77
12.8.1.
Definitions of a Medical Device Incident ..................................................77
12.8.1.1.
Documenting Medical Device Incidents...........................................77


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1.
PROTOCOL SYNOPSIS FOR STUDY PHI201753
Rationale
This is a Phase III study to evaluate the efficacy and safety of GSK1278863 in Japanese non-dialysis 
(ND) and peritoneal dialysis (PD) subjects with renal anemia. The primary objective is to demonstrate
non-inferiority of GSK1278863 to epoetin beta pegol based on hemoglobin (Hgb) in the ND patient 
population included in this study. Study results will be used as pivotal study data for an NDA 
submitted for GSK1278863 for the treatment of renal anemia in Japan. 
Objective(s)/Endpoint(s)
Objective
Endpoint
Primary (efficacy)

To demonstrate non-inferiority of 
GSK1278863 to epoetin beta pegol based 
on hemoglobin (Hgb) in ND subjects 

Mean Hgb during the primary efficacy 
evaluation period (Weeks 40 to 52)
Principal secondary (efficacy)

To demonstrate superiority of 
GSK1278863 to epoetin beta pegol in 
terms of achievement/maintenance of 
target Hgb in ND subjects

Number (%) of subjects with mean Hgb in the 
target range (11.0-13.0 g/dL) during the 
primary efficacy evaluation period (Weeks 40 
to 52)
Other secondary (efficacy, PK)

To evaluate the appropriateness of the 
starting dose of GSK1278863 in ND 
subjects using epoetin beta pegol as 
control

To evaluate the appropriateness of the 
starting dose of GSK1278863 in PD 
subjects

Change from baseline in Hgb at Week 4 (Hgb 
increase rate)

Number (%) of subjects by Hgb change from 
baseline category at Week 4

To evaluate dose adjustment scheme of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate dose adjustment scheme of 
GSK1278863 in PD subjects

Distribution of the dose level

Duration of treatment interruption due to Hgb 
>13 g/dL

Frequency of dose adjustments

To evaluate the overall Hgb control of
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate the overall Hgb control of
GSK1278863 in PD subjects

Hgb and change from baseline at each 
assessment visit

Number (%) of subjects with Hgb within the 
target range (11.0-13.0 g/dL) at each 
assessment visit

Time (%) in Hgb target range (11.0-13.0 g/dL) 
during the primary efficacy evaluation period 
(Weeks 40 to 52)

Time (in days) to reach the lower Hgb target 


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Objective
Endpoint
(11.0 g/dL) 

Number (%) of subjects who have an Hgb 
level of less than 7.5 g/dL

Number (%) of subjects who have an Hgb 
increase of more than 2 g/dL over any 4 weeks 

Number (%) of subjects who have an Hgb 
level of more than 13.0 g/dL and number of 
episodes

To evaluate the effect on iron use of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate effect on iron use of 
GSK1278863 in PD subjects

Dose of oral iron during the study period and 
the primary efficacy evaluation period 
(Weeks 40 to 52) 

Number (%) of subjects who use oral iron 
during the study period and the primary 
efficacy evaluation period (Weeks 40 to 52)

To evaluate the effect on iron metabolism
of GSK1278863 in ND subjects using
epoetin beta pegol as control

To evaluate the effect on iron metabolism 
of GSK1278863 in PD subjects

Change from baseline in ferritin

Change from baseline in transferrin saturation 
(TSAT)

Changes from baseline in hepcidin, serum iron, 
and total iron binding capacity (TIBC) 

To evaluate the PK of GSK1278863

AUC and Cmax of plasma GSK1278863
Exploratory (efficacy)

To evaluate the effect on progression of 
Chronic Kidney Disease (CKD) of 
GSK1278863 in ND subjects using
epoetin beta pegol as control

Estimated glomerular filtration rate (eGFR) 
and change from baseline

Serum creatinine and change from baseline

Urine creatinine and urine albumin, and 
changes from baseline

Urine albumin/creatinine ratio and change 
from baseline
Patient reported outcome

To evaluate the effect on health-related 
QoL (HR-QoL) of GSK1278863 in ND 
subjects using epoetin beta pegol as 
control

To evaluate the effect on HR-QoL of 
GSK1278863 in PD subjects
SF-36

Changes from baseline in SF-36 HR-QoL 
scores [Physical Component Summary (PCS), 
Mental Component Summary (MCS), and 8 
subscales]
EuroQol Health Utility Index (EQ-5D-5L)

Change from baseline in EQ-5D-5L score 

Change from baseline in EQ-5D-5L Visual 
Analog Scale (VAS) 
Safety

To evaluate the safety and tolerability of 
GSK1278863 in ND and PD subjects

Incidence and severity of AEs and SAEs, 
including AEs of special interest


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Objective
Endpoint

Reasons for discontinuation of study 
medication

Laboratory tests, ECG, vital signs, and 
ophthalmology assessments
Study Design
This is a Phase III, open-label, active-controlled, parallel-group, multi-center study to compare the efficacy 
(demonstration of non-inferiority) and safety of GSK1278863 administered for 52 weeks versus epoetin 
beta pegol in approximately 270 Japanese ND subjects with renal anemia. This study also includes an open-
label, uncontrolled part to evaluate the efficacy and safety of GSK1278863 in approximately 50 Japanese 
PD subjects. The study consists of the following 2 cohorts of different patient populations:
Patient 
population
Presence or absence of ESA therapy
(Hgb in subjects)
Treatment group
Target number of subjects
(randomized/enrolled)
Cohort 1
ND 
patient
ESA non-user (Hgb 8.0-<11.0 g/dL)
ESA user (Hgb 9.0-13.0 g/dL)
GSK1278863 group
135 subjects*
Epoetin beta pegol 
group
135 subjects*
Cohort 2
PD patient ESA non-user (Hgb 8.0-<11.0 g/dL)
ESA user (Hgb 9.0-13.0 g/dL)
GSK1278863 group
50 subjects
*: At least 50 ESA users and at least 50 ESA non-users will be randomized to Cohort 1. 
ESA: erythropoiesis-stimulating agent
In Cohort 1, 270 eligible ND subjects will be stratified by the current ESA therapy and baseline Hgb 
(ESA non-users: 9.5 g/dL, >9.5 g/dL, ESA users: <11.0 g/dL, 11.0 g/dL) and then randomized in a 
1:1 ratio to GSK1278863 or epoetin beta pegol group (135 subjects per group). 
In Cohort 2, 50 eligible PD subjects will be included in the GSK1278863 group. 
This study consists of a 4-week screening phase, a 52-week treatment phase [including the primary 
efficacy evaluation period (Weeks 40 to 52)], and a 4-week follow-up phase following the treatment 
phase. The study design is shown below. 
Screening phase
(4 weeks)
Treatment phase (52 weeks)
Follow-up phase
(4 weeks)
Primary efficacy 
evaluation period
Cohort 1
GSK1278863 group (N=135)
Non-dialysis (ND)
subjects
Epoetin beta pegol group (N=135)
Cohort 2
Peritoneal dialysis 
(PD) subjects
GSK1278863 group (N=50)
Week -4                Day 1                            Week 40          Week 52          Week 56


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Method of Administration of Study Medication in Each Treatment Group
In each treatment group, study medication will be administered as follows: 

GSK1278863 group (ND and PD subjects): Treatment with GSK1278863 will be started at a 
dose of 4 mg once daily on Day 1. From Week 4 onwards, dose adjustments will be made within 
the dose range of 1-24 mg every 4 weeks according to the prespecified dose adjustment 
algorithm to achieve and/or maintain Hgb within the target range (11.0-13 0 g/dL).

Epoetin beta pegol group (ND subjects):

ESA non-users: Subcutaneous treatment with epoetin beta pegol will be started at a dose of 
25 g once every 2 weeks on Day 1. Subsequently, dose adjustments will be made within 
the dose range of 25-150 g every 4 weeks according to the prespecified initial dose 
adjustment criteria to achieve the lower limit of the Hgb target (11.0 g/dL). Once Hgb 
increases to 11.0 g/dL or more, dose adjustments will be made according to the prespecified 
dose adjustment algorithm. After it is confirmed that all of the criteria for dosing interval 
change are met, dosing frequency will be changed to once every 4 weeks, and dose 
adjustments will be made within the dose range of 25-250 g every 4 weeks according to 
the prespecified dose adjustment algorithm to achieve and/or maintain Hgb within the target 
Hgb range (11.0-13.0 g/dL). 

ESA users: Prior ESA therapy will be replaced with subcutaneous treatment with epoetin 
beta pegol at the equivalent dose once every 4 weeks according to prespecified dose 
conversion. Subsequently, dose adjustments will be made within the dose range of 25-
250 g every 4 weeks according to the prespecified dose adjustment algorithm to achieve 
and/or maintain Hgb within the target range (11.0-13.0 g/dL).
Analysis
Assuming a non-inferiority margin of -1.0 g/dL, a treatment difference of 0.0 g/dL, and a standard 
deviation of 1.5 g/dL for mean Hgb during in the primary efficacy evaluation period in ND subjects, 
two-sample t-test has at least 99% power at a two-sided significance level of 5% with a sample size of 
100 subjects per group. Assuming a dropout rate of approximately 25%, 135 subjects will be 
randomized to each group. For PD subjects, the sample size is based on the feasibility. Assuming a 
sample size of 38 subjects and a standard deviation of 1.5 g/dL, the half the width of the 95% CI for 
mean Hgb during in the primary efficacy evaluation period is 0.493 g/dL.
The primary endpoint, which is the mean Hgb during the primary efficacy evaluation period, will be 
analyzed to demonstrate the non-inferiority of GSK1278863 to epoetin beta pegol in ND subjects. 
A mixed model for repeated measurements (MMRM) will be used to estimate the mean Hgb during 
the primary efficacy evaluation period and its 95% CI by treatment groups. As a preliminary 
assessment, it will be confirmed if the lower and upper limit of 95% CI for mean Hgb in GSK1278863 
group would lie fully within target range (11.0-13.0 g/dL) In addition, the point estimate and 95% CI 
for the treatment difference (GSK1278863-epoetin beta pegol) in mean Hgb during the primary 
efficacy evaluation period will be estimated. Non-inferiority will be established if the lower limit of 
the 95% CI is greater than -1.0 g/dL. Even if the 95% CI for the difference is completely negative (i.e. 


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lies fully within the range -0.75 to <0 g/dL) non-inferiority would still be concluded on condition that 
the mean Hgb estimate in the GSK1278863 group is within the target range.
The primary efficacy population will be the ITT Population, and the analysis will be repeated in the 
mITT and PP Population to evaluate the robustness of the conclusion. The subgroup analysis by the 
current ESA therapy (presence or absence) will also be conducted. Further details of sensitivity 
analyses will be provided in the Reporting and Analysis Plan (RAP).
The principal secondary endpoint, which is the proportion of subjects whose mean Hgb during the 
primary efficacy evaluation period is within the target range will be analyzed to demonstrate the 
superiority of GSK1278863 to epoetin beta pegol in ND subjects. 
In the mITT Population, a logistic regression model including treatment group, baseline Hgb, and the 
current ESA therapy (presence or absence) as covariates will be used to estimate the point estimate 
and 95% CI for the odds ratio (GSK1278863/epoetin beta pegol). This analysis will be performed to 
demonstrate the superiority at a two-sided significance level of 5%, conditional on the primary 
endpoint achieving noninferiority. Superiority will be established if the lower limit of the 95% CI for 
the odds ratio is greater than 1.0.


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2.
INTRODUCTION
GSK1278863 is a hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (PHI) that stimulates 
erythropoiesis in the same manner as innate response to hypoxia and is currently being developed as a 
new treatment for renal anemia.
2.1.
Study Rationale
This is a Phase III study to evaluate the efficacy and safety of GSK1278863 in Japanese non-dialysis 
(ND) and peritoneal dialysis (PD) subjects with renal anemia. The primary objective is to demonstrate 
non-inferiority of GSK1278863 to epoetin beta pegol based on hemoglobin (Hgb) in the ND patient 
population included in this study. Study results will be used as pivotal study data for an NDA 
submitted for GSK1278863 for the treatment of renal anemia in Japan. 
2.2.
Background
Renal anemia is diagnosed in many patients with CKD, and the prevalence of renal anemia increases 
with progression of CKD [Akizawa, 2011]. Causes of anemia in CKD patients include absolute or 
relative deficiency of erythropoietin (EPO), shortened erythrocyte survival, and reduced iron 
availability. Anemia is further exacerbated by chronic blood loss associated with hemodialysis 
procedure, infection, and functional hemolysis [Japanese Society for Dialysis Therapy, 2008]. 
GSK1278863 is a hypoxia-inducible factor-prolyl hydroxylase inhibitor that is currently being 
developed as a treatment for renal anemia. Data in Japanese patients have been collected from a 
Japanese Phase II 4-week treatment study in Japanese hemodialysis (HD) subjects (PHI116099: 97
Japanese subjects), an international multi-center Phase II 24-week treatment study in HD subjects 
(PHI113633: including 24 Japanese subjects), and an international multi-center Phase II 24-week 
treatment study in ND subjects (PHI113747: including 42 Japanese subjects). In these clinical studies, 
GSK1278863 increased endogenous EPO, reduced hepcidin, and increased Hgb in HD and ND 
subjects including Japanese subjects. In addition, GSK1278863 increased Hgb at lower blood EPO 
concentrations than existing erythropoiesis-stimulating agents (ESAs). 
Data from completed clinical and clinical pharmacology studies and the preclinical data safety 
package are provided in the Development Core Safety Information found in the current GSK1278863 
Investigator Brochure (IB). A benefit: risk assessment, including risk mitigation strategies, is outlined 
in Section 4.6.
3.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary (efficacy)

To demonstrate non-inferiority of 
GSK1278863 to epoetin beta pegol based 
on hemoglobin (Hgb) in ND subjects 

Mean Hgb during the primary efficacy 
evaluation period (Weeks 40 to 52)
Principal secondary (efficacy)

To demonstrate superiority of 

Number (%) of subjects with mean Hgb in the 


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Objective
Endpoint
GSK1278863 to epoetin beta pegol in 
terms of achievement/maintenance of 
target Hgb in ND subjects
target range (11.0-13.0 g/dL) during the 
primary efficacy evaluation period (Weeks 40 
to 52)
Other secondary (efficacy, PK)

To evaluate the appropriateness of the 
starting dose of GSK1278863 in ND 
subjects using epoetin beta pegol as 
control

To evaluate the appropriateness of the 
starting dose of GSK1278863 in PD 
subjects

Change in Hgb from baseline to Week 4 (Hgb 
increase rate)

Number (%) of subjects by Hgb change from 
baseline category to Week 4

To evaluate dose adjustments of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate dose adjustments of 
GSK1278863 in PD subjects

Distribution of the dose level

Duration of treatment interruption due to Hgb 
>13 g/dL

Frequency of dose adjustments

To evaluate the overall Hgb control by 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate the overall Hgb control by 
GSK1278863 in PD subjects

Hgb at each assessment time point and change 
in Hgb from baseline to each assessment time 
point

Number (%) of subjects with Hgb within the 
target range (11.0-13.0 g/dL) at each 
assessment time point

Proportion (%) of time with Hgb within the 
target range (11.0-13.0 g/dL) in the primary 
efficacy evaluation period (Weeks 40 to 52)

Time (number of days) to the lower Hgb target 
(11.0 g/dL) 

Number (%) of subjects who have an Hgb 
level of less than 7.5 g/dL

Number (%) of subjects who have an Hgb 
increase of more than 2 g/dL over any 4 weeks 
before Week 52

Number (%) of subjects who achieve an Hgb 
level of more than 13.0 g/dL and number of 
episodes

To compare the effect of GSK1278863 
versus epoetin beta pegol on iron use in 
ND subjects

To evaluate the effect of GSK1278863 on 
iron use in PD subjects

Dose of oral iron in the study period and the 
primary efficacy evaluation period (Weeks 40 
to 52) 

Number (%) of subjects who use oral iron 
during the study period and the primary 
efficacy evaluation period (Weeks 40 to 52)

To compare the effect of GSK1278863 

Change in ferritin from baseline


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Objective
Endpoint
versus epoetin beta pegol on iron 
metabolism in ND subjects

To evaluate the effect of GSK1278863 on 
iron metabolism in PD subjects

Change in transferrin saturation (TSAT) from 
baseline

Changes in hepcidin, serum iron, and total iron
binding capacity (TIBC) from baseline

To evaluate the PK of GSK1278863

AUC and Cmax of plasma GSK1278863
Exploratory (efficacy)

To compare the effect of GSK1278863 
versus epoetin beta pegol on progression 
of CKD in ND subjects

Estimated glomerular filtration rate (eGFR) 
and change from baseline

Serum creatinine and change from baseline

Urine creatinine and urine albumin, and 
changes from baseline

Urine albumin/creatinine ratio and change 
from baseline
Patient reported outcome

To compare the effect of GSK1278863 
versus epoetin beta pegol on health-
related QoL (HR-QoL) in ND subjects

To evaluate the effect of GSK1278863 on 
H-RQoL in PD subjects
SF-36

Changes in SF-36 HR-QoL scores (PCS, MCS, 
and 8 subscales) from baseline
EuroQol Health Utility Index (EQ-5D-5L)

Change in EQ-5D-5L score from baseline

Change in EQ-5D-5L Visual Analog Scale 
(VAS) from baseline
Safety

To evaluate the safety and tolerability of 
GSK1278863 in ND and PD subjects

Incidence and severity of AEs and SAEs, 
including AEs of special interest

Reasons for discontinuation of study 
medication

Laboratory tests, ECG, vital signs, and 
ophthalmology assessments
4.
STUDY DESIGN
4.1.
Overall Design 
This is a Phase III, open-label, active-controlled, parallel-group, multi-center study to compare the 
efficacy (verification of noninferiority) and safety of GSK1278863 administered for 52 weeks versus 
epoetin beta pegol in approximately 270 Japanese ND subjects with renal anemia. This study also 
includes an open-label, uncontrolled part to evaluate the efficacy and safety of GSK1278863 in 
approximately 50 Japanese PD subjects. The study consists of the following 2 cohorts of different 
patient populations. At least 50 ESA users and at least 50 ESA non-users will be randomized to 
evaluate by current ESA therapy(ESA user or ESA non-user).

Cohort 1: ND subjects (GSK1278863 and epoetin beta pegol groups)

Cohort 2: PD subjects (GSK1278863 group)


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For both patient populations, the Hgb criteria are specified according to the presence or absence of 
prior ESA: ESA non-users with an Hgb level of ≥8.0 to <11.0 g/dL and ESA users with an Hgb level 
of 9.0 to 13.0 g/dL will be included in the study. 
In Cohort 1, 270 eligible ND subjects will be stratified by the current ESA therapy (ESA non-user or 
ESA user) and baseline Hgb (ESA non-users: 9.5 g/dL, >9.5 g/dL, ESA users: <11.0 g/dL, 
11.0 g/dL) and then randomized in a 1:1 ratio to GSK1278863 or epoetin beta pegol group (135 
subjects per group). 
In Cohort 2, 50 eligible PD subjects will be included in the GSK1278863 group. 
This study consists of a 4-week screening phase, a 52-week treatment phase [including the primary 
efficacy evaluation period (Weeks 40 to 52)], and a 4-week follow-up phase following the treatment 
phase. The study design is shown in Figure 1.
Screening phase
(4 weeks)
Treatment phase (52 weeks)
Follow-up phase
(4 weeks)
Primary efficacy 
evaluation period
Cohort 1
GSK1278863 group (N=135)
Non-dialysis (ND)
subjects
Epoetin beta pegol group (N=135)
Cohort 2
Peritoneal dialysis 
(PD) subjects
GSK1278863 group (N=50)
Week -4                Day 1                            Week 40          Week 52          Week 56
Figure 1 Study Design
4.2.
Treatment Groups and Study Periods
Details for each study period and treatments are described below. In this study, a point-of-care Hgb 
analyzer (HemoCue®) will consistently be utilized for confirmation of subjects’ eligibility, withdrawal 
criteria and dose adjustments of study medication.
Screening phase
Subjects who have provided informed consent and meet all of the eligibility criteria at screening 
(Week -4) (Sections 5.1 and 5.2) will be provisionally enrolled in the study. Subjects who have used 
ESA and/or oral iron since before the start of the study must remain on the same regimen throughout 
the screening phase (intravenous iron will not be allowed). 


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Treatment phase
Subjects who meet all of the eligibility criteria at the start of the treatment phase (Day 1) will be 
enrolled in the study. Study medication (either GSK1278863 or epoetin beta pegol group) will be 
administered for 52 weeks according to randomization in Cohort 1 and GSK1278863 will be 
administered in Cohort 2 for 52 weeks. For ESA users, prior ESA will be replaced with study 
medication on Day 1. GSK1278863 will be orally administered once daily, and epoetin beta pegol will 
be subcutaneously administered once every 2 or 4 weeks. In both groups, dose adjustments for study 
medication during the treatment phase will be made according to the administration schedule specified 
in Section 6.4. to achieve and/or maintain Hgb within the target range (11.0-13.0 g/dL). In addition, 
supplemental iron therapy will be administered according to the standard initiation criteria as 
described in Section 6.12.. It should be noted that intravenous iron or dose change for oral iron will 
not be allowed from Day 1 to Week 4. 
Follow-up phase
Subjects will visit the site for follow-up assessments and observations 4 weeks after the 
completion/discontinuation of study treatment. During the follow-up phase, treatment of renal anemia 
will be allowed as necessary at the discretion of the investigator (or subinvestigator). 
4.3.
Study Subjects and Number of Subjects
In Cohort 1 involving ND subjects, a total of 270 subjects will be randomized (135 subjects in 
GSK1278863 group, 135 subjects in epoetin beta pegol group). The minimum target number of 
subjects is 50 ESA non-users and 50 ESA users to allow for evaluations by the current ESA therapy 
(ESA non-user or ESA user). Assuming a dropout rate of 35% during the screening phase, 
approximately 416 subjects need to be screened. Assuming a dropout rate of 25% after the start of 
study treatment, a total of 202 subjects are expected to complete the 52-week treatment. 
In Cohort 2 involving PD subjects, 50 subjects will be enrolled (GSK1278863 group only). Since the 
number of PD patients is very limited in Japan, the target number of subjects is not set for either ESA 
non-users or users. Assuming a dropout rate of 35% during the screening phase, approximately 77 
subjects need to be screened. Assuming a dropout rate of 25% after the start of study treatment, 38 
subjects are expected to complete the 52-week treatment. 
Table 1    Target Number of Subjects
Cohort 1 (ND subjects)
Cohort 2 (PD subjects)
Screened
416
77
Randomized/enrolled
270 *
50
Completed 52-week treatment
202
38
*: At least 50 ESA non-users and at least 50 ESA users will be randomized.
4.4.
Rationale for Study Design
Objectives and evaluations
This is a Phase III study to evaluate the efficacy and safety of GSK1278863 in Japanese ND and PD 
subjects with renal anemia. For Cohort 1, the study is designed as an active-controlled, parallel-group
comparative study to meet the primary objective, that is, to demonstrate non-inferiority of 
GSK1278863 to the existing drug in ND subjects. For Cohort 2, the study is designed as an 


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uncontrolled study because there are not many PD patients. The target Hgb range was set for study 
treatment in line with the Guidelines for Renal Anemia in Chronic Kidney Disease issued by the 
Japanese Society for Dialysis Therapy in 2008 [The Japanese Society for Dialysis Therapy, 2008] to 
demonstrate that treatment with GSK1278863 can result in achievement and/or maintenance of target 
Hgb in ND and PD subjects, and evaluate the appropriateness of the starting dose of GSK1278863. 
Control
For the ND patient population (Cohort 1), epoetin beta pegol, which has been widely used in Japanese 
patients with renal anemia, primarily ND patients, since its approval in Japan in 2011, was selected as 
control. 
Open-label
If the study is conducted as a double-blind study, it is necessary to not only administer GSK1278863 
orally (once daily) or epoetin beta pegol subcutaneously (once every 2 or 4 weeks), but also 
administer the matching placebo subcutaneously or orally. It will be more stressful for subjects and 
complicate treatment procedures to use both active drug and matching placebo for two drugs with 
different routes and intervals of administration for the purpose of maintaining the blind, and make 
dose adjustments for individual subjects according to the change in Hgb over time. Accordingly, this 
study is designed as an open-label study rather than a double-blind study, which seems infeasible. 
Since Hgb used for efficacy evaluation is an objective measure, and dose adjustments for study 
medication will be made according to the prespecified Hgb-based dose adjustment method in both 
GSK1278863 and epoetin beta pegol groups, it is unlikely that the open-label design will create any 
bias in the primary evaluation. 
4.5.
Rationale for Dose Levels
Starting dose and dose adjustments of GSK1278863
The starting dose (4 mg) and the dose adjustment method (maintenance dose range: 1-24 mg) for 
GSK1278863 are described in Section 6.4..
The starting dose and the dose adjustment algorithm selected for Japanese ND subjects in the present 
study are based on the results from a review of the longitudinal model constructed using Hgb data 
from six Japanese or overseas Phase II studies (PHI112844, PHI116581, PHI116582, PHI113633, 
PHI113747, and PHI116099) as well as the results from clinical studies. The data set used in the 
model analyses was based on the data of GSK1278863 administered in a wide dose range (0-25 mg) 
and included a Japanese Phase II 4-week treatment study (PHI116099) and international multi-center 
late Phase II 24-week treatment studies (PHI113633 and PHI113747) in which subjects in Japan 
participated. For PD subjects, the starting dose and the dose adjustment algorithm for ND subjects will 
be applied based on the PK/PD profiles in PD subjects determined from an interim analysis in an 
overseas 14-day treatment clinical pharmacology study (PHI200942). 
Starting dose
Simulation results using the longitudinal model in ND subjects as well as the results from clinical 
studies indicated that GSK1278863 given at a dose of 4 mg may slowly increase Hgb (0.5-1.0 g/dL on 
average) without a rapid increase greater than 2 g/dL after 4 weeks of treatment in ESA non-users. 
4 mg GSK1278863 may also maintain Hgb without a rapid increase greater than 2 g/dL for 4 weeks 


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after switching from prior ESA in ESA users. Covariate analyses identified baseline Hgb, body weight, 
and dose level of prior ESA as major factors affecting Hgb. However, Hgb was more greatly affected 
by inter-subject differences in drug response to GSK1278863 than these factors.
Taken together, 4 mg may be an appropriate starting dose of GSK1278863 for both ESA non-users 
and users. 
Maintenance dose range and dose adjustment algorithm
Simulation results using the longitudinal model showed that drug response to GSK1278863 greatly 
varied among subjects, indicating that the dose range from 1 to 24 mg may be necessary to achieve 
and maintain target Hgb. Accordingly, a total of 8 dose levels (1, 2, 4, 6, 8, 12, 18, and 24 mg) were 
selected as the maintenance doses, with 4 mg intended for subjects with a standard drug response. 
The dose adjustment algorithm was defined so that target Hgb (11.0-13.0 g/dL) set for the present 
study according to the Guidelines for Renal Anemia [The Japanese Society for Dialysis Therapy,
2008] can be maintained. Since the upper limit of the Hgb target (13.0 g/dL) is equivalent to the 
interruption criterion for ESA, the dose level of GSK1278863 will be reduced by one step when Hgb 
increases to more than 12.5 g/dL, and the dose level will be maintained while Hgb is in the range of 
11.5-<12.5 g/dL. Since the guidelines state that an Hgb increase of 0.5 g/dL or less per week is 
appropriate to prevent adverse reactions, the dose level will be reduced by one step when Hgb 
increases by more than 2 g/dL over 4 weeks. For subjects whose anemia needs to be corrected 
(≥7.5 g/dL and <11.5 g/dL), the dose level will be maintained while the Hgb increase per 4 weeks is 
0.5-2 g/dL, and the dose level will be increased by one step when the Hgb increase per 4 weeks is less 
than 0.5 g/dL. 
Starting dose and dose adjustments of control (epoetin beta pegol)
The starting dose and the dose adjustment algorithm for epoetin beta pegol are described in Section 
6.4..
The starting dose of epoetin beta pegol for subjects not using ESA or subjects on epoetin was selected 
based on the Prescribing Information in Japan. For subjects on darbepoetin alfa, darbepoetin alfa will 
be switched to epoetin beta pegol at a dose ratio of 6:5 according to overseas Prescribing Information, 
given no specification for dose conversion from darbepoetin currently approved in Japan to epoetin 
beta pegol. 
The dose adjustment algorithm for epoetin beta pegol was determined based on the product 
information and previous Japanese clinical studies. 
4.6.
Benefit: Risk Assessment
Summaries of findings from clinical and nonclinical studies of GSK1278863 can be found in the IB
and IB supplement. The risk assessment and risk minimization strategies for the present study are 
outlined in the following sections: 
4.6.1.
Risk Assessment
Based on the results of completed clinical and nonclinical studies of GSK1278863, the potential risks 
of clinical significance and the risk minimization strategies for the present study are outlined in 
Section 12.2. Appendix 2.


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4.6.2.
Benefit Assessment 
Study PHI201753 is a Phase 3 study in Japanese ND and PD subjects with renal anemia. Previous
clinical studies of GSK1278863 administered for up to 24 weeks in ND or HD subjects have 
demonstrated clinical efficacy (increase in and/or maintenance of Hgb) with serum EPO 
concentrations increased within the normal physiologic range in CKD subjects. Data obtained in 
Study PHI201753 will generate safety and efficacy data in Japanese ND and PD subjects with renal 
anemia for a 52-week treatment period. Study participants who will receive GSK1278863 may benefit 
from the expected clinical efficacy. Participants who will receive the control (epoetin beta pegol 
approved for the treatment of renal anemia in Japan) are also expected to benefit from the clinical 
efficacy. 
GSK1278863 may have important advantages over existing ESAs. GSK1278863, which is orally 
administered and requires no cold chain management unlike ESAs, is more convenient to patients. 
GSK1278863 is shown to increase Hgb at lower EPO concentrations than ESAs. Since increased 
exposure to EPO following administration of ESAs may be associated with an increased 
cardiovascular risk [Szczech, 2008], GSK1278863 may increase Hgb without increasing the 
cardiovascular risk. 
4.6.3.
Overall Benefit: Risk Conclusion
GSK1278863 is shown to have a positive benefit-risk balance based on the following findings: in 
studies of GSK1278863 administered for up to 24 weeks, treatment with GSK1278863 resulted in 
achievement of target Hgb, and no adverse events have been identified as related to treatment with 
GSK1278863.
The present study is intended to evaluate the efficacy and safety of GSK1278863 administered for 52
weeks in Japanese ND and PD subjects with renal anemia, and designed to administer GSK1278863 
or epoetin beta pegol as control to all enrolled subjects; therefore, subjects randomized in either 
treatment group are expected to benefit from the treatment. 
This protocol employs precautions to mitigate known and potential risks to enrolled subjects (Section 
12.2. Appendix 2). Given these precautions, as well as the potential benefit that GSK1278863 holds 
for the treatment of renal anemia compared with the current standard treatment, the overall benefit risk 
balance is considered to be positive.
5.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, and other 
pertinent information on the GSK investigational product or other study treatment that may impact 
subject eligibility is provided in the IB/IB supplement(s) and/or other pertinent documents.
Deviations from inclusion/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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5.1.
Inclusion Criteria
Subjects eligible for enrolment in the study must meet all of the inclusion criteria.
Note: Verification at both provisional enrolment (screening) and official enrolment (Day 1) is required, 
unless otherwise specified.
1.
Age (at the time of informed consent): ≥20 years of age
2.
Stage of chronic kidney disease (CKD) (ND patients only): CKD stages 3, 4, and 5 defined by 
eGFR using the Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-
CKDI) formula
3.
Dialysis: 

Not on dialysis for at least 12 weeks prior to screening (ND patients)

On peritoneal dialysis (PD patients)
4.
Use of erythropoiesis-stimulating agent (ESA): 

ESA non-users: Have not used ESAs for at least 8 weeks prior to screening

ESA users: Have used the same ESA for at least 8 weeks prior to screening. However, in the 
ND patients, the dose of darbepoetin alfa or epoetin beta pegol must be stable (administered 
once every 4 weeks and up to one-step dose change during at least 8 weeks prior to 
screening). 
5.
Hemoglobin (Hgb): Determined at the site using an Hgb analyzer (HemoCue) 

ESA non-users: ≥8.0 g/dL and <11.0 g/dL

ESA users: ≥9.0 g/dL and ≤13.0 g/dL 
6.
Iron parameters: Ferritin >100 ng/mL or transferrin saturation (TSAT) >20% (screening 
verification only)
7.
Gender (screening verification only): Female or male
Females: Not pregnant [demonstrated to be negative for human chorionic gonadotropin (hCG) in 
urine or serum], not breast-feeding, and meet at least one of the following: 
1)
Females of non-childbearing potential are defined as follows: 

Pre-menopausal with at least one of the following and no plans to utilise assisted 
reproductive techniques (e.g., in vitro fertilisation or donor embryo transfer):

History of bilateral tubal ligation or salpingectomy

History of hysteroscopic tubal occlusion and postoperatively documented bilateral 
tubal obstruction 

History of hysterectomy

History of bilateral oophorectomy

Postmenopausal defined as 1) females 60 years of age or older or 2) In females < 60 years 
of age, 12 months of spontaneous amenorrhea [in questionable cases a blood sample with 
postmenopausal follicle stimulating hormone (FSH) and estradiol concentrations is 
confirmatory (see separately specified reference ranges)]. Females on hormone replacement 
therapy (HRT) whose menopausal status is in doubt will be required to use one of the most 
effective contraception methods 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 enrolment.


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2)
Females of childbearing potential must agree to comply with one of the contraception 
methods listed as requirements in “GSK Listing of Most Effective Contraceptive Methods for 
Females of Childbearing Potential (Section 12.3. Appendix 3: Modified List of Highly Effective 
Methods for Avoiding Pregnancy in Females of reproductive potential)” from at least 28 days 
prior to the first dose of study medication until the completion of the follow-up visit (for subjects 
randomized to the GSK1278863 group) or 7 weeks after the last dose of study treatment (for 
subjects randomized to the Epoetin beta pegol group).
8.
Informed consent: Written informed consent, including adherence to the requirements and 
conditions specified in the consent form and the protocol, must be obtained from each subject as 
specified in Section 10.2..
5.2.
Exclusion Criteria
Subjects meeting any of the following criteria must not be enrolled in the study.
Note: Verification at both provisional enrolment (screening) and official enrolment (Day 1) is required, 
unless otherwise specified.
Chronic kidney disease (CKD)-related criteria 
1.
Dialysis

Cohort 1: Start or plan to initiate dialysis during the study

Cohort 2: Plan to stop peritoneal dialysis or start hemodialysis during the study
2.
Kidney transplant: Planned living-related kidney transplant during the study
Anemia-related criteria
3.
Aplasia: History of bone-marrow hypoplasia or pure red cell aplasia
4.
Other causes of anemia: pernicious anemia, thalassemia, sickle cell anemia, or myelodysplastic
syndromes
5.
Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal 
ulcer disease OR clinically significant GI bleeding within 8 weeks prior to screening or during a 
period from screening to Day 1.
Cardiovascular disease-related criteria
6.
Myocardial infarction, acute coronary syndrome, stroke, or transient ischemic attack: Diagnosed 
within 8 weeks prior to screening or during a period from screening to Day 1.
7.
Heart failure: Class IV heart failure, as defined by the New York Heart Association (NYHA) 
functional classification system
8.
QTc (screening verification only): QTc >500 msec or QTc >530 msec in subjects with bundle 
branch block 
Note: QT interval corrected using the Bazett’s formula (QTcB) will be used, and ECG can be 
mechanically or manually read. 
Other disease-related criteria
9.
Liver disease (if any of the following occurs): 

Alanine transaminase (ALT) >2×upper limit of normal (ULN)


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
Bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is acceptable if bilirubin is fractionated 
and direct bilirubin is <35%)

Current unstable active liver or biliary disease (generally defined by the onset of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, persistent 
jaundice, or cirrhosis)
Note: Stable liver disease (including asymptomatic gallstones, chronic hepatitis B/C, or 
Gilbert’s syndrome) is acceptable if the subject otherwise meets entry criteria.
10. Malignancy: History of malignancy within 2 years prior to screening, or currently receiving 
treatment for cancer, (PD patients only) complex renal cystic >3 cm (II F, III or IV based on the 
Bosniak classification)
Note (ND patients and PD patients): The only exception is squamous cell or basal cell carcinoma 
of the skin that has been definitively treated 8 weeks before screening.
11. In the opinion of the investigator, Hgb increase to the target range (11.0-13.0 g/dL) is medically 
risky.
Concomitant medication and other study treatment-related criteria
12. Iron: Planned use of intravenous iron during the screening phase or during a period from Day 1 
to Week 4
Note: Oral iron is acceptable. However, the same dose regimen must be used throughout the 
screening phase and from Day 1 to Week 4. Antihyperphosphatemic agents containing iron (e.g., 
ferric citrate hydrate) are also acceptable only if used for at least 12 weeks prior to screening. 
However, they must be continued throughout the screening phase and from Day 1 to Week 4. 
13. Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity 
to excipients in the investigational product (see the GSK1278863 IB or epoetin beta pegol
Prescribing Information)
14. Drugs and supplements: Use or planned use of any prescription or non-prescription drugs or 
dietary supplements that are prohibited during the study period (prohibited medications: strong 
inducers and inhibitor of CYP2C8, see Section 6.11.2.)
15. Prior investigational product exposure: Use of an investigational agent within 30 days or five half 
lives of the investigational agent (whichever is longer)
16. Prior treatment with GSK1278863: Any prior treatment with GSK1278863 for a treatment 
duration of >30 days
General health-related criteria
17. Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding 
that the investigator (or subinvestigator) considers would put the subject at unacceptable risk, 
which may affect study compliance or prevent understanding of the aims or investigational 
procedures or possible consequences of the study
5.3.
Screening Failures
Screen failures are defined as subjects who consent to participate in the clinical trial and are screened, 
but are not subsequently randomized in the study. A minimum set of information is required from 
screen failure subjects including Demography, Screen Failure details, Eligibility Criteria, and SAEs in 


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order to report screen failures in a reliable manner, satisfy the requirements for publication defined by 
the Consolidated Standards of Reporting Trials (CONSORT), and respond to requests of the 
regulatory authorities.
Subjects that fail screening are eligible to be rescreened up to 3 times as soon as the investigator (or 
subinvestigator) assesses they may meet study entry criteria.
5.4.
Withdrawal/Dropout Criteria
If subjects meet one of the following criteria, study treatment should be permanently discontinued and 
subjects will be withdrawn from the study. The withdrawal reason should be recorded.

Hgb <7.5 g/dL
Note: HemoCue Hgb values will be employed. If an initial Hgb value meets the Hgb stopping 
criteria, measurement will be repeated at the same study visit (using the same sample) to 
calculate the average. If the average meets the Hgb stopping criteria, study treatment will be 
discontinued.

Subject needs for maintenance dialysis or changes dialysis modality (PD subjects only) during 
the study period.

Kidney transplant

Subject becomes pregnant or intends to become pregnant during the study.

Diagnosis of new or recurrent cancer

Liver chemistry abnormalities exceeding the threshold criteria (see Section 5.4.1.)

Need for chronic (more than 14 days) use of prohibited medication

When the investigator (or subinvestigator) considers necessary to withdraw the subject from the 
study for other reasons
Subjects who meet any of the withdrawal criteria or are withdrawn for other reasons during the 
treatment phase should be assessed at withdrawal visit after study treatment is discontinued, and will 
then enter the follow-up phase. 
Should a subject fail to attend a required study visit, the investigator (or subinvestigator) should take 
the following measures: 

The investigator (or subinvestigator) or designee should attempt to contact the subject and re-
schedule the missed visit as soon as possible.

The investigator (or subinvestigator) should counsel the subject on the importance of maintaining 
the assigned visit schedule and determine whether the subject is willing to continue his/her 
participation in the study and/or whether the subject should remain in the study. 

The investigator (or subinvestigator) or designee should make every effort to regain contact with 
a subject who is deemed “Lost to Follow-up”. All efforts to contact the subject should be 
documented in the subject’s clinical charts. 

Should the subject continue to be unreachable, then and only then will he/she be considered 
“Lost to Follow-up.”


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A subject may withdraw from the study at any time at his/her own request. The investigator (or 
subinvestigator) may withdraw a subject from the study at any time for safety or compliance reasons 
or study conduct considerations. If a subject withdraws from the study, he/she may request destruction 
of any clinical samples taken, and the investigator (or subinvestigator) must document this in the site 
study records.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure subject 
safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety 
guidance).


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Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Chemistry Increased Monitoring Algorithm with Continued Therapy for ALT 3xULN 
but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in Section 12.5. 
Appendix 5


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5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by any subject 
participating in this study is not allowed.
5.5.
Subject and Study Completion
A completed subject is one who has completed all periods of the study including the follow-up visit.
The study will be completed with the last subject’s last study visit. 
6.
STUDY TREATMENTS
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any products received by the 
subject as per the protocol design. Accordingly, ‘study treatment’ sometimes refers to each product 
and sometimes refers to multiple products. 
GSK1278863 (study drug)
The study drug GSK1278863 will be supplied as fast-release film coated tablets for oral 
administration containing 1 mg, 2 mg, 4 mg, or 6 mg of GSK1278863 (Table 2). There are two sizes 
of GSK1278863 tablets.
Table 2   Description of GSK1278863 Tablets
GSK1278863 tablets of 
specific content
Description
1 mg tablets, 2 mg tablets, 
4 mg tablets
7.0 mm round, standard biconvex, white film coated tablets containing 
1 mg, 2 mg, or 4 mg of GSK1278863 as active ingredient
6 mg tablets
9.0 mm round, standard biconvex, white film coated tablets containing 
6 mg of GSK1278863 as active ingredient
GSK1278863 tablets of specific content are packed in high density polyethylene (HDPE) bottles, with 
35 tablets per bottle. Subjects are to take one to four tablets (Table 3) with water once daily according 
to the dose level indicated at each study visit. Subjects can take GSK1278863 tablets without regard to 
food or peritoneal dialysis. The administration schedule (starting dose and dose adjustment) described 
in Section 6.4.1. should be followed. 
Table 3    Dose Levels of GSK1278863 and Number of Tablets Taken
Dose level of 
GSK1278863
(once daily)
1 mg
2 mg
4 mg
6 mg
8 mg
12 mg
18 mg
24 mg
Number of 
GSK1278863
tablets taken
1 mg 
tablet
×1
2 mg 
tablet
×1
4 mg 
tablet
×1
6 mg 
tablet
×1
4 mg 
tablet
×2
6 mg 
tablet
×2
6 mg 
tablet
×3
6 mg 
tablet
×4
Subjects should be instructed to bring GSK1278863 tablets with bottles at each study visit, and all 
unused GSK1278863 tablets will be collected from subjects at each study visit.


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Epoetin beta pegol (control)
The control epoetin beta pegol (brand name: MirceraPre-filled Syringe) will be supplied by GSK. 
This product is an injectable formulation containing 25 g, 50 g, 75 g, 100 g, 150 g, 200 g, or 
250 g of epoetin beta pegol per syringe (0.3 mL) and is supplied as a glass syringe prefilled with 
epoetin beta pegol solution (clear colorless to pale yellow). 
Subjects are to receive epoetin beta pegol subcutaneously once every 2 or 4 weeks at the site (Table 4). 
The administration schedule (starting dose and dose adjustment) described in Section 6.4.2. should be 
followed. 
Table 4    Dose Levels of Epoetin Beta Pegol and Number of Subcutaneous Doses
Dose level of epoetin beta 
pegol
(once every 2 or 4 weeks)
25 g
50 g
75 g
100 g
150 g
200 g
250 g
Number of subcutaneous 
doses of epoetin beta pegol
25 g 
injection
×1
50 g 
injection
×1
75 g
injection
×1
100 g 
injection
×1
150 g 
injection
×1
200 g 
injection
×1
250 g 
injection
×1
6.2.
Medical Devices
The Epoetin beta pegol (Brand name :MIRCERA® Injection Syringe) marketed with the device (kit 
formulation which was filled liquid medication in glass syringe ) provided for use in this study.
Instructions for medical device are described in the Prescribing Infromation of MIRCERA® Injection 
Syringe.
The medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study – see Section 7.4.4.
6.3.
Treatment Assignment
The randomization schedule will be generated by GlaxoSmithKline (GSK) using the randomization 
system (Randall).
In Cohort 1 (ND subjects), subjects will be stratified by the current ESA therapy (ESA non-user or 
ESA user) and the Hgb level on Day 1 and randomized in a 1:1 ratio to one of the two treatment 
groups according to the randomization schedule. Randomization should precede the study treatment. 

GSK1278863 group

Epoetin beta pegol group
In Cohort 2 (PD subjects), all eligible subjects will start treatment with GSK1278863 on Day 1. 
Subjects will be assigned a randomization number by the Interactive Web Recognition System 
(IWRS). Once a randomization number has been assigned, it must not be re-assigned. Further details 
are provided in the Study Reference Manual (SRM).


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6.4.
Administration Schedule (Starting Dose, Dose Adjustment, and Dosing 
Frequency)
6.4.1.
GSK1278863 (ND and PD Subjects)
6.4.1.1.
Starting Dose
For ND (Cohort 1) and PD subjects (Cohort 2) randomized to the GSK1278863 group, both ESA non-
users and users will start oral treatment with GSK1278863 at the starting dose of 4 mg once daily 
(Day 1) and remain on the same regimen until the day of Week 4. 
ESA users should skip ESA on Day 1 when treatment with GSK1278863 is started. 
6.4.1.2.
Maintenance Dose
From Weeks 4 to 52, interruption of treatment or dose adjustments will be made within the 
maintenance dose range of 1-24 mg (Table 5) according to the dose adjustment algorithm (Table 6) to 
achieve and/or maintain Hgb within the target range (11.0-13.0 g/dL) based on the HemoCue Hgb 
value measured every 4 weeks. Dose changes will be made every 4 weeks. If any of the one-step dose 
reduction criteria is met during treatment at the minimum maintenance dose (1 mg), treatment should 
be interrupted; once the one-step dose increase criteria are met, treatment at 1 mg will be resumed. If 
the one-step dose increase criterion is met during treatment at the maximum maintenance dose 
(24 mg), treatment at 24 mg should be continued. 
Table 5    Maintenance Dose of GSK1278863
Dose step
1
2
3
4
5
6
7
8
Dose level of 
GSK1278863
(once daily)
1 mg
2 mg
4 mg
6 mg
8 mg
12 mg
18 mg
24 mg
Number of 
GSK1278863
tablets taken
1 mg 
tablet
×1
2 mg 
tablet
×1
4 mg 
tablet
×1
6 mg 
tablet
×1
4 mg 
tablet
×2
6 mg 
tablet
×2
6 mg 
tablet
×3
6 mg 
tablet
×4


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Table 6   Dose Adjustment Algorithm (GSK1278863)
Hgb
(g/dL)
Hgb increase over 4 weeks 
(g/dL)
Treatment
>13.0
NA
Interrupt treatment until Hgb decreases to less than 
12.5 g/dL
Resume treatment at the one lower dose level (If 
interrupted at 1 mg: resume treatment at 1 mg once 
the one-step dose increase criteria are met)
12.5-13.0
NA
One-step dose reduction
11.5-<12.5
>2.0
One-step dose reduction
2.0
Continue treatment at the current dose level
7.5-<11.5
>2.0
One-step dose reduction
0.5-2.0
Continue treatment at the current dose level
<0.5
One-step dose increase
<7.5
NA
Discontinue treatment permanently * and initiate 
another appropriate treatment
*: If an initial Hgb value is less than 7.5 g/dL, measurement will be repeated at the same study visit (using the same 
sample) to calculate the average. If the average meets the Hgb stopping criteria, study treatment will be permanently
discontinued.
6.4.2.
Epoetin Beta Pegol (ND Subjects Only)
For ND subjects (Cohort 1) randomized to the epoetin beta pegol group, ESA non-users and users will 
receive epoetin beta pegol subcutaneously according to the treatment regimens described below.
6.4.2.1.
Starting Dose for ESA Non-users
ESA non-users will start subcutaneous treatment with epoetin beta pegol at a dose of 25 μg once every 
2 weeks (Day 1). Dose adjustments will be made within the initial dose range of 25-150 μg (Table 7)
according to the dose adjustment criteria (Table 8) to increase Hgb to 11.0 g/dL (lower limit of the 
target) or more based on the HemoCue Hgb value measured every 4 weeks. Dose changes will be 
made every 4 weeks. If any of the dose reduction criteria shown in Table 8 is met during treatment 
with epoetin beta pegol at 25 μg, treatment should be interrupted; once the dose reduction criteria are 
not met any longer, treatment will be resumed at a dose of 25 μg. 
Table 7    Initial Dose of Epoetin Beta Pegol (ESA Non-users)
Dose step
1
2
3
4
5
Dose level of epoetin beta pegol
(once every 2 weeks)
25 μg
50 μg
75 μg
100 μg
150 μg
Table 8    Initial Dose Adjustment Criteria for Epoetin Beta Pego (ESA Non-users)
Hgb
Treatment
Hgb increase <1.0 g/dL over past 4 weeks, 
OR Hgb <10.0 g/dL and Hgb increase ≤2.0 g/dL over past 4 weeks
One-step dose increase
Hgb increase >2.0 g/dL over past 4 weeks
One-step dose reduction
Otherwise
Continue treatment at the 
current dose level


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Once Hgb increases to 11.0 g/dL or more, dose adjustments will be made according to the 
prespecified dose adjustment algorithm (Table 12). The dosing interval should be changed from once 
every 2 weeks to once every 4 weeks with dose conversion for dosing interval change (Table 9) after 
it is confirmed that all of the following criteria are met:

Hgb in the target range (11.0-13.0 g/dL)

Hgb change ≤2.0 g/dL over past 4 weeks

Equivalent dose will be given twice (at least 4 weeks)
Table 9    Dose Conversion of Epoetin Beta Pegol for Dosing Interval Change (ESA 
Non-users)
Initial dose of epoetin beta pegol
(given once every 2 weeks)
Dose conversion of epoetin beta pegol
(given once every 4 weeks)
25 μg
→
50 μg
50 μg
→
100 μg
75 μg
→
150 μg
100 μg
→
200 μg
150 μg
→
250 μg
6.4.2.2.
Dose Conversion for ESA Users
For ESA users, prior ESA will be replaced with epoetin beta pegol at the equivalent dose once every 4 
weeks (Day 1). 
Table 10    Replacement with Epoetin Beta Pegol-Initial Dose (ESA Users)
Prior ESA
Epoetin beta pegol
Epoetin
<4500 IU per week
100 g once every 4 weeks
4500 IU per week
150 g once every 4 weeks
Darbepoetin alfa
30 g once every 4 weeks *
25 g once every 4 weeks
60 g once every 4 weeks *
50 g once every 4 weeks
90 g once every 4 weeks *
75 g once every 4 weeks
120 g once every 4 weeks *
100 g once every 4 weeks
180 g once every 4 weeks *
150 g once every 4 weeks
Epoetin beta pegol
25, 50, 75, 100, 150, 200, 250 g
once every 4 weeks *
25, 50, 75, 100, 150, 200, 250 g
once every 4 weeks
*: Allowance of ±1 week
Maintenance treatment will be started at Week 4 as described in Section 6.4.2.3.
6.4.2.3.
Maintenance Dose (ESA Non-users and Users)
Epoetin beta pegol will be administered once every 4 weeks from dosing interval change (once every 
4 weeks) with Hgb ≥11.0 g/dL to Week 52 in ESA non-users and from Weeks 4 to 52 in ESA users. 
Interruption of treatment or dose adjustments will be made within the maintenance dose range of 25-
250 μg (Table 11) according to the dose adjustment algorithm (Table 12) to achieve and/or maintain 
Hgb within the target range (11.0-13.0 g/dL) based on the HemoCue Hgb value measured every 4 
weeks. If any of the one-step dose reduction criteria is met during treatment at the minimum 
maintenance dose (25 μg), treatment should be interrupted; once the one-step dose reduction criteria 


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are not met any longer, treatment at 25 μg will be resumed. If the one-step dose increase criterion is 
met during treatment at the maximum maintenance dose (250 μg), treatment at 250 μg should be 
continued.
Table 11    Maintenance Dose of Epoetin Beta Pegol
Dose step
1
2
3
4
5
6
7
Epoetin beta pegol
(once every 4 weeks)
25 g
50 g
75 g
100 g
150 g
200 g
250 g
Table 12  Dose Adjustment Algorithm (Epoetin Beta Pegol)
Hgb
(g/dL)
Hgb increase over 4 weeks 
(g/dL)
Treatment
>13.0
NA
Interrupt treatment until Hgb decreases to less than 
12.5 g/dL
Resume treatment at the one lower dose level 
(resume treatment at 25 g if interrupted at 25 g)
12.5-13.0
NA
One-step dose reduction
11.5-<12.5
>2.0
One-step dose reduction
2.0
Continue treatment at the current dose level
7.5-<11.5
>2.0
One-step dose reduction
1.0-2.0
Continue treatment at the current dose level
<1.0
One-step dose increase
<7.5
NA
Discontinue treatment permanently * and initiate 
another appropriate treatment
*: If an initial Hgb value is less than 7.5 g/dL, measurement will be repeated at the same study visit (using the same 
sample) to calculate the average. If the average meets the Hgb stopping criteria, study treatment will be permanently 
discontinued.
6.5.
Blinding
This is an open-label study. 
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory requirements.
6.7.
Preparation/Handling/Storage/Accountability

No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study medications must be stored in a secure 
environmentally controlled and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator (or subinvestigator) and 
authorized site staff.

Subjects must bring all of supplied study medication bottles of GSK127886 at each study visit. 
Study staff will collect all of study medication bottles supplied at the previous study visit and 
supply new study medication bottles. 


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
The investigator (or subinvestigator), institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records). 

Under normal conditions of handling and administration, study medication is not expected to 
pose significant safety risks to site staff. GSK will provide a document describing occupational 
hazards and recommended handling precautions either to the investigator (or subinvestigator) 
when necessary or upon request of the medical institution. 

Further details are provided in the SRM. 
6.8.
Compliance with Study Treatment Administration
GSK1278863
Since GSK1278863 is self-administered, compliance with GSK1278863 treatment will be assessed 
through an interview with subjects at each study visit and recorded in the source document and eCRF. 
A record of the number of GSK1278863 tablets dispensed to and taken by each subject will be 
maintained and reconciled with study treatment and compliance records. In addition, the number of 
GSK1278863 doses dispensed, used, and unused, as well as study treatment start and stop dates will 
be recorded in the eCRF (the number of doses returned and unreturned will also be recorded 
separately).
Epoetin beta pegol
Epoetin beta pegol will be subcutaneously administered to subjects at the site. Dosing details will be 
recorded in the source document and eCRF. 
6.9.
Treatment of Study Treatment Overdose
There is no specific antidote for overdose with GSK1278863. 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 hemodialysis or peritoneal dialysis 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 a suspected overdose, 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 cardiovascular events, increased heart rate and hematologic abnormalities.
Consult the respective approved Prescribing Information for information on overdose for epoetin beta 
pegol.
6.10.
Treatment after the End of the Study
Since the target disease studied is not life-threatening or severely debilitating and there is the 
alternative therapy, subjects will not receive any additional treatment from GSK after completion of 
the study. The investigator (or subinvestigator) is responsible for ensuring that consideration has been 
given to post-study care of the subject’s medical condition. 


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6.11.
Concomitant Medications and Non-Drug Therapies
Concomitant medications, including over-the-counter medications and supplements, taken during the 
study will be recorded in the eCRF. Drug names and start/stop dates will be recorded for general 
concomitant medications, while additional details, including dose, route of administration, and dosing 
frequency, will be recorded for certain medications (e.g., ESAs, iron, anti-hypertensive medications).
Further details are provided in the SRM.
6.11.1.
Permitted Medications and Non-Drug Therapies
Unless specified as a prohibited medication in Section 6.11.2., all concomitant medications should be 
considered permitted provided they are not contraindicated for the individual subject concerned.
Regular multivitamins (at recommended daily allowance) and other supplements such as calcium and 
vitamin D may be used if permitted by the investigator or his/her designee. 
CYP2C8 is involved in the primary route of metabolism of GSK1278863. Accordingly, co-
administration of GSK1278863 with moderate CYP2C8 inhibitors (e.g., clopidogrel, teriflunomide, 
deferasirox) should be performed with caution. If one of these medications is started, stopped or the 
dose is changed, Hgb should be monitored every 4 weeks for 12 weeks using a point-of-care Hgb 
analyzer. 
Antihyperphosphatemic agents containing iron (e.g., ferric citrate hydrate) may be started from 
Week 4 onwards unless any other antihyperphosphatemic agents are appropriate. Once started, iron-
containing antihyperphosphatemic agents must be continued until the end of the study wherever
possible. 
6.11.2.
Prohibited Medications and Non-Drug Therapies
Use of any of the following drugs from screening until 7 days after the last dose of study treatment is 
prohibited:

Strong inhibitors of CYP2C8 (e.g., gemfibrozil)

Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)
6.12.
Supplemental Iron Therapy
Supplemental iron therapy will be administered according to the Guidelines for Renal Anemia [The 
Japanese Society for Dialysis Therapy, 2008] if ferritin is ≤100 ng/mL and TSAT is ≤20%. The 
investigator (or subinvestigator) can choose the route of administration and dose of prescription iron. 
7.
Study Assessments and Procedures
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the Time and 
Events Table, are essential and required for study conduct.
7.1.
Time and Events Table
The time and events tables for the entire study and PK assessment are presented as Table 13 and Table 
14, respectively. To allow scheduling flexibility, study visits may occur within a window of ±7 days
on Day 1 scheduled 4 weeks after screening, within a window of ±3 days at Week 4, and within a 


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window of ±5 days for the rest of the study. However, subjects receiving the control epoetin beta 
pegol every 2 weeks should attend study visits, including those only for study treatment, within a 
window of ±3 days. Visit days are counted from Day 1.


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Table 13    Time and Events Table
Phase
Screening
Treatment
Follow-up
Week
-4
Day 1
4
8
12
16
20
24
28
32
36
40
44
48
52
Early 
withdr
awal9
4 weeks 
after 52 or 
withdrawal
Permissible range (days)
±7
-
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
-
±7
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history, demography, 
height, weight
X
Registration with IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study medication dispensing 1,2
X
X
X
X
X
X
X
X
X
X
X
X
X
Study treatment compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
Ophthalmology 3
ECG
X
X
X
HemoCue Hgb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Urinalysis (ND subjects only)
X
X
X
X
X
Pregnancy test (urine or serum 
hCG) 4
X
X
X
X
X
X
X
X
X
Estradiol, FSH 5
X
PK 6
X
X
Ferritin, TSAT
X
X
X
X
X
X
X
X
Serum iron, TIBC, UIBC, serum 
transferrin, hepcidin
X
X
X
X
X
X
X
iPTH
X
X
X
HR-QoL
X
X
X
X
X
Genetics sample 7
X
Adverse event assessment 8
Review Concomitant Medications
1.
In Cohort 1, ESA non-users randomized to the epoetin beta pegol group will start treatment with epoetin beta pegol at a dose of 25 μg once every 2 weeks. For these subjects, specified examinations will 
be performed every 4 weeks, and no study-related assessments will be necessary at study visits only for study treatment (e.g., Week 2, Week 6) (see Section 6.4.2). It should be noted that subjects 
receiving epoetin beta pegol once every 2 weeks should attend study visits within a window of ±3 days.
2.
If a subject visit the study site only to receive study medication, only registration with the IWRS, study medication dispensing, and study medication compliance will be required. 
3.
Ophthalmology exams should be conducted at the following time points.


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
Screening: anytime after consenting and prior to first dose of study medication (Day 1)

Week 12: window from weeks 10-14 (inclusive)

End of study: window from weeks 48-52 (inclusive)

Early study medication discontinuation: withdrawal eye exam as close to the last dose as possible (the repeat exams are not required if one has been performed within the 2 prior weeks).
4.
Performed in females of childbearing potential: serum pregnancy test will be performed if urine pregnancy test is not feasible.
5.
Measured in female subjects only to determine the menopausal status (see Section 5.1.)
6.
See Table 14.
7.
Informed consent for optional Genetic research should be obtained before collecting a sample (see Section 7.6.).
8.
See Section 7.4.1.1..
9.
For withdrawn subjects, specified assessments should be done wherever possible.


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Table 14    Blood Sampling Schedule for Pharmacokinetics (Only Subjects in 
GSK1278863 Group)
PK sample
Week 12 2
Week 24 2
Blood sampling timing 1
1, 2, 3, and 4 h after administration of GSK1278863
Subjects must take the study medication with regard to blood sampling time. Subjects will record the date and time of the last two 
study medication doses taken prior to blood sampling in the medication diary. Preferably, there should be an interval of at least 12 h 
between these two doses. 
1.
Blood sampling should be completed within +/- 30 min of the planned collected time.
2.
Blood sampling not performed at this visit may be postponed until the following visits. 
7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors will be assessed (documented in the eCRF) at baseline.
In addition, the following demographic information will be collected:

Year of birth

Gender

Race and ethnic

Medical history/treatment history/family history will be assessed in relation to the 
inclusion/exclusion criteria (Section 5.). 
Full details of baseline assessments are provided in Table 13.
7.3.
Efficacy
Efficacy will be assessed according to the Time and Event Table (Table 13). 
Hgb concentrations measured by the central laboratory will be mainly used for efficacy assessment 
(see Section 7.4.7.). 
GSK will supply a point-of-care Hgb analyzer (HemoCue) to each site for rapid and convenient 
measurement of Hgb and to ensure consistency of Hgb measurements across all sites participating in 
the study. Assessment for Hgb concentrations via HemoCue will be used for eligibility (Section 5.1.), 
withdrawal (Section 5.4.), and dose adjustment criteria (Section 6.4.). 
In addition, assessments of iron metabolism parameters and measures of CKD progression (e.g., 
eGFR) used for efficacy assessment are outlined with specific procedures in Section 7.4.7..
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table (Table 13).  
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.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 12.6. Appendix 6.
The investigator and their designees are responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE.


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7.4.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-up contact 
(see Section 7.4.1.3.), at the timepoints specified in the Time and Events Table (Table 13).

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 section of the CRF.

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 hours, as indicated in Section 12.6.
Appendix 6.

Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 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 must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs plus procedures 
for completing and transmitting SAE reports to GSK are provided in Section 12.6. Appendix 6.
7.4.1.2.
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?”
7.4.1.3.
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 SAEs, and non-serious AEs of special interest (as defined in Section
7.4.2.) will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up (as defined in Section 5.4.). Further information on 
follow-up procedures is given in Section 12.6. Appendix 6..
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 12.6. Appendix 6 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be required to 
be completed.  These sections include questions regarding cardiovascular (including sudden cardiac 
death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA terms.  The 
CV information should be recorded in the specific cardiovascular section of the CRF within one week 
of receipt of a CV Event data query prompting its completion.  


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The Death CRF is provided immediately after the occurrence or outcome of death is reported. Initial 
and follow-up reports regarding death must be completed within one week of when the death is 
reported.
7.4.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to study 
treatment (even for non- interventional post-marketing studies) is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects and the safety of a product under clinical 
investigation 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 the regulatory authority, Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) 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 a 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.
7.4.2.
Adverse Events of Special Interest
The investigator (or subinvestigator) or designee will be responsible for detecting, documenting, and 
reporting any AEs of special interest listed below. These events have been identified based on the 
known safety profiles of ESAs, theoretical or potential risks based on the mechanism of action of 
GSK1278863, and findings from completed nonclinical studies of GSK1278863. 

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 

Death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access

Cardiomyopathy  

Pulmonary artery hypertension

Cancer-related mortality and tumor progression and recurrence 

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization 

Exacerbation of inflammatory joint disease (e.g., rheumatoid arthritis)
Any relevant AE should be recorded in the relevant section of the subject’s eCRF.
7.4.3.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of dosing and until 
the follow-up contact.


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
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of learning of 
the pregnancy and should follow the procedures outlined in Section 12.4.. Appendix 4.
Note: Subjects randomized in the epoetin beta pegol group should be advised to inform the 
investigator if they discover pregnancy in 7 weeks after the last dose of study treatment.
7.4.4.
Medical Device Incidents (Including Malfunctions)
The medical devices are being provided for use in this study. The investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction that occur 
during the study with such devices. 
The definition of a Medical Device Incident can be found in Appendix 8 (Section 12.8.)
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes outlined in 
Section 7.4.1. and Appendix 6 (Section 12.6.) of the Protocol.
7.4.4.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident will be detected, 
documented and reported during all periods of the study in which the medical devices are 
available for use. 

If the investigator learns of any incident at any time after a subject has been discharged from the 
study, and such incident is reasonably related to a medical device provided for the study, the 
investigator will promptly notify GSK.
NOTE: The method of documenting Medical Device Incidents is provided in Appendix 8 (Section 
12.8.).
7.4.4.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE, will be followed until resolution of the event, until 
the condition stabilizes, until the condition is otherwise explained, or until the subject is lost to 
follow-up (as defined in Section 5.4.). This applies to all subjects, including those withdrawn 
prematurely. 

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as practical the nature and/or 
causality of the incident.

New or updated information will be recorded on the originally completed form ”Medical Device 
Incident Report Form” with all changes signed and dated by the investigator.
7.4.4.3.
Prompt Reporting of Medical Device Incidents to GSK

Medical device incidents will be reported to GSK within 24 hours once the investigator 
determines that the event meets the protocol definition of a medical device incident.

Facsimile transmission of the "Medical Device Incident Report Form" is the preferred method to 
transmit this information to the SAE contact information.

The same individual will be the contact for receipt of medical device reports and SAEs.

In the absence of facsimile equipment, notification by telephone is acceptable for incidents, with 
a copy of the "Medical Device Incident Report Form" sent by overnight mail.


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7.4.4.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator, or responsible person will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.
7.4.5.
Vital Signs/Height/Weight
Systolic and diastolic blood pressure and pulse rate will be measured in sitting or semi-supine position 
after at least 5 minutes rest prior to clinical examination at each visit blood pressure and pulse rate. 
One reading of blood pressure and pulse rate will be taken and recorded in the source document and 
the CRF. Height and weight will be measured at screening visit only.
7.4.6.
Electrocardiogram (ECG)
12-lead ECGs will be recorded in supine position. The heart rate, PR, QRS, and QT (pre-corrected)
intervals will be measured. QTcB should be calculated by machine or manually by designated staff at 
each site. The investigator determines whether the ECG data is assessable or not.
At the Day 1 visit when an ECG is performed, two additional ECGs are required if initial ECG 
indicates prolonged QTc using the automated or manually calculated QTcB value. The average QTcB
value of all three ECGs will be used to determine eligibility.
QTc exclusion criteria can be found in Section 5.2. Refer to SRM for further details.
7.4.7.
Clinical Laboratory Assessments
All study-required laboratory assessments will be performed by a central laboratory with the exception 
of HemoCue Hgb. The results of each HemoCue Hgb must be entered into the subject’s eCRF. Details 
are provided in the SRM. 
All laboratory assessments, as defined in Table 15, must be conducted in accordance with the 
Laboratory Manual and Protocol Time and Events Schedule. Laboratory requisition forms must be 
completed and samples must be clearly labeled with the subject number, protocol number, site/center 
number, and visit date. Details for the preparation and shipment of samples will be provided by the 
central laboratory. Reference ranges for all parameters will be provided to the site by the central 
laboratory. Details of blood sampling (including the volume of blood to be collected) as well as 
procedures for processing, storage, and shipment of samples are provided in the SRM. 
PK assessment of GSK1278863 is outlined in Section 7.5.


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Table 15    Laboratory Assessments
Laboratory 
assessment
Parameter
Hematology
Platelet count
RBC indices:
WBC count with Differential
RBC count
MCV
Neutrophils
Reticulocyte count
MCH
Lymphocytes
Hemoglobin
MCHC
Monocytes
Hematocrit
RDW
Eosinophils
Basophils
Clinical chemistry
Sodium
AST
Bicarbonate
Potassium
ALT
Inorganic phosphate
Chloride
Creatinine
Glucose
Calcium (total and albumin-
corrected)
Total bilirubin
Direct/indirect bilirubin 
Albumin
Urea nitrogen
Total cholesterol
HDL cholesterol
LDL cholesterol
Iron parameters
Serum iron
Serum ferritin
Serum transferrin
TIBC
UIBC
TSAT
Hepcidin
Urinalysis
(ND subjects only) Urine albumin
Urine creatinine
Urine albumin/creatinine ratio
Other laboratory 
tests
FSH 1
Estradiol 1
iPTH
eGFR 2
hCG (serum or urine) 3
1.
Measured in female subjects only to determine the menopausal status (see Section 5.1.) 
2.
Calculated from serum creatinine using the Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-CKDI) 
formula
3.
Performed in females of childbearing potential: serum pregnancy test will be performed if urine pregnancy test is not feasible. 
If additional non-protocol specified laboratory assessments are performed at the institution’s local 
laboratory and result in a change in subject management or are considered clinically significant by the 
investigator (or subinvestigator) (e.g., SAE or AE or dose modification), the results must be recorded 
in the eCRF.
Refer to the SPM for appropriate processing and handling of samples to avoid duplicate and/or 
additional blood draws.
All laboratory tests with values that are considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline. If such 
values do not return to normal within a period judged reasonable by the investigator (or 
subinvestigator), the etiology should be identified and the Sponsor notified.
7.4.8.
Ophthalmology
Ophthalmology exams will be performed by a study-designated ophthalmology specialist. Each 
assessment will include a comprehensive eye exam with at least the following components: 
measurement of best corrected visual acuity, intraocular pressure, an anterior aqueous chamber exam, 
and a fundoscopic exam. These exams will be used for assessment of ocular adverse events. 
Assessment results will be captured on worksheets which will be transferred to the eCRF. Additional 
details on the process for completing these assessments are provided in the SRM.


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7.5.
Pharmacokinetics
Blood samples for PK analysis of GSK1278863 will be collected from only subjects in the 
GSK1278863 group as outlined in Table 14, and the date and time of the last two study medication 
doses taken prior to blood sampling as well as the date and time of sampling must be recorded in the 
eCRF.
Blood PK analysis will be performed under the control of GSK Platform Technologies and Science-
Drug Metabolism and Pharmacokinetics (PTS-DMPK)/Scinovo and GSK-Japan Bioanalysis, the
details of which will be included in the SPM. Concentrations of parent GSK1278863 will be 
determined in blood samples using the currently approved analytical methodology. Raw data will be 
archived at the bioanalytical site.
Procedures for processing, storage, and shipment of samples are provided in the SRM. 
7.6.
Genetics
A blood sample will be collected for genetic analysis from consenting subjects. This sample can be 
collected on Day 1 once written informed consent has been obtained. Information regarding genetic 
research is included in Section 12.7. Appendix 7.
7.7.
Patient Reported Outcome (PRO)
The patient reported outcome (PRO) [e.g., symptoms, severity, health-related QOL (HR-QoL), health 
status] will be assessed using several rating scales. 
All questionnaires used in this study have been translated into Japanese and validated. 
Specific instructions on how the subject is to complete the scales and the process for data entry are 
provided in the SPM.
7.7.1.
SF-36
The SF-36 acute version is a general health status questionnaire designed to elucidate the patient’s 
perception of his/her health on several domains, including physical functioning, role physical, bodily 
pain, vitality, social functioning, role emotional, mental health, and general health over the past seven 
days. The questionnaire contains 36 Likert type questions that ask the patient to recall how he/she felt 
during the past seven days.
7.7.2.
EuroQol Health Utility Index (EQ-5D-5L)/EQ Visual Analogue Scale (EQ-VAS)
The EQ-5D-5L is intended to measure the general health status and health utility. The EQ-5D-5L 
consists of 2 concepts: self-reported health status consisting of five dimensions (mobility, self-care, 
usual activities, pain/discomfort, anxiety/depression) each of which can take one of five responses and 
self-rated health status on a visual analog scale (VAS), a thermometer-like line. 


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8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted electronically to 
GSK or designee 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.  

CRFs (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.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
A detailed description of any planned analyses will be documented in a RAP..Any deviations from the 
analyses described in the protocol will be documented in the RAP or the final study report. 
9.1.
Hypotheses
The primary objective of the study is to demonstrate the non-inferiority of GSK1278863 to epoetin 
beta pegol based on mean Hgb during the primary efficacy evaluation period (Weeks 40 to 52) in ND 
subjects (Cohort 1). 
As a preliminary assessment, it will be confirmed whether the mean Hgb during the primary efficacy 
evaluation period in GSK1278863 group would be in target range (11.0-13.0 g/dL) at first. And then 
the following non-inferioritystatistical hypotheses are to be tested at a one-sided significance level of 
2.5% (i.e. two-sided significance level of 5%):

H0: Treatment difference in mean Hgb during the primary efficacy evaluation period is -1.0 g/dL 
or less.

H1: Treatment difference in mean Hgb during the primary efficacy evaluation period is greater 
than -1.0 g/dL.
Only when the primary endpoint achieves non-inferiority, statistical testing will progress to the 
principal secondary endpoint with a focus on superiority according to the step-down procedure. More 
specifically, the superiority of GSK1278863 to epoetin beta pegol in terms of target Hgb control in 
ND subjects is to be demonstrated at a two-sided significance level of 5% by testing the following 
statistical hypotheses:

H0: The proportion of subjects whose mean Hgb during the primary efficacy evaluation period is 
within the target range (11.0-13.0 g/dL) is equal between the treatment groups.

H1: The proportion of subjects whose mean Hgb during the primary efficacy evaluation period is 
within the target range (11.0-13.0 g/dL) is different between the treatment groups. 
No hypothesis will be tested in PD subjects (Cohort 2). 


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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Assuming a non-inferiority margin of -1.0 g/dL, a treatment difference of 0.0 g/dL, and a standard 
deviation of 1.5 g/dL for mean Hgb during the primary efficacy evaluation period in ND subjects, 
two-sample t-test has at least 99% power at a one-sided significance level of 2.5% (i.e. two-sided 
significance level of 5%) with a sample size of 100 subjects per group. Assuming a dropout rate of 
approximately 25%, 135 subjects will be randomized to each group. Given the results from previous 
non-inferiority studies of similar drugs (darbepoetin alfa, epoetin beta pegol, and peginesatide), the 
non-inferiority margin of -1.0 g/dL is set. Since an increase of 1.0 g/dL indicates improvement in 
anemia according to the guidelines for renal anemia in Japan, the non-inferiority margin of -1.0 g/dL
may be the clinically acceptable largest difference in renal anemia. 
While the present study is designed to ensure long-term safety data from 100 ND subjects, and the 
primary hypothesis test has at least 99% power to estimate the efficacy very precisely, non-inferiority 
can be statistically demonstrated with a minimum between-group difference of -0.582 g/dL. 
For PD subjects, the sample size is based on the feasibility. Assuming a sample size of 38 subjects and 
a standard deviation of 1.5 g/dL, the half width of the 95% CI for mean Hgb during the primary 
efficacy evaluation period is 0.493 g/dL. 
9.2.2.
Sample Size Sensitivity
The power is shown according to treatment difference and standard deviation in Table 16. 
Table 16    Power Sensitivity (100 Subjects Evaluated, Noninferiority Margin of -1.0, 
One-Sided Significance Level of 2.5%)
Treatment 
difference
Standard deviation
1.25
1.5
1.75
0
100.0%
99.7%
98.0%
-0.1
99.9%
98.8%
95.1%
-0.2
99.5%
96.4%
89.6%
-0.3
97.6%
90.7%
80.4%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned for this study.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations

All Screening Population
The All Screening Population consists of all subjects who are given subject number and whose data 
are collected, including demographics at screening.

Intent-to-Treat (ITT) Population (All randomized population)


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The Intention-To-Treat Population consists of all subjects who are given randomization number 
regardless of whether they actually receive study treatment. Subjects will be analyzed according to 
randomized treatment. This population will be the primary population for an assessment of non-
inferiority.

modified ITT (mITT) Population
The mITT Population consists of all ITT subjects who have at least one Hgb measurement during the 
efficacy evaluation period. Subjects will be analyzed according to randomized treatment. This 
population will be the primary population for an assessment of superiority. 

Per-Protocol (PP) Population
The PP Population consists of all mITT subjects who are not major protocol violators. Subjects will be 
analyzed according to the treatment received. Details will be defined in the RAP. This population will 
be used for efficacy sensitivity analyses.

Safety Population
The Safety Population consists of all ITT subjects who receive at least one dose of study treatment. 
Subjects will be analyzed according to the treatment received. This population will be used for safety 
analyses. 

PK Population
The PK Population consists of all GSK1278863-treated subjects from whom PK samples are collected 
and analyzed. 
Additional populations may be defined in the RAP.
9.3.2.
Interim Analysis
No interim analysis is planned. 
9.3.3.
Adjustment for Multiplicity
Adjustment for multiplicity will be applied to maintain an overall type I error rate of 5%. After a 
preliminary assessment, the primary endpoint will be evaluated to demonstrate the non-inferiority at a 
one-sided significance level of 2.5% (i.e. two-sided significance level of 5%). Only when the primary 
endpoint achieves non-inferiority, statistical testing will progress to the principal secondary endpoint 
with a focus on superiority. Since the process will follow step-down manner, a multiplicity adjustment
for significance level of 5% will not be needed according to a closed test procedure. 
Other secondary endpoints, which will be evaluated on a complementary or exploratory basis, will be 
compared at a significance level of 5% without multiplicity adjustment. 
Since Cohort 2 is a single-arm cohort, no testing will be performed to evaluate the efficacy in PD 
subjects. 


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9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Efficacy Analysis
The primary endpoint, which is the mean Hgb during the primary efficacy evaluation period, will be 
analyzed to demonstrate the non-inferiority of GSK1278863 to epoetin beta pegol in ND subjects. 
MMRM will be used to estimate the mean Hgb during the primary efficacy evaluation period and its 
95% CI by treatment groups. This model includes treatment groups, baseline Hgb, assessment visits, 
interaction terms between treatment groups and assessment visits, as well as interaction terms between 
baseline Hgb and assessment visit. As a preliminary assessment, it will be confirmed if the mean Hgb 
during the primary efficacy evaluation period in GSK1278863 group would be in target range (11.0-
13.0 g/dL) at first. This confirmation will be established if the lower and upper limit of 95% CI for the 
mean Hgb in GSK1278863 group would lie fully within target range (11.0-13.0 g/dL). In addition, the 
point estimate and 95% CI for the treatment difference (GSK1278863-epoetin beta pegol) in the mean 
Hgb during the primary efficacy evaluation period will be estmated. Non-inferiority will be 
established if the lower limit of the 95% CI is greater than -1.0 g/dL. Even if the 95% CI for the 
difference is completely negative (i.e. lies fully within the range -0.75 to <0 g/dL) non-inferiority 
would still be concluded on condition that the mean Hgb estimated in the GSK1278863 group is 
within the target range.
The primary efficacy population will be the ITT Population, and the analysis will be repeated in the 
mITT and PP Population to evaluate the robustness of the conclusion. The subgroup analysis by the 
current ESA therapy (presence or absence) will also be conducted.Further details of sensitivity 
analyses will be provided in the RAP.
9.4.2.
Principal Secondary Efficacy Analysis
The principal secondary endpoint, which is the proportion of subjects whose mean Hgb during the 
primary efficacy evaluation period is within the target range will be analyzed to demonstrate the 
superiority of GSK1278863 to epoetin beta pegol in ND subjects. 
In the mITT Population, a logistic regression model including treatment group, baseline Hgb, and 
current ESA therapy (presence or absence) as covariates will be used to estimate the point estimate 
and 95% CI for the odds ratio (GSK1278863/epoetin beta pegol). This analysis will be performed to 
demonstrate the superiority at a two-sided significance level of 5%, conditional on the primary 
endpoint achieving noninferiority. Superiority will be established if the lower limit of the 95% CI 
for odds ratio is greater than 1.0.
9.4.3.
Other Secondary Efficacy Analyses
Among the secondary efficacy endpoints, the time (%) in Hgb target range during the primary efficacy 
evaluation period , proportion of subjects who have an Hgb increase of more than 2 g/dL over any 4 
weeks, and changes in iron metabolism parameters (ferritin, TSAT, hepcidin, serum iron, and TIBC), 
the point estimates and 95% CIs for the treatment difference (or odds ratio) in ND subjects will be 
calculated. Other secondary efficacy and exploratory endpoints will be summarized by each treatment 
group. 
For PD subjects, the efficacy endpoints will be descriptively summarized. 


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9.4.4.
Safety Analyses
In principle, safety data will be summarized by each cohort and each treatment group in the Safety 
Population. 
9.4.4.1.
Exposure
Exposure information will be listed for all subjects. The duration of treatment (number of days) and 
cumulative dose will be tabulated. In addition, distribution of the dose level at each assessment visit
and final dosing visit will be tabulated. Frequency of dose adjustment and duration of treatment 
interruption due to Hgb >13 g/dL will be summarized.
9.4.4.2.
Adverse Events
All AEs will be categorized by the MedDRA system organ class and preferred term to tabulate the 
number and incidence. All AEs, SAEs, AEs leading to discontinuation of study treatment, and AEs of 
special interest will be summarized separately. Similar summary will be provided for study treatment-
related AEs. 
9.4.4.3.
Other Safety Parameters
For laboratory tests, vital signs and ECG, parameters and/or changes from baseline will be 
summarized using summary statistics at each assessment visit. The number and percentage of subjects 
with values of the potential clinical importance values will be tabulated. The criteria for the potential 
clinical importance will be described in the RAP. For lipid parameters (total cholesterol, LDL 
cholesterol, and HDL cholesterol), percent changes will also be tabulated. The number (%) of subjects 
who have any change in anti-hypertensive medications (type and/or dose) due to increased blood 
pressure will be tabulated.
9.4.5.
Pharmacokinetics Analyses
For plasma concentrations of GSK1278863 over time, individual data will be listed, and summary 
statistics at each time point will be calculated for each dose level. For PK parameters (AUC 0-4 and 
Cmax), summary statistics will be calculated for each dose level, and scatter plots against the dose 
level will be generated. 
9.4.6.
PRO Data Analysis
Details of PRO data tabulation will be described in the RAP.


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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 
enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the Informed Consent 
Process
The study will be conducted in accordance with “the Ministerial Ordinance on the Standards for the 
Conduct of Clinical Trials of Medicinal Products (MHW Notification No.28 dated 27th March, 1997)” 
and the Pharmaceutical Affairs Law.
GSK will submit the CTN to the regulatory authorities in accordance with with Article 80-2 of the 
Pharmaceutical Affairs Law before conclusion of any contract for the conduct of the study with study 
sites.
The study will be conducted in accordance with all applicable regulatory requirements, and with GSK 
policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), all applicable 
subject privacy requirements, and the guiding principles of the current version of the Declaration of 
Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and amendments as 
applicable

Signed informed consent to be obtained for each subject before participation in the study (and for 
amendments as applicable) 

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or both.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical protocol and all 
optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate informed 
consent) and the clinical protocol should be concurrently submitted for approval unless 
regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the clinical protocol 
where required by regulatory authorities.  In this situation, written approval of the clinical 
protocol should state that approval of optional assessments is being deferred and the study, with 
the exception of the optional assessments, can be initiated.
Informed Consent
Prior to participation in the study, the investigator (or subinvestigator) should fully inform the 
potential subject and the subject's legally acceptable representative (as required) of the study including 
the written information. The investigator (or subinvestigator) should provide the subject and the 
subject's legally acceptable representative ample time and opportunity to inquire about details of the 
study. The subject and the subject’s legally acceptable representative should sign and personally date 
the consent form. If the subject wishes to consider the content of the written information at home, 


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he/she may take the consent form home. The person who conducted the informed consent discussion 
and study collaborator giving supplementary explanation, where applicable, should sign and 
personally date the consent form. If an impartial witness is required, the witness should sign and 
personally date the consent form. The investigator (or subinvestigator) should retain this signed and 
dated form (and other written information) together with the source medical records, such as clinical 
charts (in accordance with the rules for records retention, if any, at each medical institution) and give a 
copy to the subject and the subject’s legally acceptable representative.
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 the CRF 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.
10.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, the GSK monitor will conduct site closure
activities with the investigator or site staff, as appropriate, in accordance with applicable regulations
including GCP, and GSK Standard Operating Procedures.
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 the reasons for taking such action with the
investigator or the head of the medical institution (where applicable). When feasible, GSK will
provide advance notification to the investigator or the head of the medical institution, where


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applicable, of the impending action.
If the study is suspended or prematurely discontinued for safety reasons, GSK will promptly inform
all investigators, heads of the medical institutions (where applicable) and/or institution(s) conducting
the study. GSK will also promptly inform the relevant 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 elsewhere), in a safe and secure location.  
The records must be maintained to allow easy and timely retrieval, when needed (e.g., for a GSK audit
or regulatory inspection) and must be available for review in conjunction with assessment of the
facility, supporting systems, and relevant site 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 ensure 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, GSK standards/procedures, and/or institutional requirements.  
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 is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of Information on 
Publically Available Clinical Trials Registers and Publicatio
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.
The procedures and timing for public disclosure of the results summary and for development of a 
manuscript for publication will be in accordance with GSK Policy.


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10.8.
Study Period
See Exhibit 1
10.9.
Study Administrative Structure
Sponsor information is included in Exhibit 2. List of Medical Institutions and Investigators is included 
in Exhibit 3.


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11. REFERENCES
Akizawa Tadao, Makino Hirofumi, Matsuo Seiichi, et al. Management of anemia in chronic kidney 
disease patients: baseline findings from Chronic Kidney Disease Japan Cohort Study. Clin Exp 
Nephrol. 2011;15:248-57.
Szczech Lynda A, Barnhart Huiman X., Inrig Jula K., et al. Secondary analysis of the CHOIR trial 
epoetin-α dose and achieved hemoglobin outcomes. Kidney International. 2008;74:791-8.
Guidelines for Renal Anemia in Chronic Kidney Disease issued by the Japanese Society for Dialysis 
Therapy in 2008. Journal of Japanese Society for Dialysis Therapy. 2008;41(10):661-716


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12. APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under Curve
CKD
Chronic Kidney Disease
Cmax
Maximum concentration
CPK
Creatine Phosphokinase
CYP
Cytochrome P450
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
EPO
Erythropoietin
EQ-5D-5L
EuroQol Health Utility Index
ESA
Erythropoiesis-Stimulating Agent
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
hCG
Human Chorionic Gonadotrophin
HD
Hemodialysis
HDL
High Density Lipoprotein
HDPE
High Density Polyethylene
Hgb
Hemoglobin
HIF
Hypoxia-Inducible Factor
HRT
Hormone Replacement Therapy
ICH
International Conference on Harmonization
INR
International Normalized Ratio
iPTH
Intact Parathyroid Hormone
ITT
Intent-to-Treat
IWRS
Interactive Web Recognition System
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
MCS
Mental Component Summary
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
ND
Non dialysis
NYHA
New York Heart Association
PCS
Physical Component Summary
PD
Peritoneal Dialysis
PHI
Prolyl Hydroxylase Inhibitor
PK
Pharmacokinetic
PP
Per-Protocol
PRO
Patient Reported Outcome
QT
Q-T Interval
QTc
Q-T Interval Corrected for Heart Rate
QTcB
Bazett’s Correction of QT Interval


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RAP
Reporting and Analysis Plan
RDW
Red Blood Cell Distribution Width
RNA
Ribonucleic Acid
rhEPO
Recombinant human erythropoietin
SAE
Serious Adverse Event
SRM
Study Reference Manual
TIBC
Total Iron Binding Capacity
TSAT
Transferrin Saturation
UIBC
Unsaturated iron Binding Capacity
VAS
Visual Analog Scale
VEGF
Vascular Endothelial Growth Factor
Trademark Information
Trademarks of the GlaxoSmithKline group of 
companies
Trademarks not owned by the GlaxoSmithKline 
group of companies
None
Hemocue


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12.2.
Appendix 2: Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
GSK1278863 
Excessive erythropoiesis (polycythemia) leading to 
thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis attributed to GSK1278863 
was associated with vascular congestion, microthrombi, and tissue 
ischemia in a number of organs.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
Phase 2 dose-ranging studies, and associated statistical and exposure 
response modelling has informed Phase 3 dose rationale, starting 
doses, dose levels, and dose adjustment scheme to optimize Hgb 
management.
•
Specific eligibility criteria related to requirements for 
entry Hgb are detailed in Section 5.1.
•
Hgb will be closely monitored throughout the dosing 
period as outlined in the Time and Events Table 
Section 7.1.
•
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of GSK1278863 
based on achieved Hgb is provided in Section 6.4.1.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Risk of death, MI, stroke, congestive heart failure, venous 
thromboembolism, thrombosis of vascular access at Hgb 
levels which are within the normal range (i.e. not 
polycythemic conditions)
Marketed rhEPO/ESAs have been associated with an increased risk for 
death and serious cardiovascular events when used in patients with 
anemia of CKD.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
•
Specific eligibility criteria related to CV risk are 
outlined in Section 5.2.
•
Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Esophageal and gastric erosions
In animal studies, undesirable GI effects including emesis, abnormal 
feces and/or decreased food consumption/body weight loss and 
stomach erosions/ ulcers with hemorrhage were observed.  
In rodents stomach erosions observed with intravenous and oral 
administration of GSK1278863.
Gender-averaged systemic exposure (AUC) at the no observed adverse 
•
Suspected GI bleeding or significant symptoms
consistent with erosion should be investigated 
diagnostically (i.e. endoscopic examination) as 
clinically warranted
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
effect levels (NOAEL) are 3.3 -fold (monkeys) and 737 -fold (rats) 
above human exposure (25 mg).
In clinical trials to date, mild-moderate GI signs and symptoms 
represent the most frequently reported adverse event, however causal 
association has not been established.
Following review of clinical data received to date, GI erosions have 
not been identified as a safety concern for GSK1278863.
period.
Cancer-related mortality, tumor progression and recurrence
In clinical trials, use of rhEPO in patients with cancer has been associated with 
increased risk of cancer related morbidity and mortality.
Administration of 60 mg/kg GSK1278863 to mice caused minimal increases in 
circulating VEGF while significant EPO increases were observed.
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations, an angiogenic factor that has been 
implicated in tumor growth, was observed at doses ranging from 10 to 
150 mg. In clinical studies up to 24 weeks duration at doses up to 
25 mg, changes in VEGF plasma concentrations were variable but 
similar relative to control.
Following review of clinical data received to date, this has not been identified 
as a safety concern for GSK1278863.
•
Specific eligibility criteria related to personal history 
of malignancy are outlined in Section 5.2..
•
Stopping criteria for subjects with treatment 
emergent malignancy are outlined in Section 5.4.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Pulmonary artery hypertension (PAH)
A role for HIF-regulated pathways in the pathophysiology of PAH has 
been suggested based on well established effects of acute and chronic 
hypoxia in man on the pulmonary vasculature (vasoconstriction), and 
by findings in patients with naturally occurring mutations that result in 
decreased HIF degradation (Smith, 2006; Formenti, 2011).
There have been no histopathologic findings suggestive of PAH in pre-
clinical safety studies (up to 13-weeks duration in mice and dog, up to 
26-weeks in rat, and up to 39-weeks in monkeys.
Acute hypoxic challenge (rats): GSK1278863A produced increases in 
peak right ventricular pressure (PRVP) during acute hypoxia that were 
slightly higher than the vehicle control group. These hypoxia-induced
PRVP changes fall within the range of PRVP differences noted among 
non-treated rats.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Results from a clinical study of acute hypoxic challenge in healthy 
volunteers demonstrated that short-term therapy with GSK1278863 
5 mg or 100 mg has no clinically significant effect on 
echocardiographically estimated pulmonary artery systolic pressure 
(PASP) under either normoxic or hypoxic conditions.
ECHO assessments performed in Phase 2b studies (24 weeks treatment 
duration) did not identify any clinically meaningful changes in sPAP in 
subjects not on dialysis. Further interrogation of sPAP data in dialysis 
subjects is ongoing.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.  
Cardiomyopathy
Published data suggest that cardiac effects of HIF stabilization are 
likely a function of the mechanism, extent, and duration of the effects, 
and can range from protective to detrimental depending upon the 
specific model and experimental conditions utilized.
Small increases in cardiac troponin in 6 month rat study were 
consistent with the background finding of spontaneous rodent 
cardiomyopathy. There were no elevations observed in cardiac 
troponin in 9 month monkey study.
Cardiomyopathy has not been associated with naturally occurring 
mutation in man which results in increased HIF stabilization.
ECHO assessments performed in phase 2b studies (24 weeks treatment 
duration) did not identify any clinically meaningful changes in LVEF.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Proliferative retinopathy, macular edema, choroidal 
neovascularization
Increases in local (ocular) VEGF production with retinal 
neovascularization and macular edema observed in diabetic 
retinopathy and to choroidal leakage, edema and neovascularization 
seen in age-related macular degeneration (Campochiaro, 2006).
Administration of 60 mg/kg GSK1278863 to mice caused minimal 
increases in circulating VEGF while significant EPO increases were 
•
Ophthalmology exams will be performed during 
screening, at approximately Week 12 on-study, and 
at the end of treatment.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
observed.
No ocular abnormalities were seen in non-clinical studies of up to 13 
weeks duration in mice and dogs, 26 weeks in rats, and 39-weeks in 
monkeys.  
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations was observed at doses ranging from 10 
to 150 mg. In studies up to 24 weeks duration at doses up to 25 mg, 
changes in VEGF plasma concentrations were variable but similar 
relative to control.
Ophthalmologic assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes 
in proliferative retinopathy, macular edema, or choroidal 
neovascularization.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
period.
•
Ophthalmology exams should be specified in 
Section 7.4.8. and monitored.
Exacerbation of rheumatoid arthritis
In inflamed rheumatic joints, activation of HIF- related genes 
secondary to decreased oxygen and pro-inflammatory cytokines has 
been postulated to contribute to the neo-angiogenesis, proliferation and 
infiltration of rheumatoid synovial fibroblasts (Westra, 2010; Muz, 
2009).
No abnormalities seen in non-clinical studies conducted to date.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Drug-drug interactions
Co-administration of GSK1278863 with a strong CYP2C8 inhibitor increased 
the Cmax and AUC of GSK1278863, 4- and 19-fold, respectively, while co-
administration of a weak inhibitor increased the Cmax and AUC of 
GSK1278863 by 1.3- and 1.5-fold, respectively. Population PK analysis from 
completed Phase 2 studies suggests that co-administration of GSK1278863 
with a moderate CYP2C8 inhibitor, leads to a ~ 2-fold increase in AUC, with no 
•
Co-administration of GSK1278863 with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 
inducers (e.g., rifampin/rifampicin) is not 
permitted as outlined in Section 6.11.2.
•
Co-administration of GSK1278863 with 
moderate CYP2C8 inhibitors (i.e., clopidogrel, 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
clinically-significant increase in the measured Hgb response.
GSK1278863 is an inhibitor of CYP2C8 in vitro, with an IC50 value of 
21 µM.
Population PK analysis from completed Phase 2 studies suggests that 
co-administration of GSK1278863 with clopidogrel (a moderate 
CYP2C8 inhibitor) leads to a ~ 2-fold increase in AUC, with no 
clinically-significant increase in the measured Hgb response. Co-
administration of GSK1278863 with moderate CYP2C8 inhibitors (i.e., 
clopidogrel, teriflunomide, deferasirox) should be performed with 
caution.
Co-administration of GSK1278863 with potent BCRP inhibitors has 
the potential to increase exposure of GSK1278863. Use of BCRP 
inhibitors (mostly weak) was found to result in a small change in 
metabolite exposure (20% increase in AUC).
GSK1278863 is an inhibitor of OATP1B1/1B3 in vitro, with IC50
values of 6 µM and 11 µM, respectively. A clinical drug interaction 
study between 25mg GSK1278863 with either a CYP2C8 substrate or 
an OATP1B1/1B3 substrate showed that there is no PK interaction at 
this dose of GSK1278863.
teriflunomide, deferasirox) should be 
performed with caution. If one of these 
medications is started, stopped or the dose is 
changed, Hgb should be monitored every 4 
weeks for 12 weeks as outlined in Section 
6.11.1.
•
Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in Section 
6.11.
•
Hgb will be closely monitored throughout the dosing 
period as outlined in the Time and Events Table 
Section 7.1.
•
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of 
GSK1278863 based on achieved Hgb is 
provided in Section 6.4.1.
•
These risks have been identified as AEs of 
special interest and will be monitored 
instreamly by the internal safety review team 
throughout the study period.
Other
ESA risks (Control)
See risks outlined in table for GSK1278863 for Excessive 
erythropoiesis (polycythemia) leading to thrombosis and/or tissue 
ischemia; Risk of MI, stroke, venous thromboembolism, thrombosis of 
vascular access; and risk of cancer-related mortality and tumor 
progression.
Hepatic function disorder with increase of AST, ALT and Gamma-
glutamyltransferase, and jaundice have been reported as adverse drug 
reactions for other ESA according to the prescribing information of 
Epoetin beta pegol.

The same mitigation strategies have been 
indentified in acoordance with the mitigation 
strategies for GSK1278863 

Liver function will be monitored throughout 
the dosing period as outlined in the Time and 
Events Table provided in Section 7.1.


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References
Campochiaro et al., Ocular versus Extraocular Neovascularization: Mirror Images or Vague Resemblances; Invest Ophthalmol & Vis Sci 2006. 47:462-474.
Formenti et al., Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha 
gain-of-function mutation. FASEB J. 2011, 25(6): 2001-2011.
Muz et al., The role of hypoxia and HIF-dependent signaling events in rheumatoid arthritis, Arthritis Research & Therapy 2009. 11:201-210.
Smith et al., Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology PLOS 2006. 3:1176-1186.
Westra et al., Hypoxia-Inducible Factor-1 as Regulator of Angiogenesis in Rheumatoid Arthritis - Therapeutic Implications.  Current Medicinal Chemistry 
2010. 17:254-263.


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12.3.
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of reproductive potential
This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle 
or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long 
term and persistent basis.
1.
Contraceptive subdermal implant that meets the Prescribing Information effectiveness criteria 
including a <1% rate of failure per year, as stated in the Prescribing Information
2.
Intrauterine device or intrauterine system that meets the Prescribing Information effectiveness 
criteria including a <1% rate of failure per year, as stated in the Prescribing Information
[Hatcher, 2011]
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female subject's entry 
into the study, and this male is the sole partner for that subject [Hatcher, 2011].  
These allowed methods of contraception are only effective when used consistently, correctly and in 
accordance with the Prescribing Information. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception.
References
Trussell J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, Kowal D, and 
Policar M (editors). Contraceptive Technology: Twentieth Revised Edition. New York: Ardent Media, 
2011.


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12.4.
Appendix 4: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes pregnant 
while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 weeks of 
learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The investigator will collect 
follow up information on mother and infant, which will be forwarded to GSK. Generally, follow-
up will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as such.  

Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related 
to the study treatment by the investigator, will be reported to GSK as described in Section 12.6.
Appendix 6. While the investigator is not obligated to actively seek this information in former 
study participants, he or she may learn of an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating

will discontinue study medication or be withdrawn from the study


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12.5.
Appendix 5: Liver Safety Required Actions and Follow up Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance).
Phase III-IV liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted

If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments 
MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) and 
quantitative hepatitis B DNA 

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 24 hours after last 
dose5

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:


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hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  
24-72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct 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 computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, (for ND patients only) if serum bilirubin fractionation testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if 
INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold 
value stated will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody or Hepatitis E RNA
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
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 in the 
SRM.  
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 


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<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and 
<8xULN to ≥3xULN but <5xULN, continue to 
monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to 
within baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute 
Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, Follow-
Up and Reporting of Adverse Events
12.6.1.
Definition of Adverse Events
Adverse Event Definition:

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 AE definition 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).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE.  However, the signs and symptoms and/or clinical sequelae resulting from lack 
of efficacy will be reported if they fulfil the definition of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the 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.


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12.6.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of 
disease, etc).
Serious Adverse Event (SAE) is defined as 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
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
e.
Is a congenital anomaly/birth defect
f.
Other situations:

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; (for ND patients only) if 


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unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury. 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.
12.6.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF 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
12.6.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in the CRF

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 CRF page.

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.

PRO questionnaires and the collection of AE data are independent components of the study.

Responses to each question in PRO 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.
12.6.5.
Evaluating AEs and SAEs
Assessment of Intensity


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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.
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

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 


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histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated reporting time 
frames.
12.6.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use the paper SAE 
data collection tool and fax it to the SAE contact.

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 subject 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 the SAE contact by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the Sponsor/Medical 
Monitor Contact Information page.


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12.7.
Appendix 7 - Genetic Research
Background
Naturally occurring genetic variation may contribute to inter-individual variability in response to 
medicines, as well as an individual's risk of developing specific diseases. Genetic factors associated 
with disease characteristics may also be associated with response to therapy, and could help to explain 
some clinical study outcomes. For example, genetic variants associated with age-related macular 
degeneration (AMD) are reported to account for much of the risk for the condition [Gorin, 2012] with 
certain variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the genetic 
etiology of disease may better inform understanding of disease and the development of medicines. 
Additionally, genetic variability may impact the pharmacokinetics (absorption, distribution, 
metabolism, and elimination), or pharmacodynamics (relationship between concentration and 
pharmacologic effects or the time course of pharmacologic effects) of a specific medicine and/or 
clinical outcomes (efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objective of the genetic research is to understand the response to GSK1278863. To achieve this 
objective, the relationship between genetic variants and the followings may be investigated.

Response to medicine, including GSK1278863, ESA, other study medicines or any concomitant 
medicines;

Nephrogenic anemia and related conditions susceptibility, severity, and progression 
Genetic data may be generated while the study is underway or following completion of the study.  
Genetic evaluations may include focused candidate gene approaches and/or examination of a large 
number of genetic variants throughout the genome (whole genome analyses). Genetic analyses which 
will be conducted for this study will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data from multiple 
clinical studies related to GSK1278863 to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed description of any 
planned analyses will be documented in a Reporting and Analysis Plan (RAP) prior to initiation of the 
analysis. Planned analyses and results of genetic investigations will be reported either as part of the 
clinical RAP and study report, or in a separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in the genetic research. Any subject who has 
received an allogeneic bone marrow transplant must be excluded from the genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during clinical studies. 
Collection of samples, even when no a priori hypothesis has been identified, may enable future 
genetic analyses to be conducted, align with the purpose of the genetic research, to help understand 
variability in disease and medicine response.  


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
A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A Blood 
sample is collected at the baseline visit, after the subject has been randomized and provided 
informed consent for genetic research. Instructions for collection and shipping of the genetic 
sample are described in the laboratory manual. The DNA from the blood sample may undergo 
quality control analyses to confirm the integrity of the sample. If there are concerns regarding the 
quality of the sample, then the sample may be destroyed. The blood sample is taken on a single 
occasion unless a duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to label other 
samples and data in the study. This number 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). 
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 only use samples collected from the study for the purpose stated in this protocol and 
in the informed consent form. Samples may be used as part of the development of a companion 
diagnostic to support the GSK medicinal product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the study.  
Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic 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 genetic sample, if already collected:

Continue to participate in the genetic research in which case the genetic DNA sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA sample 
If a subject withdraws consent for genetic 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. 
Genotype data may be generated during the study or after completion of the study and may be 
analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been analyzed, it 
will not be analyzed or used for future research.  


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
Genetic data that has been analyzed at the time of withdrawn consent will continue to be stored 
and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject does not meet 
the entry criteria for participation in the study, then the investigator should instruct the subject that 
their genetic 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.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or separately and may 
publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific understanding in 
alignment with the informed consent. GSK does not inform the subject, family members, 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 genetic studies is generally preliminary in nature, and therefore the significance and 
scientific validity of the results are undetermined. Further, data generated in a research laboratory may 
not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular Degeneration 
(AMD) Susceptibility Gene CFH and Treatment Response of AMD: A Meta-Analysis. PloS ONE 
2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies addressing risk, 
causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.


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12.8.
Appendix 8: Definition of and Procedures for Documenting Medical Device 
Incidents
12.8.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all medical devices 
provided for use in the study (see Section 6.2. for the list of the medical devices).
Medical Device Incident Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance of a device, 
as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, 
might lead to or might have led to the death of a patient/user/other persons or to a serious 
deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health. The non-occurrence of such a 
result might have been due to other fortunate circumstances or to the intervention of health care 
personnel.
It is sufficient that:

an incident associated with a device happened and

the incident was such that, if it occurred again, might lead to death or a serious deterioration in 
health.
A serious deterioration in state of health can include:

life-threatening illness

permanent impairment of body function or permanent damage to a body structure

a condition necessitating medical or surgical intervention to prevent one of the above 

fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of a medical device failure or its 
misuse

a patient’s treatment is interrupted or compromised by a medical device failure

misdiagnosis due to medical device failure leads to inappropriate treatment

a patient’s health deteriorates due to medical device failure
12.8.1.1.
Documenting Medical Device Incidents
Medical Device Incident Documenting:

Any medical device incident occurring during the study will be documented in the subject’s 
medical records, in accordance with the investigator’s normal clinical practice, and on the 
appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE CRF page 
will be completed as described in Section 12.6. (Appendix 6).).

The form will be completed as thoroughly as possible and signed by the investigator before 
transmittal to GSK.


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
It is very important that the investigator provides his/her assessment of causality to the medical 
device provided by GSK at the time of the initial report, and describes any corrective or remedial 
actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a device where 
such action is necessary to prevent recurrence of an incident. This includes any amendment to the 
design to prevent recurrence.


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TITLE PAGE
Division：Worldwide Development
Information Type：Clinical Protocol
Title：A 52-week, Phase III, open-label, multi-center study to evaluate efficacy and safety of 
GSK1278863 in Japanese non-dialysis and peritoneal dialysis subjects with anemia associated with 
chronic kidney disease.
Compound Number：
GSK1278863
Development Phase
III
Effective Date：
18-FEB-2016
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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Sponsor Signatory:
Hiromu Nakajima
Head,
Medicines Development,
Japan Development and Medical Affairs (JDMA),
GlaxoSmithKline K. K.
Date


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time 
Phone 
Number
Fax Number
Site Address
Medical Monitor
M.D., Ph.D.
GlaxoSmithKline K.K.
6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-8566 
JAPAN
SAE contact  
information
Person in charge 
of GSK1278863
Clinical 
Operations dept. 
GlaxoSmithKline K.K.
6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-8566 
JAPAN
Emergency Contact
Emergency Contact (Mon to Fri 10am to 6pm, except for national holiday and year-end and New Year
holidays)
Person in charge of GSK1278863, Clinical Operations dept. R&D, Glaxo Smith Kline K.K
TEL:
FAX:
Emergency Contact at night and holiday (Mon to Fri 6pm to 10am, Sat, Sun, national holiday and 
year-end and New Year holidays)
Bell Medical Solutions Inc.
Responsible Person: 
TEL:
(toll free)
FAX:
(toll free)
Sponsor Legal Registered Address:
6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566 JAPAN
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

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 Signature
Date


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TABLE OF CONTENTS
Page
1.
PROTOCOL SYNOPSIS FOR STUDY PHI201753 ........................................................9
2.
INTRODUCTION............................................................................................................14
2.1.
Study Rationale....................................................................................................14
2.2.
Background..........................................................................................................14
3.
OBJECTIVES AND ENDPOINTS..................................................................................14
4.
STUDY DESIGN.............................................................................................................16
4.1.
Overall Design......................................................................................................16
4.2.
Treatment Groups and Study Periods...............................................................17
4.3.
Study Subjects and Number of Subjects..........................................................18
4.4.
Rationale for Study Design.................................................................................18
4.5.
Rationale for Dose Levels...................................................................................19
4.6.
Benefit: Risk Assessment...................................................................................20
4.6.1.
Risk Assessment ........................................................................................20
4.6.2.
Benefit Assessment....................................................................................21
4.6.3.
Overall Benefit: Risk Conclusion..............................................................21
5.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ...........................................21
5.1.
Inclusion Criteria..................................................................................................22
5.2.
Exclusion Criteria ................................................................................................23
5.3.
Screening Failures...............................................................................................24
5.4.
Withdrawal/Dropout Criteria...............................................................................25
5.4.1.
Liver Chemistry Stopping Criteria.............................................................26
5.4.1.1.
Study Treatment Restart or Rechallenge.........................................28
5.5.
Subject and Study Completion ..........................................................................28
6.
STUDY TREATMENTS..................................................................................................28
6.1.
Investigational Product and Other Study Treatment.......................................28
6.2.
Treatment Assignment........................................................................................29
6.3.
Administration Schedule (Starting Dose, Dose Adjustment, and 
Dosing Frequency) ..............................................................................................29
6.3.1.
GSK1278863 (ND and PD Subjects)..........................................................29
6.3.1.1.
Starting Dose ......................................................................................29
6.3.1.2.
Maintenance Dose..............................................................................30
6.3.2.
Epoetin Beta Pegol (ND Subjects Only) ...................................................30
6.3.2.1.
Starting Dose for ESA Non-users.....................................................30
6.3.2.2.
Dose Conversion for ESA Users ......................................................31
6.3.2.3.
Maintenance Dose (ESA Non-users and Users) .............................32


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6.4.
Blinding.................................................................................................................33
6.5.
Packaging and Labeling......................................................................................33
6.6.
Preparation/Handling/Storage/Accountability..................................................33
6.7.
Compliance with Study Treatment Administration..........................................33
6.8.
Treatment of Study Treatment Overdose..........................................................34
6.9.
Treatment after the End of the Study ................................................................34
6.10.
Concomitant Medications and Non-Drug Therapies .......................................34
6.10.1.
Permitted Medications and Non-Drug Therapies ....................................34
6.10.2.
Prohibited Medications and Non-Drug Therapies...................................35
6.11.
Supplemental Iron Therapy ................................................................................35
7.
Study Assessments and Procedures.........................................................................35
7.1.
Time and Events Table........................................................................................35
7.2.
Screening and Critical Baseline Assessments ................................................38
7.3.
Efficacy .................................................................................................................38
7.4.
Safety ....................................................................................................................38
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)....................38
7.4.1.1.
Time period and Frequency for collecting AE and SAE 
information..........................................................................................39
7.4.1.2.
Method of Detecting AEs and SAEs.................................................39
7.4.1.3.
Follow-up of AEs and SAEs ..............................................................39
7.4.1.4.
Cardiovascular and Death Events....................................................39
7.4.1.5.
Regulatory Reporting Requirements for SAEs...............................40
7.4.2.
Adverse Events of Special Interest...........................................................40
7.4.3.
Pregnancy....................................................................................................40
7.4.4.
Vital Signs/Height/Weight ..........................................................................41
7.4.5.
Electrocardiogram (ECG) ...........................................................................41
7.4.6.
Clinical Laboratory Assessments.............................................................41
7.4.7.
Ophthalmology............................................................................................42
7.5.
Pharmacokinetics................................................................................................43
7.6.
Genetics................................................................................................................43
7.7.
Patient Reported Outcome (PRO)......................................................................43
7.7.1.
SF-36.............................................................................................................43
7.7.2.
EuroQol Health Utility Index (EQ-5D-5L)/EQ Visual Analogue 
Scale (EQ-VAS)............................................................................................43
8.
DATA MANAGEMENT ..................................................................................................44
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .....................................44
9.1.
Hypotheses...........................................................................................................44


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9.2.
Sample Size Considerations ..............................................................................45
9.2.1.
Sample Size Assumptions .........................................................................45
9.2.2.
Sample Size Sensitivity ..............................................................................45
9.2.3.
Sample Size Re-estimation or Adjustment...............................................45
9.3.
Data Analysis Considerations............................................................................45
9.3.1.
Analysis Populations..................................................................................45
9.3.2.
Interim Analysis ..........................................................................................46
9.3.3.
Adjustment for Multiplicity.........................................................................46
9.4.
Key Elements of Analysis Plan ..........................................................................47
9.4.1.
Primary Efficacy Analysis..........................................................................47
9.4.2.
Principal Secondary Efficacy Analysis.....................................................47
9.4.3.
Other Secondary Efficacy Analyses .........................................................47
9.4.4.
Safety Analyses...........................................................................................48
9.4.4.1.
Exposure .............................................................................................48
9.4.4.2.
Adverse Events...................................................................................48
9.4.4.3.
Other Safety Parameters ...................................................................48
9.4.5.
Pharmacokinetics Analyses ......................................................................48
9.4.6.
PRO Data Analysis......................................................................................48
10. STUDY GOVERNANCE CONSIDERATIONS ..............................................................49
10.1.
Posting of Information on Publicly Available Clinical Trial Registers...........49
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process..................................................................................................49
10.3.
Quality Control (Study Monitoring)....................................................................50
10.4.
Quality Assurance ...............................................................................................50
10.5.
Study and Site Closure .......................................................................................50
10.6.
Records Retention...............................................................................................51
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publicatio....................51
10.8.
Study Period.........................................................................................................52
10.9.
Study Administrative Structure..........................................................................52
11. REFERENCES...............................................................................................................53
12. APPENDICES ................................................................................................................54
12.1.
Appendix 1: Abbreviations and Trademarks....................................................54
12.2.
Appendix 2:  Risk Assessment.........................................................................56
12.3.
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of reproductive potential.............................................62
12.4.
Appendix 4: Collection of Pregnancy Information...........................................63


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12.5.
Appendix 5: Liver Safety Required Actions and Follow up 
Assessments........................................................................................................64
12.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events ...................................................67
12.6.1.
Definition of Adverse Events.....................................................................67
12.6.2.
Definition of Serious Adverse Events.......................................................68
12.6.3.
Definition of Cardiovascular Events.........................................................69
12.6.4.
Recording of AEs and SAEs......................................................................69
12.6.5.
Evaluating AEs and SAEs..........................................................................69
12.6.6.
Reporting of SAEs to GSK.........................................................................71
12.7.
Appendix 7 - Genetic Research..........................................................................72


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1.
PROTOCOL SYNOPSIS FOR STUDY PHI201753
Rationale
This is a Phase III study to evaluate the efficacy and safety of GSK1278863 in Japanese non-dialysis 
(ND) and peritoneal dialysis (PD) subjects with renal anemia. The primary objective is to demonstrate
non-inferiority of GSK1278863 to epoetin beta pegol based on hemoglobin (Hgb) in the ND patient 
population included in this study. Study results will be used as pivotal study data for an NDA 
submitted for GSK1278863 for the treatment of renal anemia in Japan. 
Objective(s)/Endpoint(s)
Objective
Endpoint
Primary (efficacy)

To demonstrate non-inferiority of 
GSK1278863 to epoetin beta pegol based 
on hemoglobin (Hgb) in ND subjects 

Mean Hgb during the primary efficacy 
evaluation period (Weeks 40 to 52)
Principal secondary (efficacy)

To demonstrate superiority of 
GSK1278863 to epoetin beta pegol in 
terms of achievement/maintenance of 
target Hgb in ND subjects

Number (%) of subjects with mean Hgb in the 
target range (11.0-13.0 g/dL) during the 
primary efficacy evaluation period (Weeks 40 
to 52)
Other secondary (efficacy, PK)

To evaluate the appropriateness of the 
starting dose of GSK1278863 in ND 
subjects using epoetin beta pegol as 
control

To evaluate the appropriateness of the 
starting dose of GSK1278863 in PD 
subjects

Change from baseline in Hgb at Week 4 (Hgb 
increase rate)

Number (%) of subjects by Hgb change from 
baseline category at Week 4

To evaluate dose adjustment scheme of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate dose adjustment scheme of 
GSK1278863 in PD subjects

Distribution of the dose level

Duration of treatment interruption due to Hgb 
>13 g/dL

Frequency of dose adjustments

To evaluate the overall Hgb control of
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate the overall Hgb control of
GSK1278863 in PD subjects

Hgb and change from baseline at each 
assessment visit

Number (%) of subjects with Hgb within the 
target range (11.0-13.0 g/dL) at each 
assessment visit

Time (%) in Hgb target range (11.0-13.0 g/dL) 
during the primary efficacy evaluation period 
(Weeks 40 to 52)

Time (in days) to reach the lower Hgb target 


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Objective
Endpoint
(11.0 g/dL) 

Number (%) of subjects who have an Hgb 
level of less than 7.5 g/dL

Number (%) of subjects who have an Hgb 
increase of more than 2 g/dL over any 4 weeks 

Number (%) of subjects who have an Hgb 
level of more than 13.0 g/dL and number of 
episodes

To evaluate the effect on iron use of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate effect on iron use of 
GSK1278863 in PD subjects

Dose of oral iron during the study period and 
the primary efficacy evaluation period 
(Weeks 40 to 52) 

Number (%) of subjects who use oral iron 
during the study period and the primary 
efficacy evaluation period (Weeks 40 to 52)

To evaluate the effect on iron metabolism
of GSK1278863 in ND subjects using
epoetin beta pegol as control

To evaluate the effect on iron metabolism 
of GSK1278863 in PD subjects

Change from baseline in ferritin

Change from baseline in transferrin saturation 
(TSAT)

Changes from baseline in hepcidin, serum iron, 
and total iron binding capacity (TIBC) 

To evaluate the PK of GSK1278863

AUC and Cmax of plasma GSK1278863
Exploratory (efficacy)

To evaluate the effect on progression of 
Chronic Kidney Disease (CKD) of 
GSK1278863 in ND subjects using
epoetin beta pegol as control

Estimated glomerular filtration rate (eGFR) 
and change from baseline

Serum creatinine and change from baseline

Urine creatinine and urine albumin, and 
changes from baseline

Urine albumin/creatinine ratio and change 
from baseline
Patient reported outcome

To evaluate the effect on health-related 
QoL (HR-QoL) of GSK1278863 in ND 
subjects using epoetin beta pegol as 
control

To evaluate the effect on HR-QoL of 
GSK1278863 in PD subjects
SF-36

Changes from baseline in SF-36 HR-QoL 
scores [Physical Component Summary (PCS), 
Mental Component Summary (MCS), and 8 
subscales]
EuroQol Health Utility Index (EQ-5D-5L)

Change from baseline in EQ-5D-5L score 

Change from baseline in EQ-5D-5L Visual 
Analog Scale (VAS) 
Safety

To evaluate the safety and tolerability of 
GSK1278863 in ND and PD subjects

Incidence and severity of AEs and SAEs, 
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Objective
Endpoint

Reasons for discontinuation of study 
medication

Laboratory tests, ECG, vital signs, and 
ophthalmology assessments
Study Design
This is a Phase III, open-label, active-controlled, parallel-group, multi-center study to compare the efficacy 
(demonstration of non-inferiority) and safety of GSK1278863 administered for 52 weeks versus epoetin 
beta pegol in approximately 270 Japanese ND subjects with renal anemia. This study also includes an open-
label, uncontrolled part to evaluate the efficacy and safety of GSK1278863 in approximately 50 Japanese 
PD subjects. The study consists of the following 2 cohorts of different patient populations:
Patient 
population
Presence or absence of ESA therapy
(Hgb in subjects)
Treatment group
Target number of subjects
(randomized/enrolled)
Cohort 1
ND 
patient
ESA non-user (Hgb 8.0-<11.0 g/dL)
ESA user (Hgb 9.0-13.0 g/dL)
GSK1278863 group
135 subjects*
Epoetin beta pegol 
group
135 subjects*
Cohort 2
PD patient ESA non-user (Hgb 8.0-<11.0 g/dL)
ESA user (Hgb 9.0-13.0 g/dL)
GSK1278863 group
50 subjects
*: At least 50 ESA users and at least 50 ESA non-users will be randomized to Cohort 1. 
ESA: erythropoiesis-stimulating agent
In Cohort 1, 270 eligible ND subjects will be stratified by the current ESA therapy and baseline Hgb 
(ESA non-users: 9.5 g/dL, >9.5 g/dL, ESA users: <11.0 g/dL, 11.0 g/dL) and then randomized in a 
1:1 ratio to GSK1278863 or epoetin beta pegol group (135 subjects per group). 
In Cohort 2, 50 eligible PD subjects will be included in the GSK1278863 group. 
This study consists of a 4-week screening phase, a 52-week treatment phase [including the primary 
efficacy evaluation period (Weeks 40 to 52)], and a 4-week follow-up phase following the treatment 
phase. The study design is shown below. 
Screening phase
(4 weeks)
Treatment phase (52 weeks)
Follow-up phase
(4 weeks)
Primary efficacy 
evaluation period
Cohort 1
GSK1278863 group (N=135)
Non-dialysis (ND)
subjects
Epoetin beta pegol group (N=135)
Cohort 2
Peritoneal dialysis 
(PD) subjects
GSK1278863 group (N=50)


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Week -4                Day 1                            Week 40          Week 52          Week 56
Method of Administration of Study Medication in Each Treatment Group
In each treatment group, study medication will be administered as follows: 

GSK1278863 group (ND and PD subjects): Treatment with GSK1278863 will be started at a 
dose of 4 mg once daily on Day 1. From Week 4 onwards, dose adjustments will be made within 
the dose range of 1-24 mg every 4 weeks according to the prespecified dose adjustment 
algorithm to achieve and/or maintain Hgb within the target range (11.0-13 0 g/dL).

Epoetin beta pegol group (ND subjects): 

ESA non-users: Subcutaneous treatment with epoetin beta pegol will be started at a dose of 
25 g once every 2 weeks on Day 1. Subsequently, dose adjustments will be made within 
the dose range of 25-150 g every 4 weeks according to the prespecified treatment criteria
to achieve the lower limit of the Hgb target (11.0 g/dL). Once Hgb increases to 11.0 g/dL or 
more, dosing frequency will be changed to once every 4 weeks, and dose adjustments will 
be made within the dose range of 25-250 g every 4 weeks according to the prespecified 
dose adjustment algorithm to achieve and/or maintain Hgb within the target Hgb range 
(11.0-13.0 g/dL). 

ESA users: Prior ESA therapy will be replaced with subcutaneous treatment with epoetin 
beta pegol at the equivalent dose once every 4 weeks according to prespecified dose 
conversion. Subsequently, dose adjustments will be made within the dose range of 25-
250 g every 4 weeks according to the prespecified dose adjustment algorithm to achieve 
and/or maintain Hgb within the target range (11.0-13.0 g/dL).
Analysis
Assuming a non-inferiority margin of -1.0 g/dL, a treatment difference of 0.0 g/dL, and a standard 
deviation of 1.5 g/dL for mean Hgb during in the primary efficacy evaluation period in ND subjects, 
two-sample t-test has at least 99% power at a two-sided significance level of 5% with a sample size of 
100 subjects per group. Assuming a dropout rate of approximately 25%, 135 subjects will be 
randomized to each group. For PD subjects, the sample size is based on the feasibility. Assuming a 
sample size of 38 subjects and a standard deviation of 1.5 g/dL, the half the width of the 95% CI for 
mean Hgb during in the primary efficacy evaluation period is 0.493 g/dL.
The primary endpoint, which is the mean Hgb during the primary efficacy evaluation period, will be
analyzed to demonstrate the non-inferiority of GSK1278863 to epoetin beta pegol in ND subjects. 
A mixed model for repeated measurements (MMRM) will be used to estimate the mean Hgb during 
the primary efficacy evaluation period and its 95% CI by treatment groups. As a preliminary 
assessment, it will be confirmed if the lower and upper limit of 95% CI for mean Hgb in GSK1278863 
group would lie fully within target range (11.0-13.0 g/dL) In addition, the point estimate and 95% CI 
for the treatment difference (GSK1278863-epoetin beta pegol) in mean Hgb during the primary 
efficacy evaluation period will be estimated. Non-inferiority will be established if the lower limit of 
the 95% CI is greater than -1.0 g/dL. Even if the 95% CI for the difference is completely negative (i.e. 
lies fully within the range -0.75 to <0 g/dL) non-inferiority would still be concluded on condition that 
the mean Hgb estimate in the GSK1278863 group is within the target range.


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The primary efficacy population will be the ITT Population, and the analysis will be repeated in the 
mITT and PP Population to evaluate the robustness of the conclusion. The subgroup analysis by the 
current ESA therapy (presence or absence) will also be conducted. Further details of sensitivity 
analyses will be provided in the Reporting and Analysis Plan (RAP).
The principal secondary endpoint, which is the proportion of subjects whose mean Hgb during the 
primary efficacy evaluation period is within the target range will be analyzed to demonstrate the 
superiority of GSK1278863 to epoetin beta pegol in ND subjects. 
In the mITT Population, a logistic regression model including treatment group, baseline Hgb, and the 
current ESA therapy (presence or absence) as covariates will be used to estimate the point estimate 
and 95% CI for the odds ratio (GSK1278863/epoetin beta pegol). This analysis will be performed to 
demonstrate the superiority at a two-sided significance level of 5%, conditional on the primary 
endpoint achieving noninferiority. Superiority will be established if the lower limit of the 95% CI for 
the odds ratio is greater than 1.0.


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2.
INTRODUCTION
GSK1278863 is a hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (PHI) that stimulates 
erythropoiesis in the same manner as innate response to hypoxia and is currently being developed as a 
new treatment for renal anemia.
2.1.
Study Rationale
This is a Phase III study to evaluate the efficacy and safety of GSK1278863 in Japanese non-dialysis 
(ND) and peritoneal dialysis (PD) subjects with renal anemia. The primary objective is to demonstrate 
non-inferiority of GSK1278863 to epoetin beta pegol based on hemoglobin (Hgb) in the ND patient 
population included in this study. Study results will be used as pivotal study data for an NDA 
submitted for GSK1278863 for the treatment of renal anemia in Japan. 
2.2.
Background
Renal anemia is diagnosed in many patients with CKD, and the prevalence of renal anemia increases 
with progression of CKD [Akizawa, 2011]. Causes of anemia in CKD patients include absolute or 
relative deficiency of erythropoietin (EPO), shortened erythrocyte survival, and reduced iron 
availability. Anemia is further exacerbated by chronic blood loss associated with hemodialysis 
procedure, infection, and functional hemolysis [Japanese Society for Dialysis Therapy, 2008]. 
GSK1278863 is a hypoxia-inducible factor-prolyl hydroxylase inhibitor that is currently being 
developed as a treatment for renal anemia. Data in Japanese patients have been collected from a 
Japanese Phase II 4-week treatment study in Japanese hemodialysis (HD) subjects (PHI116099: 97 
Japanese subjects), an international multi-center Phase II 24-week treatment study in HD subjects 
(PHI113633: including 24 Japanese subjects), and an international multi-center Phase II 24-week 
treatment study in ND subjects (PHI113747: including 42 Japanese subjects). In these clinical studies, 
GSK1278863 increased endogenous EPO, reduced hepcidin, and increased Hgb in HD and ND 
subjects including Japanese subjects. In addition, GSK1278863 increased Hgb at lower blood EPO 
concentrations than existing erythropoiesis-stimulating agents (ESAs). 
Data from completed clinical and clinical pharmacology studies and the preclinical data safety 
package are provided in the Development Core Safety Information found in the current GSK1278863 
Investigator Brochure (IB). A benefit: risk assessment, including risk mitigation strategies, is outlined 
in Section 4.6.
3.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary (efficacy)

To demonstrate non-inferiority of 
GSK1278863 to epoetin beta pegol based 
on hemoglobin (Hgb) in ND subjects 

Mean Hgb during the primary efficacy 
evaluation period (Weeks 40 to 52)
Principal secondary (efficacy)

To demonstrate superiority of 

Number (%) of subjects with mean Hgb in the 


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Objective
Endpoint
GSK1278863 to epoetin beta pegol in 
terms of achievement/maintenance of 
target Hgb in ND subjects
target range (11.0-13.0 g/dL) during the 
primary efficacy evaluation period (Weeks 40 
to 52)
Other secondary (efficacy, PK)

To evaluate the appropriateness of the 
starting dose of GSK1278863 in ND 
subjects using epoetin beta pegol as 
control

To evaluate the appropriateness of the 
starting dose of GSK1278863 in PD 
subjects

Change in Hgb from baseline to Week 4 (Hgb 
increase rate)

Number (%) of subjects by Hgb change from 
baseline category to Week 4

To evaluate dose adjustments of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate dose adjustments of 
GSK1278863 in PD subjects

Distribution of the dose level

Duration of treatment interruption due to Hgb 
>13 g/dL

Frequency of dose adjustments

To evaluate the overall Hgb control by 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate the overall Hgb control by 
GSK1278863 in PD subjects

Hgb at each assessment time point and change 
in Hgb from baseline to each assessment time 
point

Number (%) of subjects with Hgb within the 
target range (11.0-13.0 g/dL) at each 
assessment time point

Proportion (%) of time with Hgb within the 
target range (11.0-13.0 g/dL) in the primary 
efficacy evaluation period (Weeks 40 to 52)

Time (number of days) to the lower Hgb target 
(11.0 g/dL) 

Number (%) of subjects who have an Hgb 
level of less than 7.5 g/dL

Number (%) of subjects who have an Hgb 
increase of more than 2 g/dL over any 4 weeks 
before Week 52

Number (%) of subjects who achieve an Hgb 
level of more than 13.0 g/dL and number of 
episodes

To compare the effect of GSK1278863 
versus epoetin beta pegol on iron use in 
ND subjects

To evaluate the effect of GSK1278863 on 
iron use in PD subjects

Dose of oral iron in the study period and the 
primary efficacy evaluation period (Weeks 40 
to 52) 

Number (%) of subjects who use oral iron 
during the study period and the primary 
efficacy evaluation period (Weeks 40 to 52)

To compare the effect of GSK1278863 

Change in ferritin from baseline


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Objective
Endpoint
versus epoetin beta pegol on iron 
metabolism in ND subjects

To evaluate the effect of GSK1278863 on 
iron metabolism in PD subjects

Change in transferrin saturation (TSAT) from 
baseline

Changes in hepcidin, serum iron, and total iron 
binding capacity (TIBC) from baseline

To evaluate the PK of GSK1278863

AUC and Cmax of plasma GSK1278863
Exploratory (efficacy)

To compare the effect of GSK1278863 
versus epoetin beta pegol on progression 
of CKD in ND subjects

Estimated glomerular filtration rate (eGFR) 
and change from baseline

Serum creatinine and change from baseline

Urine creatinine and urine albumin, and 
changes from baseline

Urine albumin/creatinine ratio and change 
from baseline
Patient reported outcome

To compare the effect of GSK1278863 
versus epoetin beta pegol on health-
related QoL (HR-QoL) in ND subjects

To evaluate the effect of GSK1278863 on 
H-RQoL in PD subjects
SF-36

Changes in SF-36 HR-QoL scores (PCS, MCS, 
and 8 subscales) from baseline
EuroQol Health Utility Index (EQ-5D-5L)

Change in EQ-5D-5L score from baseline

Change in EQ-5D-5L Visual Analog Scale 
(VAS) from baseline
Safety

To evaluate the safety and tolerability of 
GSK1278863 in ND and PD subjects

Incidence and severity of AEs and SAEs, 
including AEs of special interest

Reasons for discontinuation of study 
medication

Laboratory tests, ECG, vital signs, and 
ophthalmology assessments
4.
STUDY DESIGN
4.1.
Overall Design 
This is a Phase III, open-label, active-controlled, parallel-group, multi-center study to compare the 
efficacy (verification of noninferiority) and safety of GSK1278863 administered for 52 weeks versus 
epoetin beta pegol in approximately 270 Japanese ND subjects with renal anemia. This study also 
includes an open-label, uncontrolled part to evaluate the efficacy and safety of GSK1278863 in 
approximately 50 Japanese PD subjects. The study consists of the following 2 cohorts of different 
patient populations. At least 50 ESA users and at least 50 ESA non-users will be randomized to 
evaluate by current ESA therapy(ESA user or ESA non-user).

Cohort 1: ND subjects (GSK1278863 and epoetin beta pegol groups)

Cohort 2: PD subjects (GSK1278863 group)


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For both patient populations, the Hgb criteria are specified according to the presence or absence of 
prior ESA: ESA non-users with an Hgb level of ≥8.0 to <11.0 g/dL and ESA users with an Hgb level 
of 9.0 to 13.0 g/dL will be included in the study. 
In Cohort 1, 270 eligible ND subjects will be stratified by the current ESA therapy (ESA non-user or 
ESA user) and baseline Hgb (ESA non-users: 9.5 g/dL, >9.5 g/dL, ESA users: <11.0 g/dL, 
11.0 g/dL) and then randomized in a 1:1 ratio to GSK1278863 or epoetin beta pegol group (135 
subjects per group). 
In Cohort 2, 50 eligible PD subjects will be included in the GSK1278863 group. 
This study consists of a 4-week screening phase, a 52-week treatment phase [including the primary 
efficacy evaluation period (Weeks 40 to 52)], and a 4-week follow-up phase following the treatment 
phase. The study design is shown in Figure 1.
Screening phase
(4 weeks)
Treatment phase (52 weeks)
Follow-up phase
(4 weeks)
Primary efficacy 
evaluation period
Cohort 1
GSK1278863 group (N=135)
Non-dialysis (ND)
subjects
Epoetin beta pegol group (N=135)
Cohort 2
Peritoneal dialysis 
(PD) subjects
GSK1278863 group (N=50)
Week -4                Day 1                            Week 40          Week 52          Week 56
Figure 1 Study Design
4.2.
Treatment Groups and Study Periods
Details for each study period and treatments are described below. In this study, a point-of-care Hgb 
analyzer (HemoCue®) will consistently be utilized for confirmation of subjects’ eligibility, withdrawal 
criteria and dose adjustments of study medication.
Screening phase
Subjects who have provided informed consent and meet all of the eligibility criteria at screening 
(Week -4) (Sections 5.1 and 5.2) will be provisionally enrolled in the study. Subjects who have used 
ESA and/or oral iron since before the start of the study must remain on the same regimen throughout 
the screening phase (intravenous iron will not be allowed). 


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Treatment phase
Subjects who meet all of the eligibility criteria at the start of the treatment phase (Day 1) will be 
enrolled in the study. Study medication (either GSK1278863 or epoetin beta pegol group) will be 
administered for 52 weeks according to randomization in Cohort 1 and GSK1278863 will be 
administered in Cohort 2 for 52 weeks. For ESA users, prior ESA will be replaced with study 
medication on Day 1. GSK1278863 will be orally administered once daily, and epoetin beta pegol will 
be subcutaneously administered once every 2 or 4 weeks. In both groups, dose adjustments for study 
medication during the treatment phase will be made according to the administration schedule specified 
in Section 6.3. to achieve and/or maintain Hgb within the target range (11.0-13.0 g/dL). In addition, 
supplemental iron therapy will be administered according to the standard initiation criteria as 
described in Section 6.11.. It should be noted that intravenous iron or dose change for oral iron will 
not be allowed from Day 1 to Week 4. 
Follow-up phase
Subjects will visit the site for follow-up assessments and observations 4 weeks after the 
completion/discontinuation of study treatment. During the follow-up phase, treatment of renal anemia 
will be allowed as necessary at the discretion of the investigator (or subinvestigator). 
4.3.
Study Subjects and Number of Subjects
In Cohort 1 involving ND subjects, a total of 270 subjects will be randomized (135 subjects in 
GSK1278863 group, 135 subjects in epoetin beta pegol group). The minimum target number of 
subjects is 50 ESA non-users and 50 ESA users to allow for evaluations by the current ESA therapy 
(ESA non-user or ESA user). Assuming a dropout rate of 35% during the screening phase, 
approximately 416 subjects need to be screened. Assuming a dropout rate of 25% after the start of 
study treatment, a total of 202 subjects are expected to complete the 52-week treatment. 
In Cohort 2 involving PD subjects, 50 subjects will be enrolled (GSK1278863 group only). Since the 
number of PD patients is very limited in Japan, the target number of subjects is not set for either ESA 
non-users or users. Assuming a dropout rate of 35% during the screening phase, approximately 77 
subjects need to be screened. Assuming a dropout rate of 25% after the start of study treatment, 38 
subjects are expected to complete the 52-week treatment. 
Table 1    Target Number of Subjects
Cohort 1 (ND subjects)
Cohort 2 (PD subjects)
Screened
416
77
Randomized/enrolled
270 *
50
Completed 52-week treatment
202
38
*: At least 50 ESA non-users and at least 50 ESA users will be randomized.
4.4.
Rationale for Study Design
Objectives and evaluations
This is a Phase III study to evaluate the efficacy and safety of GSK1278863 in Japanese ND and PD 
subjects with renal anemia. For Cohort 1, the study is designed as an active-controlled, parallel-group
comparative study to meet the primary objective, that is, to demonstrate non-inferiority of 
GSK1278863 to the existing drug in ND subjects. For Cohort 2, the study is designed as an 


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uncontrolled study because there are not many PD patients. The target Hgb range was set for study 
treatment in line with the Guidelines for Renal Anemia in Chronic Kidney Disease issued by the 
Japanese Society for Dialysis Therapy in 2008 [The Japanese Society for Dialysis Therapy, 2008] to 
demonstrate that treatment with GSK1278863 can result in achievement and/or maintenance of target 
Hgb in ND and PD subjects, and evaluate the appropriateness of the starting dose of GSK1278863. 
Control
For the ND patient population (Cohort 1), epoetin beta pegol, which has been widely used in Japanese 
patients with renal anemia, primarily ND patients, since its approval in Japan in 2011, was selected as 
control. 
Open-label
If the study is conducted as a double-blind study, it is necessary to not only administer GSK1278863 
orally (once daily) or epoetin beta pegol subcutaneously (once every 2 or 4 weeks), but also 
administer the matching placebo subcutaneously or orally. It will be more stressful for subjects and 
complicate treatment procedures to use both active drug and matching placebo for two drugs with 
different routes and intervals of administration for the purpose of maintaining the blind, and make 
dose adjustments for individual subjects according to the change in Hgb over time. Accordingly, this 
study is designed as an open-label study rather than a double-blind study, which seems infeasible. 
Since Hgb used for efficacy evaluation is an objective measure, and dose adjustments for study 
medication will be made according to the prespecified Hgb-based dose adjustment method in both 
GSK1278863 and epoetin beta pegol groups, it is unlikely that the open-label design will create any 
bias in the primary evaluation. 
4.5.
Rationale for Dose Levels
Starting dose and dose adjustments of GSK1278863
The starting dose (4 mg) and the dose adjustment method (maintenance dose range: 1-24 mg) for 
GSK1278863 are described in Section 6.3..
The starting dose and the dose adjustment algorithm selected for Japanese ND subjects in the present 
study are based on the results from a review of the longitudinal model constructed using Hgb data 
from six Japanese or overseas Phase II studies (PHI112844, PHI116581, PHI116582, PHI113633, 
PHI113747, and PHI116099) as well as the results from clinical studies. The data set used in the 
model analyses was based on the data of GSK1278863 administered in a wide dose range (0-25 mg) 
and included a Japanese Phase II 4-week treatment study (PHI116099) and international multi-center 
late Phase II 24-week treatment studies (PHI113633 and PHI113747) in which subjects in Japan 
participated. For PD subjects, the starting dose and the dose adjustment algorithm for ND subjects will 
be applied based on the PK/PD profiles in PD subjects determined from an interim analysis in an 
overseas 14-day treatment clinical pharmacology study (PHI200942). 
Starting dose
Simulation results using the longitudinal model in ND subjects as well as the results from clinical 
studies indicated that GSK1278863 given at a dose of 4 mg may slowly increase Hgb (0.5-1.0 g/dL on 
average) without a rapid increase greater than 2 g/dL after 4 weeks of treatment in ESA non-users. 
4 mg GSK1278863 may also maintain Hgb without a rapid increase greater than 2 g/dL for 4 weeks 


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after switching from prior ESA in ESA users. Covariate analyses identified baseline Hgb, body weight, 
and dose level of prior ESA as major factors affecting Hgb. However, Hgb was more greatly affected 
by inter-subject differences in drug response to GSK1278863 than these factors.
Taken together, 4 mg may be an appropriate starting dose of GSK1278863 for both ESA non-users 
and users. 
Maintenance dose range and dose adjustment algorithm
Simulation results using the longitudinal model showed that drug response to GSK1278863 greatly 
varied among subjects, indicating that the dose range from 1 to 24 mg may be necessary to achieve 
and maintain target Hgb. Accordingly, a total of 8 dose levels (1, 2, 4, 6, 8, 12, 18, and 24 mg) were 
selected as the maintenance doses, with 4 mg intended for subjects with a standard drug response. 
The dose adjustment algorithm was defined so that target Hgb (11.0-13.0 g/dL) set for the present 
study according to the Guidelines for Renal Anemia [The Japanese Society for Dialysis Therapy,
2008] can be maintained. Since the upper limit of the Hgb target (13.0 g/dL) is equivalent to the 
interruption criterion for ESA, the dose level of GSK1278863 will be reduced by one step when Hgb 
increases to more than 12.5 g/dL, and the dose level will be maintained while Hgb is in the range of 
11.5-<12.5 g/dL. Since the guidelines state that an Hgb increase of 0.5 g/dL or less per week is 
appropriate to prevent adverse reactions, the dose level will be reduced by one step when Hgb 
increases by more than 2 g/dL over 4 weeks. For subjects whose anemia needs to be corrected 
(≥7.5 g/dL and <11.5 g/dL), the dose level will be maintained while the Hgb increase per 4 weeks is 
0.5-2 g/dL, and the dose level will be increased by one step when the Hgb increase per 4 weeks is less 
than 0.5 g/dL. 
Starting dose and dose adjustments of control (epoetin beta pegol)
The starting dose and the dose adjustment algorithm for epoetin beta pegol are described in Section 
6.3..
The starting dose of epoetin beta pegol for subjects not using ESA or subjects on epoetin was selected 
based on the Prescribing Information in Japan. For subjects on darbepoetin alfa, darbepoetin alfa will 
be switched to epoetin beta pegol at a dose ratio of 6:5 according to overseas Prescribing Information, 
given no specification for dose conversion from darbepoetin currently approved in Japan to epoetin 
beta pegol. 
The dose adjustment algorithm for epoetin beta pegol was determined based on the product 
information and previous Japanese clinical studies. 
4.6.
Benefit: Risk Assessment
Summaries of findings from clinical and nonclinical studies of GSK1278863 can be found in the IB
and IB supplement. The risk assessment and risk minimization strategies for the present study are 
outlined in the following sections: 
4.6.1.
Risk Assessment
Based on the results of completed clinical and nonclinical studies of GSK1278863, the potential risks 
of clinical significance and the risk minimization strategies for the present study are outlined in 
Section 12.2. Appendix 2.


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4.6.2.
Benefit Assessment 
Study PHI201753 is a Phase 3 study in Japanese ND and PD subjects with renal anemia. Previous
clinical studies of GSK1278863 administered for up to 24 weeks in ND or HD subjects have 
demonstrated clinical efficacy (increase in and/or maintenance of Hgb) with serum EPO 
concentrations increased within the normal physiologic range in CKD subjects. Data obtained in 
Study PHI201753 will generate safety and efficacy data in Japanese ND and PD subjects with renal 
anemia for a 52-week treatment period. Study participants who will receive GSK1278863 may benefit 
from the expected clinical efficacy. Participants who will receive the control (epoetin beta pegol 
approved for the treatment of renal anemia in Japan) are also expected to benefit from the clinical 
efficacy. 
GSK1278863 may have important advantages over existing ESAs. GSK1278863, which is orally 
administered and requires no cold chain management unlike ESAs, is more convenient to patients. 
GSK1278863 is shown to increase Hgb at lower EPO concentrations than ESAs. Since increased 
exposure to EPO following administration of ESAs may be associated with an increased 
cardiovascular risk [Szczech, 2008], GSK1278863 may increase Hgb without increasing the 
cardiovascular risk. 
4.6.3.
Overall Benefit: Risk Conclusion
GSK1278863 is shown to have a positive benefit-risk balance based on the following findings: in 
studies of GSK1278863 administered for up to 24 weeks, treatment with GSK1278863 resulted in 
achievement of target Hgb, and no adverse events have been identified as related to treatment with 
GSK1278863.
The present study is intended to evaluate the efficacy and safety of GSK1278863 administered for 52
weeks in Japanese ND and PD subjects with renal anemia, and designed to administer GSK1278863 
or epoetin beta pegol as control to all enrolled subjects; therefore, subjects randomized in either 
treatment group are expected to benefit from the treatment. 
This protocol employs precautions to mitigate known and potential risks to enrolled subjects (Section 
12.2. Appendix 2). Given these precautions, as well as the potential benefit that GSK1278863 holds 
for the treatment of renal anemia compared with the current standard treatment, the overall benefit risk 
balance is considered to be positive.
5.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, and other 
pertinent information on the GSK investigational product or other study treatment that may impact 
subject eligibility is provided in the IB/IB supplement(s) and/or other pertinent documents.
Deviations from inclusion/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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5.1.
Inclusion Criteria
Subjects eligible for enrolment in the study must meet all of the inclusion criteria.
Note: Verification at both provisional enrolment (screening) and official enrolment (Day 1) is required, 
unless otherwise specified.
1.
Age (at the time of informed consent): ≥20 years of age
2.
Stage of chronic kidney disease (CKD) (ND patients only): CKD stages 3, 4, and 5 defined by 
eGFR using the Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-
CKDI) formula
3.
Dialysis: 

Not on dialysis for at least 12 weeks prior to screening (ND patients)

On peritoneal dialysis (PD patients)
4.
Use of erythropoiesis-stimulating agent (ESA): 

ESA non-users: Have not used ESAs for at least 8 weeks prior to screening

ESA users: Have used the same ESA for at least 8 weeks prior to screening. However, in the 
ND patients, the dose of darbepoetin alfa or epoetin beta pegol must be stable (administered 
once every 4 weeks and up to one-step dose change during at least 8 weeks prior to 
screening). 
5.
Hemoglobin (Hgb): Determined at the site using an Hgb analyzer (HemoCue) 

ESA non-users: ≥8.0 g/dL and <11.0 g/dL

ESA users: ≥9.0 g/dL and ≤13.0 g/dL 
6.
Iron parameters: Ferritin >100 ng/mL or transferrin saturation (TSAT) >20% (screening 
verification only)
7.
Gender (screening verification only): Female or male
Females: Not pregnant [demonstrated to be negative for human chorionic gonadotropin (hCG) in 
urine or serum], not breast-feeding, and meet at least one of the following: 
1)
Females of non-childbearing potential are defined as follows: 

Pre-menopausal with at least one of the following and no plans to utilise assisted 
reproductive techniques (e.g., in vitro fertilisation or donor embryo transfer):

History of bilateral tubal ligation or salpingectomy

History of hysteroscopic tubal occlusion and postoperatively documented bilateral 
tubal obstruction 

History of hysterectomy

History of bilateral oophorectomy

Postmenopausal defined as 1) females 60 years of age or older or 2) In females < 60 years 
of age, 12 months of spontaneous amenorrhea [in questionable cases a blood sample with 
postmenopausal follicle stimulating hormone (FSH) and estradiol concentrations is 
confirmatory (see separately specified reference ranges)]. Females on hormone replacement 
therapy (HRT) whose menopausal status is in doubt will be required to use one of the most 
effective contraception methods 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 enrolment.


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2)
Females of childbearing potential must agree to comply with one of the contraception 
methods listed as requirements in “GSK Listing of Most Effective Contraceptive Methods for 
Females of Childbearing Potential (Section 12.3. Appendix 3: Modified List of Highly Effective 
Methods for Avoiding Pregnancy in Females of reproductive potential)” from at least 28 days 
prior to the first dose of study medication until the completion of the follow-up visit (for subjects 
randomized to the GSK1278863 group) or 7 weeks after the last dose of study treatment (for 
subjects randomized to the Epoetin beta pegol group).
8.
Informed consent: Written informed consent, including adherence to the requirements and 
conditions specified in the consent form and the protocol, must be obtained from each subject as 
specified in Section 10.2..
5.2.
Exclusion Criteria
Subjects meeting any of the following criteria must not be enrolled in the study.
Note: Verification at both provisional enrolment (screening) and official enrolment (Day 1) is required, 
unless otherwise specified.
Chronic kidney disease (CKD)-related criteria 
1.
Dialysis

Cohort 1: Start or plan to initiate dialysis during the study

Cohort 2: Plan to stop peritoneal dialysis or start hemodialysis during the study
2.
Kidney transplant: Planned living-related kidney transplant during the study
Anemia-related criteria
3.
Aplasia: History of bone-marrow hypoplasia or pure red cell aplasia
4.
Other causes of anemia: pernicious anemia, thalassemia, sickle cell anemia, or myelodysplastic
syndromes
5.
Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal 
ulcer disease OR clinically significant GI bleeding within 8 weeks prior to screening or during a 
period from screening to Day 1.
Cardiovascular disease-related criteria
6.
Myocardial infarction, acute coronary syndrome, stroke, or transient ischemic attack: Diagnosed 
within 8 weeks prior to screening or during a period from screening to Day 1.
7.
Heart failure: Class IV heart failure, as defined by the New York Heart Association (NYHA) 
functional classification system
8.
QTc (screening verification only): QTc >500 msec or QTc >530 msec in subjects with bundle 
branch block 
Note: QT interval corrected using the Bazett’s formula (QTcB) will be used, and ECG can be 
mechanically or manually read. 
Other disease-related criteria
9.
Liver disease (if any of the following occurs): 

Alanine transaminase (ALT) >2×upper limit of normal (ULN)


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
Bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is acceptable if bilirubin is fractionated 
and direct bilirubin is <35%)

Current unstable active liver or biliary disease (generally defined by the onset of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, persistent 
jaundice, or cirrhosis)
Note: Stable liver disease (including asymptomatic gallstones, chronic hepatitis B/C, or 
Gilbert’s syndrome) is acceptable if the subject otherwise meets entry criteria.
10. Malignancy: History of malignancy within 2 years prior to screening, or currently receiving 
treatment for cancer, (PD patients only) complex renal cystic >3 cm (II F, III or IV based on the 
Bosniak classification)
Note (ND patients and PD patients): The only exception is squamous cell or basal cell carcinoma 
of the skin that has been definitively treated 8 weeks before screening.
11. In the opinion of the investigator, Hgb increase to the target range (11.0-13.0 g/dL) is medically 
risky.
Concomitant medication and other study treatment-related criteria
12. Iron: Planned use of intravenous iron during the screening phase or during a period from Day 1 
to Week 4
Note: Oral iron is acceptable. However, the same dose regimen must be used throughout the 
screening phase and from Day 1 to Week 4. Antihyperphosphatemic agents containing iron (e.g., 
ferric citrate hydrate) are also acceptable only if used for at least 12 weeks prior to screening. 
However, they must be continued throughout the screening phase and from Day 1 to Week 4. 
13. Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity 
to excipients in the investigational product (see the GSK1278863 IB or epoetin beta pegol
Prescribing Information)
14. Drugs and supplements: Use or planned use of any prescription or non-prescription drugs or 
dietary supplements that are prohibited during the study period (prohibited medications: strong 
inducers and inhibitor of CYP2C8, see Section 6.10.2.)
15. Prior investigational product exposure: Use of an investigational agent within 30 days or five half 
lives of the investigational agent (whichever is longer)
16. Prior treatment with GSK1278863: Any prior treatment with GSK1278863 for a treatment 
duration of >30 days
General health-related criteria
17. Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding 
that the investigator (or subinvestigator) considers would put the subject at unacceptable risk, 
which may affect study compliance or prevent understanding of the aims or investigational 
procedures or possible consequences of the study
5.3.
Screening Failures
Screen failures are defined as subjects who consent to participate in the clinical trial and are screened, 
but are not subsequently randomized in the study. A minimum set of information is required from 
screen failure subjects including Demography, Screen Failure details, Eligibility Criteria, and SAEs in 


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order to report screen failures in a reliable manner, satisfy the requirements for publication defined by 
the Consolidated Standards of Reporting Trials (CONSORT), and respond to requests of the 
regulatory authorities.
Subjects that fail screening are eligible to be rescreened up to 3 times as soon as the investigator (or 
subinvestigator) assesses they may meet study entry criteria.
5.4.
Withdrawal/Dropout Criteria
If subjects meet one of the following criteria, study treatment should be permanently discontinued and 
subjects will be withdrawn from the study. The withdrawal reason should be recorded.

Hgb <7.5 g/dL
Note: HemoCue Hgb values will be employed. If an initial Hgb value meets the Hgb stopping 
criteria, measurement will be repeated at the same study visit (using the same sample) to 
calculate the average. If the average meets the Hgb stopping criteria, study treatment will be 
discontinued.

Kidney transplant

Subject becomes pregnant or intends to become pregnant during the study.

Diagnosis of new or recurrent cancer

Liver chemistry abnormalities exceeding the threshold criteria (see Section 5.4.1.)

Need for chronic (more than 14 days) use of prohibited medication

When the investigator (or subinvestigator) considers necessary to withdraw the subject from the 
study for other reasons
Subjects who meet any of the withdrawal criteria or are withdrawn for other reasons during the 
treatment phase should be assessed at withdrawal visit after study treatment is discontinued, and will 
then enter the follow-up phase. Subjects who start dialysis or change dialysis modality (from PD to 
hemodialysis) during the study period will remain in the study if they are willing to continue their 
participation in the study. 
Should a subject fail to attend a required study visit, the investigator (or subinvestigator) should take 
the following measures: 

The investigator (or subinvestigator) or designee should attempt to contact the subject and re-
schedule the missed visit as soon as possible.

The investigator (or subinvestigator) should counsel the subject on the importance of maintaining 
the assigned visit schedule and determine whether the subject is willing to continue his/her 
participation in the study and/or whether the subject should remain in the study. 

The investigator (or subinvestigator) or designee should make every effort to regain contact with 
a subject who is deemed “Lost to Follow-up”. All efforts to contact the subject should be 
documented in the subject’s clinical charts. 

Should the subject continue to be unreachable, then and only then will he/she be considered 
“Lost to Follow-up.”
A subject may withdraw from the study at any time at his/her own request. The investigator (or 
subinvestigator) may withdraw a subject from the study at any time for safety or compliance reasons 


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or study conduct considerations. If a subject withdraws from the study, he/she may request destruction 
of any clinical samples taken, and the investigator (or subinvestigator) must document this in the site 
study records.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure subject 
safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety 
guidance).


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Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Chemistry Increased Monitoring Algorithm with Continued Therapy for ALT 3xULN 
but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in Section 12.5. 
Appendix 5


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5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by any subject 
participating in this study is not allowed.
5.5.
Subject and Study Completion
A completed subject is one who has completed all periods of the study including the follow-up visit.
The study will be completed with the last subject’s last study visit. 
6.
STUDY TREATMENTS
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any products received by the 
subject as per the protocol design. Accordingly, ‘study treatment’ sometimes refers to each product 
and sometimes refers to multiple products. 
GSK1278863 (study drug)
The study drug GSK1278863 will be supplied as fast-release film coated tablets for oral 
administration containing 1 mg, 2 mg, 4 mg, or 6 mg of GSK1278863 (Table 2). There are two sizes 
of GSK1278863 tablets.
Table 2   Description of GSK1278863 Tablets
GSK1278863 tablets of 
specific content
Description
1 mg tablets, 2 mg tablets, 
4 mg tablets
7.0 mm round, standard biconvex, white film coated tablets containing 
1 mg, 2 mg, or 4 mg of GSK1278863 as active ingredient
6 mg tablets
9.0 mm round, standard biconvex, white film coated tablets containing 
6 mg of GSK1278863 as active ingredient
GSK1278863 tablets of specific content are packed in high density polyethylene (HDPE) bottles, with 
35 tablets per bottle. Subjects are to take one to four tablets (Table 3) with water once daily according 
to the dose level indicated at each study visit. Subjects can take GSK1278863 tablets without regard to 
food or peritoneal dialysis. The administration schedule (starting dose and dose adjustment) described 
in Section 6.3.1. should be followed. 
Table 3    Dose Levels of GSK1278863 and Number of Tablets Taken
Dose level of 
GSK1278863
(once daily)
1 mg
2 mg
4 mg
6 mg
8 mg
12 mg
18 mg
24 mg
Number of 
GSK1278863
tablets taken
1 mg 
tablet
×1
2 mg 
tablet
×1
4 mg 
tablet
×1
6 mg 
tablet
×1
4 mg 
tablet
×2
6 mg 
tablet
×2
6 mg 
tablet
×3
6 mg 
tablet
×4
Subjects should be instructed to bring GSK1278863 tablets with bottles at each study visit, and all 
unused GSK1278863 tablets will be collected from subjects at each study visit.


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Epoetin beta pegol (control)
The control epoetin beta pegol (brand name: MirceraPre-filled Syringe) will be supplied by GSK. 
This product is an injectable formulation containing 25 g, 50 g, 75 g, 100 g, 150 g, 200 g, or 
250 g of epoetin beta pegol per syringe (0.3 mL) and is supplied as a glass syringe prefilled with 
epoetin beta pegol solution (clear colorless to pale yellow). 
Subjects are to receive epoetin beta pegol subcutaneously once every 2 or 4 weeks at the site (Table 4). 
The administration schedule (starting dose and dose adjustment) described in Section 6.3.2. should be 
followed. 
Table 4    Dose Levels of Epoetin Beta Pegol and Number of Subcutaneous Doses
Dose level of epoetin beta 
pegol
(once every 2 or 4 weeks)
25 g
50 g
75 g
100 g
150 g
200 g
250 g
Number of subcutaneous 
doses of epoetin beta pegol
25 g 
injection
×1
50 g 
injection
×1
75 g
injection
×1
100 g 
injection
×1
150 g 
injection
×1
200 g 
injection
×1
250 g 
injection
×1
6.2.
Treatment Assignment
The randomization schedule will be generated by GlaxoSmithKline (GSK) using the randomization 
system (Randall).
In Cohort 1 (ND subjects), subjects will be stratified by the current ESA therapy (ESA non-user or 
ESA user) and the Hgb level on Day 1 and randomized in a 1:1 ratio to one of the two treatment 
groups according to the randomization schedule. Randomization should precede the study treatment. 

GSK1278863 group

Epoetin beta pegol group
In Cohort 2 (PD subjects), all eligible subjects will start treatment with GSK1278863 on Day 1. 
Subjects will be assigned a randomization number by the Interactive Web Recognition System 
(IWRS). Once a randomization number has been assigned, it must not be re-assigned. Further details 
are provided in the Study Reference Manual (SRM).
6.3.
Administration Schedule (Starting Dose, Dose Adjustment, and Dosing 
Frequency)
6.3.1.
GSK1278863 (ND and PD Subjects)
6.3.1.1.
Starting Dose
For ND (Cohort 1) and PD subjects (Cohort 2) randomized to the GSK1278863 group, both ESA non-
users and users will start oral treatment with GSK1278863 at the starting dose of 4 mg once daily 
(Day 1) and remain on the same regimen until the day of Week 4. 
ESA users should skip ESA on Day 1 when treatment with GSK1278863 is started. 


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6.3.1.2.
Maintenance Dose
From Weeks 4 to 52, interruption of treatment or dose adjustments will be made within the 
maintenance dose range of 1-24 mg (Table 5) according to the dose adjustment algorithm (Table 6) to 
achieve and/or maintain Hgb within the target range (11.0-13.0 g/dL) based on the HemoCue Hgb 
value measured every 4 weeks. Dose changes will be made every 4 weeks. If any of the one-step dose 
reduction criteria is met during treatment at the minimum maintenance dose (1 mg), treatment should 
be interrupted; once the one-step dose increase criteria are met, treatment at 1 mg will be resumed. If 
the one-step dose increase criterion is met during treatment at the maximum maintenance dose 
(24 mg), treatment at 24 mg should be continued. 
Table 5    Maintenance Dose of GSK1278863
Dose step
1
2
3
4
5
6
7
8
Dose level of 
GSK1278863
(once daily)
1 mg
2 mg
4 mg
6 mg
8 mg
12 mg
18 mg
24 mg
Number of 
GSK1278863
tablets taken
1 mg 
tablet
×1
2 mg 
tablet
×1
4 mg 
tablet
×1
6 mg 
tablet
×1
4 mg 
tablet
×2
6 mg 
tablet
×2
6 mg 
tablet
×3
6 mg 
tablet
×4
Table 6   Dose Adjustment Algorithm (GSK1278863)
Hgb
(g/dL)
Hgb increase over 4 weeks 
(g/dL)
Treatment
>13.0
NA
Interrupt treatment until Hgb decreases to less than 
12.5 g/dL
Resume treatment at the one lower dose level (If 
interrupted at 1 mg: resume treatment at 1 mg once 
the one-step dose increase criteria are met)
12.5-13.0
NA
One-step dose reduction
11.5-<12.5
>2.0
One-step dose reduction
2.0
Continue treatment at the current dose level
7.5-<11.5
>2.0
One-step dose reduction
0.5-2.0
Continue treatment at the current dose level
<0.5
One-step dose increase
<7.5
NA
Discontinue treatment permanently * and initiate 
another appropriate treatment
*: If an initial Hgb value is less than 7.5 g/dL, measurement will be repeated at the same study visit (using the same 
sample) to calculate the average. If the average meets the Hgb stopping criteria, study treatment will be permanently
discontinued.
6.3.2.
Epoetin Beta Pegol (ND Subjects Only)
For ND subjects (Cohort 1) randomized to the epoetin beta pegol group, ESA non-users and users will 
receive epoetin beta pegol subcutaneously according to the treatment regimens described below.
6.3.2.1.
Starting Dose for ESA Non-users
ESA non-users will start subcutaneous treatment with epoetin beta pegol at a dose of 25 μg once every 
2 weeks (Day 1). Dose adjustments will be made within the initial dose range of 25-150 μg (Table 7)


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according to the dose adjustment criteria (Table 8) to increase Hgb to 11.0 g/dL (lower limit of the 
target) or more based on the HemoCue Hgb value measured every 4 weeks. Dose changes will be 
made every 4 weeks. If any of the dose reduction criteria shown in Table 8 is met during treatment 
with epoetin beta pegol at 25 μg, treatment should be interrupted; once the dose reduction criteria are 
not met any longer, treatment will be resumed at a dose of 25 μg. 
Table 7    Initial Dose of Epoetin Beta Pegol (ESA Non-users)
Dose step
1
2
3
4
5
Dose level of epoetin beta pegol
(once every 2 weeks)
25 μg
50 μg
75 μg
100 μg
150 μg
Table 8    Initial Dose Adjustment Criteria for Epoetin Beta Pego (ESA Non-users)
Hgb
Treatment
Hgb increase <1.0 g/dL over past 4 weeks, 
OR Hgb <10.0 g/dL and Hgb increase ≤2.0 g/dL over past 4 weeks
One-step dose increase
Hgb increase >2.0 g/dL over past 4 weeks
One-step dose reduction
Otherwise
Continue treatment at the 
current dose level
Once Hgb increases to 11.0 g/dL or more, the dosing interval should be changed from once every 2 
weeks to once every 4 weeks with dose conversion for dosing interval change (Table 9) after it is 
confirmed that all of the following criteria are met:

Hgb in the target range (11.0-13.0 g/dL)

Hgb change ≤2.0 g/dL over past 4 weeks

Equivalent dose will be given twice (at least 4 weeks)
Table 9    Dose Conversion of Epoetin Beta Pegol for Dosing Interval Change (ESA 
Non-users)
Initial dose of epoetin beta pegol
(given once every 2 weeks)
Dose conversion of epoetin beta pegol
(given once every 4 weeks)
25 μg
→
50 μg
50 μg
→
100 μg
75 μg
→
150 μg
100 μg
→
200 μg
150 μg
→
250 μg
After the dosing interval is changed to once every 4 weeks according to the criteria described above, 
maintenance treatment will be started as described in Section 6.3.2.3.
6.3.2.2.
Dose Conversion for ESA Users
For ESA users, prior ESA will be replaced with epoetin beta pegol at the equivalent dose once every 4 
weeks (Day 1). 


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Table 10    Replacement with Epoetin Beta Pegol-Initial Dose (ESA Users)
Prior ESA
Epoetin beta pegol
Epoetin
<4500 IU per week
100 g once every 4 weeks
4500 IU per week
150 g once every 4 weeks
Darbepoetin alfa
30 g once every 4 weeks *
25 g once every 4 weeks
60 g once every 4 weeks *
50 g once every 4 weeks
90 g once every 4 weeks *
75 g once every 4 weeks
120 g once every 4 weeks *
100 g once every 4 weeks
180 g once every 4 weeks *
150 g once every 4 weeks
Epoetin beta pegol
25, 50, 75, 100, 150, 200, 250 g
once every 4 weeks *
25, 50, 75, 100, 150, 200, 250 g
once every 4 weeks
*: Allowance of ±1 week
Maintenance treatment will be started at Week 4 as described in Section 6.3.2.3.
6.3.2.3.
Maintenance Dose (ESA Non-users and Users)
Epoetin beta pegol will be administered once every 4 weeks from dosing interval change (once every 
4 weeks) with Hgb ≥11.0 g/dL to Week 52 in ESA non-users and from Weeks 4 to 52 in ESA users. 
Interruption of treatment or dose adjustments will be made within the maintenance dose range of 25-
250 μg (Table 11) according to the dose adjustment algorithm (Table 12) to achieve and/or maintain 
Hgb within the target range (11.0-13.0 g/dL) based on the HemoCue Hgb value measured every 4 
weeks. If any of the one-step dose reduction criteria is met during treatment at the minimum 
maintenance dose (25 μg), treatment should be interrupted; once the one-step dose reduction criteria 
are not met any longer, treatment at 25 μg will be resumed. If the one-step dose increase criterion is 
met during treatment at the maximum maintenance dose (250 μg), treatment at 250 μg should be 
continued.
Table 11    Maintenance Dose of Epoetin Beta Pegol
Dose step
1
2
3
4
5
6
7
Epoetin beta pegol
(once every 4 weeks)
25 g
50 g
75 g
100 g
150 g
200 g
250 g
Table 12  Dose Adjustment Algorithm (Epoetin Beta Pegol)
Hgb
(g/dL)
Hgb increase over 4 weeks 
(g/dL)
Treatment
>13.0
NA
Interrupt treatment until Hgb decreases to less than 
12.5 g/dL
Resume treatment at the one lower dose level 
(resume treatment at 25 g if interrupted at 25 g)
12.5-13.0
NA
One-step dose reduction
11.5-<12.5
>2.0
One-step dose reduction
2.0
Continue treatment at the current dose level
7.5-<11.5
>2.0
One-step dose reduction
1.0-2.0
Continue treatment at the current dose level
<1.0
One-step dose increase
<7.5
NA
Discontinue treatment permanently * and initiate 


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another appropriate treatment
*: If an initial Hgb value is less than 7.5 g/dL, measurement will be repeated at the same study visit (using the same 
sample) to calculate the average. If the average meets the Hgb stopping criteria, study treatment will be permanently 
discontinued.
6.4.
Blinding
This is an open-label study. 
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory requirements.
6.6.
Preparation/Handling/Storage/Accountability

No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study medications must be stored in a secure 
environmentally controlled and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator (or subinvestigator) and 
authorized site staff.

Subjects must bring all of supplied study medication bottles of GSK127886 at each study visit. 
Study staff will collect all of study medication bottles supplied at the previous study visit and 
supply new study medication bottles. 

The investigator (or subinvestigator), institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records). 

Under normal conditions of handling and administration, study medication is not expected to 
pose significant safety risks to site staff. GSK will provide a document describing occupational 
hazards and recommended handling precautions either to the investigator (or subinvestigator) 
when necessary or upon request of the medical institution. 

Further details are provided in the SRM. 
6.7.
Compliance with Study Treatment Administration
GSK1278863
Since GSK1278863 is self-administered, compliance with GSK1278863 treatment will be assessed 
through an interview with subjects at each study visit and recorded in the source document and eCRF. 
A record of the number of GSK1278863 tablets dispensed to and taken by each subject will be 
maintained and reconciled with study treatment and compliance records. In addition, the number of 
GSK1278863 doses dispensed, used, and unused, as well as study treatment start and stop dates will 
be recorded in the eCRF (the number of doses returned and unreturned will also be recorded 
separately).
Epoetin beta pegol
Epoetin beta pegol will be subcutaneously administered to subjects at the site. Dosing details will be 
recorded in the source document and eCRF. 


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6.8.
Treatment of Study Treatment Overdose
There is no specific antidote for overdose with GSK1278863. 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 hemodialysis or peritoneal dialysis 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 a suspected overdose, 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 cardiovascular events, increased heart rate and hematologic abnormalities.
Consult the respective approved Prescribing Information for information on overdose for epoetin beta 
pegol.
6.9.
Treatment after the End of the Study
Since the target disease studied is not life-threatening or severely debilitating and there is the 
alternative therapy, subjects will not receive any additional treatment from GSK after completion of 
the study. The investigator (or subinvestigator) is responsible for ensuring that consideration has been 
given to post-study care of the subject’s medical condition. 
6.10.
Concomitant Medications and Non-Drug Therapies
Concomitant medications, including over-the-counter medications and supplements, taken during the 
study will be recorded in the eCRF. Drug names and start/stop dates will be recorded for general 
concomitant medications, while additional details, including dose, route of administration, and dosing 
frequency, will be recorded for certain medications (e.g., ESAs, iron, anti-hypertensive medications).
Further details are provided in the SRM.
6.10.1.
Permitted Medications and Non-Drug Therapies
Unless specified as a prohibited medication in Section 6.10.2., all concomitant medications should be 
considered permitted provided they are not contraindicated for the individual subject concerned.
Regular multivitamins (at recommended daily allowance) and other supplements such as calcium and 
vitamin D may be used if permitted by the investigator or his/her designee. 
CYP2C8 is involved in the primary route of metabolism of GSK1278863. Accordingly, co-
administration of GSK1278863 with moderate CYP2C8 inhibitors (e.g., clopidogrel, teriflunomide, 
deferasirox) should be performed with caution. If one of these medications is started, stopped or the 
dose is changed, Hgb should be monitored every 4 weeks for 12 weeks using a point-of-care Hgb 
analyzer. 
Antihyperphosphatemic agents containing iron (e.g., ferric citrate hydrate) may be started from 
Week 4 onwards unless any other antihyperphosphatemic agents are appropriate. Once started, iron-
containing antihyperphosphatemic agents must be continued until the end of the study wherever 
possible. 


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6.10.2.
Prohibited Medications and Non-Drug Therapies
Use of any of the following drugs from screening until 7 days after the last dose of study treatment is 
prohibited:

Strong inhibitors of CYP2C8 (e.g., gemfibrozil)

Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)
6.11.
Supplemental Iron Therapy
Supplemental iron therapy will be administered according to the Guidelines for Renal Anemia [The 
Japanese Society for Dialysis Therapy, 2008] if ferritin is ≤100 ng/mL and TSAT is ≤20%. The 
investigator (or subinvestigator) can choose the route of administration and dose of prescription iron. 
7.
Study Assessments and Procedures
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the Time and 
Events Table, are essential and required for study conduct.
7.1.
Time and Events Table
The time and events tables for the entire study and PK assessment are presented as Table 13 and Table 
14, respectively. To allow scheduling flexibility, study visits may occur within a window of ±7 days
on Day 1 scheduled 4 weeks after screening, within a window of ±3 days at Week 4, and within a 
window of ±5 days for the rest of the study. However, subjects receiving the control epoetin beta 
pegol every 2 weeks should attend study visits, including those only for study treatment, within a 
window of ±3 days. Visit days are counted from Day 1.


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Table 13    Time and Events Table
Phase
Screening
Treatment
Follow-up
Week
-4
Day 1
4
8
12
16
20
24
28
32
36
40
44
48
52
Early 
withdr
awal10
4 weeks 
after 52 or 
withdrawal
Permissible range (days)
±7
-
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
-
±7
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history, demography, 
height, weight
X
Registration with IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study medication dispensing 1,2
X
X
X
X
X
X
X
X
X
X
X
X
X
Study treatment compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs 3
X
X
X
X
X
X
X
X
X
Ophthalmology 4
ECG
X
X
X
HemoCue Hgb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Urinalysis (ND subjects only)
X
X
X
X
X
Pregnancy test (urine or serum 
hCG) 5
X
X
X
X
X
X
X
X
X
Estradiol, FSH 6
X
PK 7
X
X
Ferritin, TSAT
X
X
X
X
X
X
X
X
Serum iron, TIBC, UIBC, serum 
transferrin, hepcidin
X
X
X
X
X
X
X
iPTH
X
X
X
HR-QoL
X
X
X
X
X
Genetics sample 8
X
Adverse event assessment 9
Review Concomitant Medications
1.
In Cohort 1, ESA non-users randomized to the epoetin beta pegol group will start treatment with epoetin beta pegol at a dose of 25 μg once every 2 weeks. For these subjects, specified examinations will 
be performed every 4 weeks, and no study-related assessments will be necessary at study visits only for study treatment (e.g., Week 2, Week 6) (see Section 6.3.2). It should be noted that subjects 
receiving epoetin beta pegol once every 2 weeks should attend study visits within a window of ±3 days.
2.
If a subject visit the study site only to receive study medication, only registration with the IWRS, study medication dispensing, and study medication compliance will be required. 
3.
Vital signs will be measured before and after dialysis if applicable.


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4.
Ophthalmology exams should be conducted at the following time points.

Screening: anytime after consenting and prior to first dose of study medication (Day 1)

Week 12: window from weeks 10-14 (inclusive)

End of study: window from weeks 48-52 (inclusive)

Early study medication discontinuation: withdrawal eye exam as close to the last dose as possible
5.
Performed in females of childbearing potential: serum pregnancy test will be performed if urine pregnancy test is not feasible.
6.
Measured in female subjects only to determine the menopausal status (see Section 5.1.)
7.
See Table 14.
8.
Informed consent for optional Genetic research should be obtained before collecting a sample (see Section 7.6.).
9.
See Section 7.4.1.1..
10.
For withdrawn subjects, specified assessments should be done wherever possible.


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Table 14    Blood Sampling Schedule for Pharmacokinetics (Only Subjects in 
GSK1278863 Group)
PK sample
Week 12 2
Week 24 2
Blood sampling timing 1
1, 2, 3, and 4 h after administration of GSK1278863
Subjects must take the study medication with regard to blood sampling time. Subjects will record the date and time of the last two 
study medication doses taken prior to blood sampling in the medication diary. Preferably, there should be an interval of at least 12 h 
between these two doses. 
1.
Blood sampling should be completed within +/- 30 min of the planned collected time.
2.
Blood sampling not performed at this visit may be postponed until the following visits. 
7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors will be assessed (documented in the eCRF) at baseline.
In addition, the following demographic information will be collected:

Year of birth

Gender

Race and ethnic

Medical history/treatment history/family history will be assessed in relation to the 
inclusion/exclusion criteria (Section 5.). 
Full details of baseline assessments are provided in Table 13.
7.3.
Efficacy
Efficacy will be assessed according to the Time and Event Table (Table 13). 
Hgb concentrations measured by the central laboratory will be mainly used for efficacy assessment 
(see Section 7.4.6.). 
GSK will supply a point-of-care Hgb analyzer (HemoCue) to each site for rapid and convenient 
measurement of Hgb and to ensure consistency of Hgb measurements across all sites participating in 
the study. Assessment for Hgb concentrations via HemoCue will be used for eligibility (Section 5.1.), 
withdrawal (Section 5.4.), and dose adjustment criteria (Section 6.3.). 
In addition, assessments of iron metabolism parameters and measures of CKD progression (e.g., 
eGFR) used for efficacy assessment are outlined with specific procedures in Section 7.4.6..
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table (Table 13).  
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.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 12.6. Appendix 6.
The investigator and their designees are responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE.


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7.4.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-up contact 
(see Section 7.4.1.3.), at the timepoints specified in the Time and Events Table (Table 13).

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 section of the CRF.

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 hours, as indicated in Section 12.6.
Appendix 6.

Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 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 must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs plus procedures 
for completing and transmitting SAE reports to GSK are provided in Section 12.6. Appendix 6.
7.4.1.2.
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?”
7.4.1.3.
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 SAEs, and non-serious AEs of special interest (as defined in Section
7.4.2.) will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up (as defined in Section 5.4.). Further information on 
follow-up procedures is given in Section 12.6. Appendix 6..
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 12.6. Appendix 6 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be required to 
be completed.  These sections include questions regarding cardiovascular (including sudden cardiac 
death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA terms.  The 
CV information should be recorded in the specific cardiovascular section of the CRF within one week 
of receipt of a CV Event data query prompting its completion.  


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The Death CRF is provided immediately after the occurrence or outcome of death is reported. Initial 
and follow-up reports regarding death must be completed within one week of when the death is 
reported.
7.4.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to study 
treatment (even for non- interventional post-marketing studies) is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects and the safety of a product under clinical 
investigation 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 the regulatory authority, Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) 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 a 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.
7.4.2.
Adverse Events of Special Interest
The investigator (or subinvestigator) or designee will be responsible for detecting, documenting, and 
reporting any AEs of special interest listed below. These events have been identified based on the 
known safety profiles of ESAs, theoretical or potential risks based on the mechanism of action of 
GSK1278863, and findings from completed nonclinical studies of GSK1278863. 

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 

Death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access

Cardiomyopathy  

Pulmonary artery hypertension

Cancer-related mortality and tumor progression and recurrence 

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization 

Exacerbation of inflammatory joint disease (e.g., rheumatoid arthritis)
Any relevant AE should be recorded in the relevant section of the subject’s eCRF.
7.4.3.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of dosing and until 
the follow-up contact.


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
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of learning of 
the pregnancy and should follow the procedures outlined in Section 12.4.. Appendix 4.
Note: Subjects randomized in the epoetin beta pegol group should be advised to inform the 
investigator if they discover pregnancy in 7 weeks after the last dose of study treatment.
7.4.4.
Vital Signs/Height/Weight
Systolic and diastolic blood pressure and pulse rate will be measured in sitting or semi-supine position 
after at least 5 minutes rest prior to clinical examination at each visit blood pressure and pulse rate. 
One reading of blood pressure and pulse rate will be taken and recorded in the source document and 
the CRF. Height and weight will be measured at screening visit only.
7.4.5.
Electrocardiogram (ECG)
12-lead ECGs will be recorded in supine position. The heart rate, PR, QRS, and QT (pre-corrected)
intervals will be measured. QTcB should be calculated by machine or manually by designated staff at 
each site. The investigator determines whether the ECG data is assessable or not.
At the Day 1 visit when an ECG is performed, two additional ECGs are required if initial ECG 
indicates prolonged QTc using the automated or manually calculated QTcB value. The average QTcB 
value of all three ECGs will be used to determine eligibility.
QTc exclusion criteria can be found in Section 5.2. Refer to SRM for further details.
7.4.6.
Clinical Laboratory Assessments
All study-required laboratory assessments will be performed by a central laboratory with the exception 
of HemoCue Hgb. The results of each HemoCue Hgb must be entered into the subject’s eCRF. Details 
are provided in the SRM. 
All laboratory assessments, as defined in Table 15, must be conducted in accordance with the 
Laboratory Manual and Protocol Time and Events Schedule. Laboratory requisition forms must be 
completed and samples must be clearly labeled with the subject number, protocol number, site/center 
number, and visit date. Details for the preparation and shipment of samples will be provided by the 
central laboratory. Reference ranges for all parameters will be provided to the site by the central 
laboratory. Details of blood sampling (including the volume of blood to be collected) as well as 
procedures for processing, storage, and shipment of samples are provided in the SRM. 
PK assessment of GSK1278863 is outlined in Section 7.5.


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Table 15    Laboratory Assessments
Laboratory 
assessment
Parameter
Hematology
Platelet count
RBC indices:
WBC count with Differential
RBC count
MCV
Neutrophils
Reticulocyte count
MCH
Lymphocytes
Hemoglobin
MCHC
Monocytes
Hematocrit
RDW
Eosinophils
Basophils
Clinical chemistry
Sodium
AST
Bicarbonate
Potassium
ALT
Inorganic phosphate
Chloride
Creatinine
Glucose
Calcium (total and albumin-
corrected)
Total bilirubin
Direct/indirect bilirubin 
Albumin
Urea nitrogen
Total cholesterol
HDL cholesterol
LDL cholesterol
Iron parameters
Serum iron
Serum ferritin
Serum transferrin
TIBC
UIBC
TSAT
Hepcidin
Urinalysis
(ND subjects only) Urine albumin
Urine creatinine
Urine albumin/creatinine ratio
Other laboratory 
tests
FSH 1
Estradiol 1
iPTH
eGFR 2
hCG (serum or urine) 3
1.
Measured in female subjects only to determine the menopausal status (see Section 5.1.) 
2.
Calculated from serum creatinine using the Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-CKDI)
formula
3.
Performed in females of childbearing potential: serum pregnancy test will be performed if urine pregnancy test is not feasible. 
If additional non-protocol specified laboratory assessments are performed at the institution’s local 
laboratory and result in a change in subject management or are considered clinically significant by the 
investigator (or subinvestigator) (e.g., SAE or AE or dose modification), the results must be recorded 
in the eCRF.
Refer to the SPM for appropriate processing and handling of samples to avoid duplicate and/or 
additional blood draws.
All laboratory tests with values that are considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline. If such 
values do not return to normal within a period judged reasonable by the investigator (or 
subinvestigator), the etiology should be identified and the Sponsor notified.
7.4.7.
Ophthalmology
Ophthalmology exams will be performed by a study-designated ophthalmology specialist. Each 
assessment will include a comprehensive eye exam with at least the following components: 
measurement of best corrected visual acuity, intraocular pressure, an anterior aqueous chamber exam, 
and a fundoscopic exam. These exams will be used for assessment of ocular adverse events. 
Assessment results will be captured on worksheets which will be transferred to the eCRF. Additional 
details on the process for completing these assessments are provided in the SRM.


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7.5.
Pharmacokinetics
Blood samples for PK analysis of GSK1278863 will be collected from only subjects in the 
GSK1278863 group as outlined in Table 14, and the date and time of the last two study medication 
doses taken prior to blood sampling as well as the date and time of sampling must be recorded in the 
eCRF.
Blood PK analysis will be performed under the control of GSK Platform Technologies and Science-
Drug Metabolism and Pharmacokinetics (PTS-DMPK)/Scinovo and GSK-Japan Bioanalysis, the 
details of which will be included in the SPM. Concentrations of parent GSK1278863 will be 
determined in blood samples using the currently approved analytical methodology. Raw data will be 
archived at the bioanalytical site.
Procedures for processing, storage, and shipment of samples are provided in the SRM. 
7.6.
Genetics
A blood sample will be collected for genetic analysis from consenting subjects. This sample can be 
collected on Day 1 once written informed consent has been obtained. Information regarding genetic 
research is included in Section 12.7. Appendix 7.
7.7.
Patient Reported Outcome (PRO)
The patient reported outcome (PRO) [e.g., symptoms, severity, health-related QOL (HR-QoL), health 
status] will be assessed using several rating scales. 
All questionnaires used in this study have been translated into Japanese and validated. 
Specific instructions on how the subject is to complete the scales and the process for data entry are 
provided in the SPM.
7.7.1.
SF-36
The SF-36 acute version is a general health status questionnaire designed to elucidate the patient’s 
perception of his/her health on several domains, including physical functioning, role physical, bodily 
pain, vitality, social functioning, role emotional, mental health, and general health over the past seven 
days. The questionnaire contains 36 Likert type questions that ask the patient to recall how he/she felt 
during the past seven days.
7.7.2.
EuroQol Health Utility Index (EQ-5D-5L)/EQ Visual Analogue Scale (EQ-VAS)
The EQ-5D-5L is intended to measure the general health status and health utility. The EQ-5D-5L 
consists of 2 concepts: self-reported health status consisting of five dimensions (mobility, self-care, 
usual activities, pain/discomfort, anxiety/depression) each of which can take one of five responses and 
self-rated health status on a visual analog scale (VAS), a thermometer-like line. 


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8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted electronically to 
GSK or designee 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.  

CRFs (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.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
A detailed description of any planned analyses will be documented in a RAP..Any deviations from the 
analyses described in the protocol will be documented in the RAP or the final study report. 
9.1.
Hypotheses
The primary objective of the study is to demonstrate the non-inferiority of GSK1278863 to epoetin 
beta pegol based on mean Hgb during the primary efficacy evaluation period (Weeks 40 to 52) in ND 
subjects (Cohort 1). 
As a preliminary assessment, it will be confirmed whether the mean Hgb during the primary efficacy 
evaluation period in GSK1278863 group would be in target range (11.0-13.0 g/dL) at first. And then 
the following non-inferioritystatistical hypotheses are to be tested at a one-sided significance level of 
2.5% (i.e. two-sided significance level of 5%):

H0: Treatment difference in mean Hgb during the primary efficacy evaluation period is -1.0 g/dL 
or less.

H1: Treatment difference in mean Hgb during the primary efficacy evaluation period is greater 
than -1.0 g/dL.
Only when the primary endpoint achieves non-inferiority, statistical testing will progress to the 
principal secondary endpoint with a focus on superiority according to the step-down procedure. More 
specifically, the superiority of GSK1278863 to epoetin beta pegol in terms of target Hgb control in 
ND subjects is to be demonstrated at a two-sided significance level of 5% by testing the following 
statistical hypotheses:

H0: The proportion of subjects whose mean Hgb during the primary efficacy evaluation period is 
within the target range (11.0-13.0 g/dL) is equal between the treatment groups.

H1: The proportion of subjects whose mean Hgb during the primary efficacy evaluation period is 
within the target range (11.0-13.0 g/dL) is different between the treatment groups. 
No hypothesis will be tested in PD subjects (Cohort 2). 


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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Assuming a non-inferiority margin of -1.0 g/dL, a treatment difference of 0.0 g/dL, and a standard 
deviation of 1.5 g/dL for mean Hgb during the primary efficacy evaluation period in ND subjects, 
two-sample t-test has at least 99% power at a one-sided significance level of 2.5% (i.e. two-sided 
significance level of 5%) with a sample size of 100 subjects per group. Assuming a dropout rate of 
approximately 25%, 135 subjects will be randomized to each group. Given the results from previous 
non-inferiority studies of similar drugs (darbepoetin alfa, epoetin beta pegol, and peginesatide), the 
non-inferiority margin of -1.0 g/dL is set. Since an increase of 1.0 g/dL indicates improvement in 
anemia according to the guidelines for renal anemia in Japan, the non-inferiority margin of -1.0 g/dL
may be the clinically acceptable largest difference in renal anemia. 
While the present study is designed to ensure long-term safety data from 100 ND subjects, and the 
primary hypothesis test has at least 99% power to estimate the efficacy very precisely, non-inferiority 
can be statistically demonstrated with a minimum between-group difference of -0.582 g/dL. 
For PD subjects, the sample size is based on the feasibility. Assuming a sample size of 38 subjects and 
a standard deviation of 1.5 g/dL, the half width of the 95% CI for mean Hgb during the primary 
efficacy evaluation period is 0.493 g/dL. 
9.2.2.
Sample Size Sensitivity
The power is shown according to treatment difference and standard deviation in Table 16. 
Table 16    Power Sensitivity (100 Subjects Evaluated, Noninferiority Margin of -1.0, 
One-Sided Significance Level of 2.5%)
Treatment 
difference
Standard deviation
1.25
1.5
1.75
0
100.0%
99.7%
98.0%
-0.1
99.9%
98.8%
95.1%
-0.2
99.5%
96.4%
89.6%
-0.3
97.6%
90.7%
80.4%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned for this study.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations

All Screening Population
The All Screening Population consists of all subjects who are given subject number and whose data 
are collected, including demographics at screening.

Intent-to-Treat (ITT) Population (All randomized population)


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The Intention-To-Treat Population consists of all subjects who are given randomization number 
regardless of whether they actually receive study treatment. Subjects will be analyzed according to 
randomized treatment. This population will be the primary population for an assessment of non-
inferiority.

modified ITT (mITT) Population
The mITT Population consists of all ITT subjects who have at least one Hgb measurement during the 
efficacy evaluation period. Subjects will be analyzed according to randomized treatment. This 
population will be the primary population for an assessment of superiority. 

Per-Protocol (PP) Population
The PP Population consists of all mITT subjects who are not major protocol violators. Subjects will be 
analyzed according to the treatment received. Details will be defined in the RAP. This population will 
be used for efficacy sensitivity analyses.

Safety Population
The Safety Population consists of all ITT subjects who receive at least one dose of study treatment. 
Subjects will be analyzed according to the treatment received. This population will be used for safety 
analyses. 

PK Population
The PK Population consists of all GSK1278863-treated subjects from whom PK samples are collected 
and analyzed. 
Additional populations may be defined in the RAP.
9.3.2.
Interim Analysis
No interim analysis is planned. 
9.3.3.
Adjustment for Multiplicity
Adjustment for multiplicity will be applied to maintain an overall type I error rate of 5%. After a 
preliminary assessment, the primary endpoint will be evaluated to demonstrate the non-inferiority at a 
one-sided significance level of 2.5% (i.e. two-sided significance level of 5%). Only when the primary 
endpoint achieves non-inferiority, statistical testing will progress to the principal secondary endpoint 
with a focus on superiority. Since the process will follow step-down manner, a multiplicity adjustment
for significance level of 5% will not be needed according to a closed test procedure. 
Other secondary endpoints, which will be evaluated on a complementary or exploratory basis, will be 
compared at a significance level of 5% without multiplicity adjustment. 
Since Cohort 2 is a single-arm cohort, no testing will be performed to evaluate the efficacy in PD 
subjects. 


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9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Efficacy Analysis
The primary endpoint, which is the mean Hgb during the primary efficacy evaluation period, will be 
analyzed to demonstrate the non-inferiority of GSK1278863 to epoetin beta pegol in ND subjects. 
MMRM will be used to estimate the mean Hgb during the primary efficacy evaluation period and its 
95% CI by treatment groups. This model includes treatment groups, baseline Hgb, assessment visits, 
interaction terms between treatment groups and assessment visits, as well as interaction terms between 
baseline Hgb and assessment visit. As a preliminary assessment, it will be confirmed if the mean Hgb 
during the primary efficacy evaluation period in GSK1278863 group would be in target range (11.0-
13.0 g/dL) at first. This confirmation will be established if the lower and upper limit of 95% CI for the 
mean Hgb in GSK1278863 group would lie fully within target range (11.0-13.0 g/dL). In addition, the 
point estimate and 95% CI for the treatment difference (GSK1278863-epoetin beta pegol) in the mean 
Hgb during the primary efficacy evaluation period will be estmated. Non-inferiority will be 
established if the lower limit of the 95% CI is greater than -1.0 g/dL. Even if the 95% CI for the 
difference is completely negative (i.e. lies fully within the range -0.75 to <0 g/dL) non-inferiority 
would still be concluded on condition that the mean Hgb estimated in the GSK1278863 group is 
within the target range.
The primary efficacy population will be the ITT Population, and the analysis will be repeated in the 
mITT and PP Population to evaluate the robustness of the conclusion. The subgroup analysis by the 
current ESA therapy (presence or absence) will also be conducted.Further details of sensitivity 
analyses will be provided in the RAP.
9.4.2.
Principal Secondary Efficacy Analysis
The principal secondary endpoint, which is the proportion of subjects whose mean Hgb during the 
primary efficacy evaluation period is within the target range will be analyzed to demonstrate the 
superiority of GSK1278863 to epoetin beta pegol in ND subjects. 
In the mITT Population, a logistic regression model including treatment group, baseline Hgb, and 
current ESA therapy (presence or absence) as covariates will be used to estimate the point estimate 
and 95% CI for the odds ratio (GSK1278863/epoetin beta pegol). This analysis will be performed to 
demonstrate the superiority at a two-sided significance level of 5%, conditional on the primary 
endpoint achieving noninferiority. Superiority will be established if the lower limit of the 95% CI 
for odds ratio is greater than 1.0.
9.4.3.
Other Secondary Efficacy Analyses
Among the secondary efficacy endpoints, the time (%) in Hgb target range during the primary efficacy 
evaluation period , proportion of subjects who have an Hgb increase of more than 2 g/dL over any 4 
weeks, and changes in iron metabolism parameters (ferritin, TSAT, hepcidin, serum iron, and TIBC), 
the point estimates and 95% CIs for the treatment difference (or odds ratio) in ND subjects will be 
calculated. Other secondary efficacy and exploratory endpoints will be summarized by each treatment 
group. 
For PD subjects, the efficacy endpoints will be descriptively summarized. 


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9.4.4.
Safety Analyses
In principle, safety data will be summarized by each cohort and each treatment group in the Safety 
Population. 
9.4.4.1.
Exposure
Exposure information will be listed for all subjects. The duration of treatment (number of days) and 
cumulative dose will be tabulated. In addition, distribution of the dose level at each assessment visit
and final dosing visit will be tabulated. Frequency of dose adjustment and duration of treatment 
interruption due to Hgb >13 g/dL will be summarized.
9.4.4.2.
Adverse Events
All AEs will be categorized by the MedDRA system organ class and preferred term to tabulate the 
number and incidence. All AEs, SAEs, AEs leading to discontinuation of study treatment, and AEs of 
special interest will be summarized separately. Similar summary will be provided for study treatment-
related AEs. 
9.4.4.3.
Other Safety Parameters
For laboratory tests, vital signs and ECG, parameters and/or changes from baseline will be 
summarized using summary statistics at each assessment visit. The number and percentage of subjects 
with values of the potential clinical importance values will be tabulated. The criteria for the potential 
clinical importance will be described in the RAP. For lipid parameters (total cholesterol, LDL 
cholesterol, and HDL cholesterol), percent changes will also be tabulated. The number (%) of subjects 
who have any change in anti-hypertensive medications (type and/or dose) due to increased blood 
pressure will be tabulated.
9.4.5.
Pharmacokinetics Analyses
For plasma concentrations of GSK1278863 over time, individual data will be listed, and summary 
statistics at each time point will be calculated for each dose level. For PK parameters (AUC 0-4 and 
Cmax), summary statistics will be calculated for each dose level, and scatter plots against the dose 
level will be generated. 
9.4.6.
PRO Data Analysis
Details of PRO data tabulation will be described in the RAP.


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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 
enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the Informed Consent 
Process
The study will be conducted in accordance with “the Ministerial Ordinance on the Standards for the 
Conduct of Clinical Trials of Medicinal Products (MHW Notification No.28 dated 27th March, 1997)” 
and the Pharmaceutical Affairs Law.
GSK will submit the CTN to the regulatory authorities in accordance with with Article 80-2 of the 
Pharmaceutical Affairs Law before conclusion of any contract for the conduct of the study with study 
sites.
The study will be conducted in accordance with all applicable regulatory requirements, and with GSK 
policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), all applicable 
subject privacy requirements, and the guiding principles of the current version of the Declaration of 
Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and amendments as 
applicable

Signed informed consent to be obtained for each subject before participation in the study (and for 
amendments as applicable) 

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or both.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical protocol and all 
optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate informed 
consent) and the clinical protocol should be concurrently submitted for approval unless 
regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the clinical protocol 
where required by regulatory authorities.  In this situation, written approval of the clinical 
protocol should state that approval of optional assessments is being deferred and the study, with 
the exception of the optional assessments, can be initiated.
Informed Consent
Prior to participation in the study, the investigator (or subinvestigator) should fully inform the 
potential subject and the subject's legally acceptable representative (as required) of the study including 
the written information. The investigator (or subinvestigator) should provide the subject and the 
subject's legally acceptable representative ample time and opportunity to inquire about details of the 
study. The subject and the subject’s legally acceptable representative should sign and personally date 
the consent form. If the subject wishes to consider the content of the written information at home, 


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he/she may take the consent form home. The person who conducted the informed consent discussion 
and study collaborator giving supplementary explanation, where applicable, should sign and 
personally date the consent form. If an impartial witness is required, the witness should sign and 
personally date the consent form. The investigator (or subinvestigator) should retain this signed and 
dated form (and other written information) together with the source medical records, such as clinical 
charts (in accordance with the rules for records retention, if any, at each medical institution) and give a 
copy to the subject and the subject’s legally acceptable representative.
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 the CRF 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.
10.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, the GSK monitor will conduct site closure
activities with the investigator or site staff, as appropriate, in accordance with applicable regulations
including GCP, and GSK Standard Operating Procedures.
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 the reasons for taking such action with the
investigator or the head of the medical institution (where applicable). When feasible, GSK will
provide advance notification to the investigator or the head of the medical institution, where


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applicable, of the impending action.
If the study is suspended or prematurely discontinued for safety reasons, GSK will promptly inform
all investigators, heads of the medical institutions (where applicable) and/or institution(s) conducting
the study. GSK will also promptly inform the relevant 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 elsewhere), in a safe and secure location.  
The records must be maintained to allow easy and timely retrieval, when needed (e.g., for a GSK audit
or regulatory inspection) and must be available for review in conjunction with assessment of the
facility, supporting systems, and relevant site 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 ensure 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, GSK standards/procedures, and/or institutional requirements.  
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 is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of Information on 
Publically Available Clinical Trials Registers and Publicatio
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.
The procedures and timing for public disclosure of the results summary and for development of a 
manuscript for publication will be in accordance with GSK Policy.


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10.8.
Study Period
See Exhibit 1
10.9.
Study Administrative Structure
Sponsor information is included in Exhibit 2. List of Medical Institutions and Investigators is included 
in Exhibit 3.


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11. REFERENCES
Akizawa Tadao, Makino Hirofumi, Matsuo Seiichi, et al. Management of anemia in chronic kidney 
disease patients: baseline findings from Chronic Kidney Disease Japan Cohort Study. Clin Exp 
Nephrol. 2011;15:248-57.
Szczech Lynda A, Barnhart Huiman X., Inrig Jula K., et al. Secondary analysis of the CHOIR trial 
epoetin-α dose and achieved hemoglobin outcomes. Kidney International. 2008;74:791-8.
Guidelines for Renal Anemia in Chronic Kidney Disease issued by the Japanese Society for Dialysis 
Therapy in 2008. Journal of Japanese Society for Dialysis Therapy. 2008;41(10):661-716


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12. APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under Curve
CKD
Chronic Kidney Disease
Cmax
Maximum concentration
CPK
Creatine Phosphokinase
CYP
Cytochrome P450
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
EPO
Erythropoietin
EQ-5D-5L
EuroQol Health Utility Index
ESA
Erythropoiesis-Stimulating Agent
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
hCG
Human Chorionic Gonadotrophin
HD
Hemodialysis
HDL
High Density Lipoprotein
HDPE
High Density Polyethylene
Hgb
Hemoglobin
HIF
Hypoxia-Inducible Factor
HRT
Hormone Replacement Therapy
ICH
International Conference on Harmonization
INR
International Normalized Ratio
iPTH
Intact Parathyroid Hormone
ITT
Intent-to-Treat
IWRS
Interactive Web Recognition System
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
MCS
Mental Component Summary
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
ND
Non dialysis
NYHA
New York Heart Association
PCS
Physical Component Summary
PD
Peritoneal Dialysis
PHI
Prolyl Hydroxylase Inhibitor
PK
Pharmacokinetic
PP
Per-Protocol
PRO
Patient Reported Outcome
QT
Q-T Interval
QTc
Q-T Interval Corrected for Heart Rate
QTcB
Bazett’s Correction of QT Interval


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RAP
Reporting and Analysis Plan
RDW
Red Blood Cell Distribution Width
RNA
Ribonucleic Acid
rhEPO
Recombinant human erythropoietin
SAE
Serious Adverse Event
SRM
Study Reference Manual
TIBC
Total Iron Binding Capacity
TSAT
Transferrin Saturation
UIBC
Unsaturated iron Binding Capacity
VAS
Visual Analog Scale
VEGF
Vascular Endothelial Growth Factor
Trademark Information
Trademarks of the GlaxoSmithKline group of 
companies
Trademarks not owned by the GlaxoSmithKline 
group of companies
None
Hemocue


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12.2.
Appendix 2: Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
GSK1278863 
Excessive erythropoiesis (polycythemia) leading to 
thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis attributed to GSK1278863 
was associated with vascular congestion, microthrombi, and tissue 
ischemia in a number of organs.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
Phase 2 dose-ranging studies, and associated statistical and exposure 
response modelling has informed Phase 3 dose rationale, starting 
doses, dose levels, and dose adjustment scheme to optimize Hgb 
management.
•
Specific eligibility criteria related to requirements for 
entry Hgb are detailed in Section 5.1.
•
Hgb will be closely monitored throughout the dosing 
period as outlined in the Time and Events Table 
Section 7.1.
•
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of GSK1278863 
based on achieved Hgb is provided in Section 6.3.1.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Risk of death, MI, stroke, congestive heart failure, venous 
thromboembolism, thrombosis of vascular access at Hgb 
levels which are within the normal range (i.e. not 
polycythemic conditions)
Marketed rhEPO/ESAs have been associated with an increased risk for 
death and serious cardiovascular events when used in patients with 
anemia of CKD.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
•
Specific eligibility criteria related to CV risk are 
outlined in Section 5.2.
•
Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Esophageal and gastric erosions
In animal studies, undesirable GI effects including emesis, abnormal 
feces and/or decreased food consumption/body weight loss and 
stomach erosions/ ulcers with hemorrhage were observed.  
In rodents stomach erosions observed with intravenous and oral 
administration of GSK1278863.
Gender-averaged systemic exposure (AUC) at the no observed adverse 
•
Suspected GI bleeding or significant symptoms
consistent with erosion should be investigated 
diagnostically (i.e. endoscopic examination) as 
clinically warranted
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
effect levels (NOAEL) are 3.3 -fold (monkeys) and 737 -fold (rats) 
above human exposure (25 mg).
In clinical trials to date, mild-moderate GI signs and symptoms 
represent the most frequently reported adverse event, however causal 
association has not been established.
Following review of clinical data received to date, GI erosions have 
not been identified as a safety concern for GSK1278863.
period.
Cancer-related mortality, tumor progression and recurrence
In clinical trials, use of rhEPO in patients with cancer has been associated with 
increased risk of cancer related morbidity and mortality.
Administration of 60 mg/kg GSK1278863 to mice caused minimal increases in 
circulating VEGF while significant EPO increases were observed.
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations, an angiogenic factor that has been 
implicated in tumor growth, was observed at doses ranging from 10 to 
150 mg. In clinical studies up to 24 weeks duration at doses up to 
25 mg, changes in VEGF plasma concentrations were variable but 
similar relative to control.
Following review of clinical data received to date, this has not been identified 
as a safety concern for GSK1278863.
•
Specific eligibility criteria related to personal history 
of malignancy are outlined in Section 5.2..
•
Stopping criteria for subjects with treatment 
emergent malignancy are outlined in Section 5.4.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Pulmonary artery hypertension (PAH)
A role for HIF-regulated pathways in the pathophysiology of PAH has 
been suggested based on well established effects of acute and chronic 
hypoxia in man on the pulmonary vasculature (vasoconstriction), and 
by findings in patients with naturally occurring mutations that result in 
decreased HIF degradation (Smith, 2006; Formenti, 2011).
There have been no histopathologic findings suggestive of PAH in pre-
clinical safety studies (up to 13-weeks duration in mice and dog, up to 
26-weeks in rat, and up to 39-weeks in monkeys.
Acute hypoxic challenge (rats): GSK1278863A produced increases in 
peak right ventricular pressure (PRVP) during acute hypoxia that were 
slightly higher than the vehicle control group. These hypoxia-induced
PRVP changes fall within the range of PRVP differences noted among 
non-treated rats.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Results from a clinical study of acute hypoxic challenge in healthy 
volunteers demonstrated that short-term therapy with GSK1278863 
5 mg or 100 mg has no clinically significant effect on 
echocardiographically estimated pulmonary artery systolic pressure 
(PASP) under either normoxic or hypoxic conditions.
ECHO assessments performed in Phase 2b studies (24 weeks treatment 
duration) did not identify any clinically meaningful changes in sPAP in 
subjects not on dialysis. Further interrogation of sPAP data in dialysis 
subjects is ongoing.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.  
Cardiomyopathy
Published data suggest that cardiac effects of HIF stabilization are 
likely a function of the mechanism, extent, and duration of the effects, 
and can range from protective to detrimental depending upon the 
specific model and experimental conditions utilized.
Small increases in cardiac troponin in 6 month rat study were 
consistent with the background finding of spontaneous rodent 
cardiomyopathy. There were no elevations observed in cardiac 
troponin in 9 month monkey study.
Cardiomyopathy has not been associated with naturally occurring 
mutation in man which results in increased HIF stabilization.
ECHO assessments performed in phase 2b studies (24 weeks treatment 
duration) did not identify any clinically meaningful changes in LVEF.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Proliferative retinopathy, macular edema, choroidal 
neovascularization
Increases in local (ocular) VEGF production with retinal 
neovascularization and macular edema observed in diabetic 
retinopathy and to choroidal leakage, edema and neovascularization 
seen in age-related macular degeneration (Campochiaro, 2006).
Administration of 60 mg/kg GSK1278863 to mice caused minimal 
increases in circulating VEGF while significant EPO increases were 
•
Ophthalmology exams will be performed during 
screening, at approximately Week 12 on-study, and 
at the end of treatment.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
observed.
No ocular abnormalities were seen in non-clinical studies of up to 13 
weeks duration in mice and dogs, 26 weeks in rats, and 39-weeks in 
monkeys.  
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations was observed at doses ranging from 10 
to 150 mg. In studies up to 24 weeks duration at doses up to 25 mg, 
changes in VEGF plasma concentrations were variable but similar 
relative to control.
Ophthalmologic assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes 
in proliferative retinopathy, macular edema, or choroidal 
neovascularization.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
period.
•
Ophthalmology exams should be specified in 
Section 7.4.7. and monitored.
Exacerbation of rheumatoid arthritis
In inflamed rheumatic joints, activation of HIF- related genes 
secondary to decreased oxygen and pro-inflammatory cytokines has 
been postulated to contribute to the neo-angiogenesis, proliferation and 
infiltration of rheumatoid synovial fibroblasts (Westra, 2010; Muz, 
2009).
No abnormalities seen in non-clinical studies conducted to date.
Following review of clinical data received to date, this has not been 
identified as a safety concern for GSK1278863.
•
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period.
Drug-drug interactions
Co-administration of GSK1278863 with a strong CYP2C8 inhibitor increased 
the Cmax and AUC of GSK1278863, 4- and 19-fold, respectively, while co-
administration of a weak inhibitor increased the Cmax and AUC of 
GSK1278863 by 1.3- and 1.5-fold, respectively. Population PK analysis from 
completed Phase 2 studies suggests that co-administration of GSK1278863 
with a moderate CYP2C8 inhibitor, leads to a ~ 2-fold increase in AUC, with no 
•
Co-administration of GSK1278863 with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 
inducers (e.g., rifampin/rifampicin) is not 
permitted as outlined in Section 6.10.2.
•
Co-administration of GSK1278863 with 
moderate CYP2C8 inhibitors (i.e., clopidogrel, 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
clinically-significant increase in the measured Hgb response.
GSK1278863 is an inhibitor of CYP2C8 in vitro, with an IC50 value of 
21 µM.
Population PK analysis from completed Phase 2 studies suggests that 
co-administration of GSK1278863 with clopidogrel (a moderate 
CYP2C8 inhibitor) leads to a ~ 2-fold increase in AUC, with no 
clinically-significant increase in the measured Hgb response. Co-
administration of GSK1278863 with moderate CYP2C8 inhibitors (i.e., 
clopidogrel, teriflunomide, deferasirox) should be performed with 
caution.
Co-administration of GSK1278863 with potent BCRP inhibitors has 
the potential to increase exposure of GSK1278863. Use of BCRP 
inhibitors (mostly weak) was found to result in a small change in 
metabolite exposure (20% increase in AUC).
GSK1278863 is an inhibitor of OATP1B1/1B3 in vitro, with IC50
values of 6 µM and 11 µM, respectively. A clinical drug interaction 
study between 25mg GSK1278863 with either a CYP2C8 substrate or 
an OATP1B1/1B3 substrate showed that there is no PK interaction at 
this dose of GSK1278863.
teriflunomide, deferasirox) should be 
performed with caution. If one of these 
medications is started, stopped or the dose is 
changed, Hgb should be monitored every 4 
weeks for 12 weeks as outlined in Section 
6.10.1.
•
Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in Section 
6.10.
•
Hgb will be closely monitored throughout the dosing 
period as outlined in the Time and Events Table 
Section 7.1.
•
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of 
GSK1278863 based on achieved Hgb is 
provided in Section 6.3.1.
•
These risks have been identified as AEs of 
special interest and will be monitored 
instreamly by the internal safety review team 
throughout the study period.
Other
ESA risks (Control)
See risks outlined in table for GSK1278863 for Excessive 
erythropoiesis (polycythemia) leading to thrombosis and/or tissue 
ischemia; Risk of MI, stroke, venous thromboembolism, thrombosis of 
vascular access; and risk of cancer-related mortality and tumor 
progression.
Hepatic function disorder with increase of AST, ALT and Gamma-
glutamyltransferase, and jaundice have been reported as adverse drug 
reactions for other ESA according to the prescribing information of 
Epoetin beta pegol.

The same mitigation strategies have been 
indentified in acoordance with the mitigation 
strategies for GSK1278863.

Liver function will be monitored throughout 
the dosing period as outlined in the Time and 
Events Table provided in Section 7.1.


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References
Campochiaro et al., Ocular versus Extraocular Neovascularization: Mirror Images or Vague Resemblances; Invest Ophthalmol & Vis Sci 2006. 47:462-474.
Formenti et al., Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha 
gain-of-function mutation. FASEB J. 2011, 25(6): 2001-2011.
Muz et al., The role of hypoxia and HIF-dependent signaling events in rheumatoid arthritis, Arthritis Research & Therapy 2009. 11:201-210.
Smith et al., Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology PLOS 2006. 3:1176-1186.
Westra et al., Hypoxia-Inducible Factor-1 as Regulator of Angiogenesis in Rheumatoid Arthritis - Therapeutic Implications.  Current Medicinal Chemistry 
2010. 17:254-263.


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12.3.
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of reproductive potential
This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle 
or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long 
term and persistent basis.
1.
Contraceptive subdermal implant that meets the Prescribing Information effectiveness criteria 
including a <1% rate of failure per year, as stated in the Prescribing Information
2.
Intrauterine device or intrauterine system that meets the Prescribing Information effectiveness 
criteria including a <1% rate of failure per year, as stated in the Prescribing Information
[Hatcher, 2011]
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female subject's entry 
into the study, and this male is the sole partner for that subject [Hatcher, 2011].  
These allowed methods of contraception are only effective when used consistently, correctly and in 
accordance with the Prescribing Information. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception.
References
Trussell J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, Kowal D, and 
Policar M (editors). Contraceptive Technology: Twentieth Revised Edition. New York: Ardent Media, 
2011.


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12.4.
Appendix 4: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes pregnant 
while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 weeks of 
learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The investigator will collect 
follow up information on mother and infant, which will be forwarded to GSK. Generally, follow-
up will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as such.  

Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related 
to the study treatment by the investigator, will be reported to GSK as described in Section 12.6.
Appendix 6. While the investigator is not obligated to actively seek this information in former 
study participants, he or she may learn of an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating

will discontinue study medication or be withdrawn from the study


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12.5.
Appendix 5: Liver Safety Required Actions and Follow up Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance).
Phase III-IV liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted

If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments 
MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) and 
quantitative hepatitis B DNA 

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 24 hours after last 
dose5

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:


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hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  
24-72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, (for ND patients only) if serum bilirubin fractionation testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if 
INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold 
value stated will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody or Hepatitis E RNA
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
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 in the 
SRM.  
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 


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be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and 
<8xULN to ≥3xULN but <5xULN, continue to 
monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to 
within baseline.


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12.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, Follow-
Up and Reporting of Adverse Events
12.6.1.
Definition of Adverse Events
Adverse Event Definition:

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 AE definition 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).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE.  However, the signs and symptoms and/or clinical sequelae resulting from lack
of efficacy will be reported if they fulfil the definition of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the 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.


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12.6.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of 
disease, etc).
Serious Adverse Event (SAE) is defined as 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
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
e.
Is a congenital anomaly/birth defect
f.
Other situations:

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; (for ND patients only) if 


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unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury. 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.
12.6.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF 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
12.6.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in the CRF

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 CRF page.

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.

PRO questionnaires and the collection of AE data are independent components of the study.

Responses to each question in PRO 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.
12.6.5.
Evaluating AEs and SAEs
Assessment of Intensity


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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.
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

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 


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histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated reporting time 
frames.
12.6.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use the paper SAE 
data collection tool and fax it to the SAE contact.

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 subject 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 the SAE contact by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the Sponsor/Medical 
Monitor Contact Information page.


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12.7.
Appendix 7 - Genetic Research
Background
Naturally occurring genetic variation may contribute to inter-individual variability in response to 
medicines, as well as an individual's risk of developing specific diseases. Genetic factors associated 
with disease characteristics may also be associated with response to therapy, and could help to explain 
some clinical study outcomes. For example, genetic variants associated with age-related macular 
degeneration (AMD) are reported to account for much of the risk for the condition [Gorin, 2012] with 
certain variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the genetic 
etiology of disease may better inform understanding of disease and the development of medicines. 
Additionally, genetic variability may impact the pharmacokinetics (absorption, distribution, 
metabolism, and elimination), or pharmacodynamics (relationship between concentration and 
pharmacologic effects or the time course of pharmacologic effects) of a specific medicine and/or 
clinical outcomes (efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objective of the genetic research is to understand the response to GSK1278863. To achieve this 
objective, the relationship between genetic variants and the followings may be investigated.

Response to medicine, including GSK1278863, ESA, other study medicines or any concomitant 
medicines;

Nephrogenic anemia and related conditions susceptibility, severity, and progression 
Genetic data may be generated while the study is underway or following completion of the study.  
Genetic evaluations may include focused candidate gene approaches and/or examination of a large 
number of genetic variants throughout the genome (whole genome analyses). Genetic analyses which 
will be conducted for this study will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data from multiple 
clinical studies related to GSK1278863 to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed description of any 
planned analyses will be documented in a Reporting and Analysis Plan (RAP) prior to initiation of the 
analysis. Planned analyses and results of genetic investigations will be reported either as part of the 
clinical RAP and study report, or in a separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in the genetic research. Any subject who has 
received an allogeneic bone marrow transplant must be excluded from the genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during clinical studies. 
Collection of samples, even when no a priori hypothesis has been identified, may enable future 
genetic analyses to be conducted, align with the purpose of the genetic research, to help understand 
variability in disease and medicine response.  


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
A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A Blood 
sample is collected at the baseline visit, after the subject has been randomized and provided 
informed consent for genetic research. Instructions for collection and shipping of the genetic 
sample are described in the laboratory manual. The DNA from the blood sample may undergo 
quality control analyses to confirm the integrity of the sample. If there are concerns regarding the 
quality of the sample, then the sample may be destroyed. The blood sample is taken on a single 
occasion unless a duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to label other 
samples and data in the study. This number 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). 
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 only use samples collected from the study for the purpose stated in this protocol and 
in the informed consent form. Samples may be used as part of the development of a companion 
diagnostic to support the GSK medicinal product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the study.  
Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic 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 genetic sample, if already collected:

Continue to participate in the genetic research in which case the genetic DNA sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA sample 
If a subject withdraws consent for genetic 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. 
Genotype data may be generated during the study or after completion of the study and may be 
analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been analyzed, it 
will not be analyzed or used for future research.  


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
Genetic data that has been analyzed at the time of withdrawn consent will continue to be stored 
and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject does not meet 
the entry criteria for participation in the study, then the investigator should instruct the subject that 
their genetic 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.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or separately and may 
publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific understanding in 
alignment with the informed consent. GSK does not inform the subject, family members, 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 genetic studies is generally preliminary in nature, and therefore the significance and 
scientific validity of the results are undetermined. Further, data generated in a research laboratory may 
not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular Degeneration 
(AMD) Susceptibility Gene CFH and Treatment Response of AMD: A Meta-Analysis. PloS ONE 
2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies addressing risk, 
causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.

SAP_001.pdf: 
CONFIDENTIAL
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Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 201753 
A 52-week, Phase III, open-label, multi-center study to 
evaluate efficacy and safety of GSK1278863 in Japanese 
non-dialysis and peritoneal dialysis subjects with anemia 
associated with chronic kidney disease
Compound Number 
:
GSK1278863
Effective Date 
:
19-NOV-2018
Description:

This RAP is an amendment version 1.

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 201753.

This RAP is intended to describe the final analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Author
Date
Approval Method
Lead
NA
NA
Biostatistics Group 2, Biomedical Data Sciences 
Japan
Co-Authors
Biostatistics Group 2, Biomedical Data Sciences 
Japan
16-NOV-2018
E-mail
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited
2018N378935_00
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RAP Team Review Confirmations
Reviewer
Date
Approval Method
 
16-NOV-2018
E-mail
Lead Programmer; Statistical Programming & 
Reporting Group, Biomedical Data Sciences 
Japan
16-NOV-2018
E-mail
Clinical Investigation Leader; Infectious 
Disease/Future Pipelines Discovery Office, 
Medicines Development
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
19-NOV-2018
Pharma TMF
Lead Authors Line Manager; Biostatistics Group 
2, Biomedical Data Sciences Japan
19-NOV-2018
Pharma TMF
Lead Programmers Line Manager; Statistical 
Programming & Reporting Group, Biomedical 
Data Sciences Japan
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................7
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................8
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................12
3.
PLANNED ANALYSES ..........................................................................................14
3.1.
Interim Analyses .........................................................................................14
3.2.
Final Analyses ............................................................................................14
4.
ANALYSIS POPULATIONS ...................................................................................14
4.1.
Protocol Deviations.....................................................................................17
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................18
5.1.
Study Treatment & Sub-group Display Descriptors.....................................18
5.2.
Baseline Definitions ....................................................................................18
5.3.
Multicentre Studies .....................................................................................19
5.4.
Examination of Covariates, Other Strata and Subgroups............................19
5.4.1.
Covariates and Other Strata ........................................................19
5.4.2.
Examination of Subgroups...........................................................19
5.5.
Multiple Comparisons and Multiplicity .........................................................20
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................21
6.
STUDY POPULATION ANALYSES .......................................................................22
6.1.
Overview of Planned Study Population Analyses........................................22
6.2.
Planned Summary Display Details..............................................................23
7.
EFFICACY ANALYSES..........................................................................................27
7.1.
Primary Efficacy Analyses ..........................................................................27
7.1.1.
Endpoint / Variables.....................................................................27
7.1.2.
Summary Measure ......................................................................28
7.1.3.
Population of Interest...................................................................29
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................29
7.1.5.
Statistical Analyses / Methods .....................................................29
7.1.5.1.
Statistical Methodology Specification..........................30
7.1.6.
Sensitivity and Supportive Analyses ............................................31
7.1.6.1.
Evaluable Hgb............................................................32
7.1.6.2.
Analysis of Covariance (ANCOVA).............................33
7.1.6.3.
Tipping Point Analysis ................................................34
7.2.
Principal Secondary Efficacy Analyses .......................................................36
7.2.1.
Endpoint / Variables.....................................................................36
7.2.2.
Summary Measure ......................................................................37
7.2.3.
Population of Interest...................................................................37
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................37
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7.2.5.
Statistical Analyses / Methods .....................................................38
7.2.5.1.
Statistical Methodology Specification..........................38
7.3.
Secondary Efficacy Analyses......................................................................40
7.3.1.
Endpoint / Variables.....................................................................40
7.3.2.
Summary Measure ......................................................................42
7.3.3.
Population of Interest...................................................................47
7.3.4.
Strategy for Intercurrent (Post-Randomization) Events ................47
7.3.5.
Statistical Analyses / Methods .....................................................47
7.3.5.1.
Statistical Methodology Specification..........................47
7.4.
Exploratory Efficacy Analyses.....................................................................49
7.4.1.
Endpoint / Variables.....................................................................49
7.4.2.
Summary Measure ......................................................................50
7.4.3.
Population of Interest...................................................................50
7.4.4.
Strategy for Intercurrent (Post-Randomization) Events ................51
7.4.5.
Statistical Analyses / Methods .....................................................51
8.
SAFETY ANALYSES .............................................................................................52
8.1.
Adverse Events Analyses ...........................................................................52
8.1.1.
Planned Adverse Events Analyses Displays ................................53
8.2.
Adverse Events of Special Interest Analyses..............................................56
8.2.1.
Planned Adverse Events of Special Interest Analyses 
Displays.......................................................................................56
8.3.
Clinical Laboratory Analyses.......................................................................56
8.3.1.
Planned Clinical Laboratory Analyses Displays ...........................58
8.4.
Other Safety Analyses ................................................................................59
8.4.1.
Planned Other Safety Analyses Displays.....................................59
9.
PATIENT REPORTED OUTCOME ANALYSES.....................................................61
9.1.
Endpoint / Variables....................................................................................61
9.2.
Summary Measure .....................................................................................62
9.3.
Population of Interest..................................................................................62
9.4.
Strategy for Intercurrent (Post-Randomization) Events ...............................62
9.5.
Statistical Analyses / Methods ....................................................................63
9.5.1.
Statistical Methodology Specification...........................................63
10. PHARMACOKINETIC ANALYSES.........................................................................64
10.1.
Pharmacokinetic Analyses..........................................................................64
10.1.1.
Endpoint / Variables.....................................................................64
10.1.1.1.
Drug Concentration Measures....................................64
10.1.1.2.
Derived Pharmacokinetic Parameters.........................64
10.1.2.
Summary Measure ......................................................................65
10.1.3.
Population of Interest...................................................................65
10.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................66
11. POPULATION PHARMACOKINETIC (POPPK) ANALYSES..................................66
12. PHARMACODYNAMIC ANALYSES.......................................................................66
13. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................66
14. REFERENCES.......................................................................................................67
15. APPENDICES........................................................................................................68
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15.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................68
15.1.1.
Exclusions from Per Protocol Population .....................................68
15.2.
Appendix 2: Schedule of Activities ..............................................................69
15.2.1.
Protocol Defined Schedule of Events...........................................69
15.3.
Appendix 3: Assessment Windows .............................................................71
15.3.1.
Definitions of Assessment Windows for Analyses........................71
15.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................72
15.4.1.
Study Phases ..............................................................................72
15.4.1.1.
Study Phases for Hgb Data ........................................72
15.4.1.2.
Study Phases for AE Data..........................................72
15.4.1.3.
Study Phases for Concomitant Medication .................72
15.5.
Appendix 5: Data Display Standards & Handling Conventions....................75
15.5.1.
Reporting Process .......................................................................75
15.5.2.
Reporting Standards....................................................................75
15.5.3.
Reporting Standards for Pharmacokinetic....................................76
15.6.
Appendix 6: Derived and Transformed Data ...............................................77
15.6.1.
General........................................................................................77
15.6.2.
Study Population..........................................................................78
15.6.3.
Efficacy........................................................................................83
15.6.4.
Safety ..........................................................................................90
15.6.5.
Pharmacokinetic ..........................................................................92
15.6.6.
Exploratory Endpoint ...................................................................93
15.6.7.
Patient Reported Outcome ..........................................................93
15.7.
Appendix 7: Reporting Standards for Missing Data.....................................95
15.7.1.
Premature Withdrawals................................................................95
15.7.2.
Handling of Missing Data.............................................................95
15.7.2.1.
Handling of Missing and Partial Dates ........................95
15.8.
Appendix 8: Values of Potential Clinical Importance ...................................96
15.8.1.
Laboratory Values........................................................................96
15.8.2.
Vital Signs....................................................................................97
15.9.
Appendix 9 Abbreviations & Trade Marks ...................................................98
15.9.1.
Abbreviations...............................................................................98
15.9.2.
Trademarks .................................................................................99
15.10. Appendix 10: List of Data Displays............................................................100
15.10.1. Data Display Numbering............................................................100
15.10.2. Mock Example Shell Referencing ..............................................100
15.10.3. Table of Contents for Headline Results Deliverable...................101
15.10.4. Table of Contents for SAC Deliverable ......................................103
15.10.4.1. Study Population Tables...........................................103
15.10.4.2. Efficacy Tables.........................................................108
15.10.4.3. Efficacy Figures........................................................119
15.10.4.4. Safety Tables ...........................................................128
15.10.4.5. Safety Figures ..........................................................139
15.10.4.6. Patient Reported Outcome Tables............................140
15.10.4.7. Pharmacokinetic Tables ...........................................143
15.10.4.8. Pharmacokinetic Figures ..........................................144
15.10.4.9. ICH Listings..............................................................146
15.10.4.10.
Other Listings .......................................150
15.10.4.11.
Patient Profile Listings ..........................153
15.11. Appendix 11: Example Mock Shells for Data Displays ..............................154
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16. REVISION HISTORY ...........................................................................................155
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 2015N266248_04.
Revision Chronology:
Final_V1
08-MAY-2018
Original
Amendment_Final_V1
19-NOV-2018
Amendment 1
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol 
amendment 04 (Dated: 03/JUL/2017) are outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
9.3.3
Adjustment for Multiplicity
Adjustment for multiplicity will be 
applied to maintain an overall type I 
error rate of 5%. After a preliminary 
assessment, the primary endpoint 
will be evaluated to demonstrate the 
non-inferiority at a one-sided 
significance level of 2.5% (i.e. two-
sided significance level of 5%).
5.5
Multiple Comparisons and 
Multiplicity
Adjustment for multiplicity will be 
applied to maintain an overall type I 
error rate of 2.5% (one-sided). After 
a preliminary assessment, the 
primary endpoint will be evaluated to 
demonstrate the non-inferiority at a 
one-sided significance level of 2.5%.
An overall type I error rate 
() of 2.5% is a one-sided 
nature of the non-inferiority 
test, which is the primary 
analysis for this study. This 
can be applicable to the 
following superiority test to 
maintain =2.5%. 
Practically, this is equivalent 
to two-sided significance 
level of 5%.
9.4.1 Primary Efficacy Analysis
Analysis of covariance (ANCOVA) 
will be conducted as sensitivity 
analysis to MMRM. This model 
includes treatment group and 
baseline Hgb.
7.1.6 Sensitivity and Supportive 
Analyses
Analysis of covariance (ANCOVA); it 
will be conducted as supplementary 
analysis to MMRM. This model 
includes treatment group, baseline 
Hgb, and prior ESA use.
Prior ESA use is considered 
as important factor 
impacting Hgb.
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2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To demonstrate non-inferiority of 
GSK1278863 to epoetin beta pegol 
based on hemoglobin (Hgb) in ND 
subjects

Mean Hgb during the primary efficacy evaluation period 
(Weeks 40 to 52)
Principal Secondary Objectives
Principal Secondary Endpoints

To demonstrate superiority of 
GSK1278863 to epoetin beta pegol in 
terms of achievement/maintenance of 
target Hgb in ND subjects

Number (%) of subjects with mean Hgb in the target 
range (11.0-13.0 g/dL) during the primary efficacy 
evaluation period (Weeks 40 to 52)
Other Secondary Objectives
Other Secondary Endpoints

To evaluate the appropriateness of 
the starting dose of GSK1278863 in 
ND subjects using epoetin beta pegol 
as control

To evaluate the appropriateness of 
the starting dose of GSK1278863 in 
PD subjects

Change in Hgb from baseline to Week 4 (Hgb increase 
rate)

Number (%) of subjects by Hgb change category in Hgb
from baseline to Week 4

To evaluate dose adjustments of 
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate dose adjustments of 
GSK1278863 in PD subjects

Distribution of the dose level

Duration of treatment interruption due to Hgb >13 g/dL

Frequency of dose adjustments 

To evaluate the overall Hgb control by
GSK1278863 in ND subjects using 
epoetin beta pegol as control

To evaluate the overall Hgb control by
GSK1278863 in PD subjects

Hgb at each assessment time point and change in Hgb
from baseline to each assessment time point

Number (%) of subjects with Hgb within the target range 
(11.0-13.0 g/dL) at each assessment time point

Proportion (%) of time with Hgb within the target range
(11.0-13.0 g/dL) in the primary efficacy evaluation period 
(Weeks 40 to 52)

Time (number of days) to the lower Hgb target (11.0 g/dL) 

Number (%) of subjects who have an Hgb level of less 
than 7.5 g/dL

Number (%) of subjects who have an Hgb increase of 
more than 2 g/dL over any 4 weeks before Week 52

Number (%) of subjects who achieve an Hgb level of 
more than 13.0 g/dL and number of episodes

To compare the effect of 
GSK1278863 versus epoetin beta 
pegol on iron use in ND subjects

To evaluate effect of GSK1278863 on 
iron use in PD subjects

Dose of oral iron in the study period and the primary 
efficacy evaluation period (Weeks 40 to 52) 

Number (%) of subjects who use oral iron during the 
primary efficacy evaluation period (Weeks 40 to 52)

To compare the effect of 
GSK1278863 versus epoetin beta 
pegol on iron metabolism in ND 
subjects

To evaluate the effect of GSK1278863 
on iron metabolism in PD subjects

Change in ferritin from baseline

Change in transferrin saturation (TSAT) from baseline

Changes in hepcidin, serum iron, and total iron binding 
capacity (TIBC) from baseline
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Objectives
Endpoints

To evaluate the PK of GSK1278863

AUC and Cmax of plasma GSK1278863
Exploratory Objectives
Exploratory Endpoints

To compare the effect of 
GSK1278863 versus epoetin beta 
pegol on progression of CKD in ND 
subjects

Estimated glomerular filtration rate (eGFR) and change 
from baseline

Serum creatinine and change from baseline

Urine creatinine and urine albumin, and changes from 
baseline

Urine albumin/creatinine ratio and change from baseline
Patient Reported Outcome
Patient Reported Outcome Endpoints

To compare the effect of 
GSK1278863 versus epoetin beta 
pegol on health-related QoL (HR-QoL) 
in ND subjects

To evaluate the effect of GSK1278863 
on HR-QoL in PD subjects
SF-36

Changes in SF-36 HR-QoL scores (PCS, MCS, and 8 
subscales) from baseline 
EuroQol Health Utility Index (EQ-5D-5L)

Change in EQ-5D-5L score from baseline 

Change in EQ-5D-5L Visual Analog Scale (VAS) from 
baseline
Safety Objectives
Safety Endpoints

To evaluate the safety and tolerability 
of GSK1278863 in ND and PD 
subjects

Incidence and severity of AEs and SAEs, including AEs of 
special interest

Reasons for discontinuation of study medication

Laboratory tests, ECG, vital signs, and ophthalmology 
assessments
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2.3.
Study Design
Overview of Study Design and Key Features
Screening 
phase
(4 weeks)
Treatment phase (52 weeks)
Follow-up 
phase
(4 weeks)
Primary 
efficacy 
evaluation 
period
Cohort 1
GSK1278863 group
Non-dialysis 
(ND)
subjects
Epoetin beta pegol group
Cohort 2
Peritoneal 
dialysis (PD) 
subjects
GSK1278863 group
Cohort 3
GSK1278863 group
Non-dialysis 
(ND)
subjects
Epoetin beta pegol group
Week -4                Day 1                            Week 40     
Week 52          Week 56
Design
Features

This is a Phase III, open-label, active-controlled, parallel-group, 
multi-center study to compare the efficacy (verification of 
noninferiority) and safety of GSK1278863 administered for 52 
weeks versus epoetin beta pegol in approximately 286 Japanese 
ND subjects with renal anemia.

This study also includes an open-label, uncontrolled part to 
evaluate the efficacy and safety of GSK1278863 in 
approximately 50 Japanese PD subjects.

Cohort 1 (ND subjects) and Cohort 2 (PD subjects) were set for 
target population of this study when the study was planned.

Cohort 3 is newly added in amendment (Amendment No. 3). ND 
subjects will be randomized not to Cohort 1 but to Cohort 3 after 
amendment No.3.
Dosing
GSK1278863
Starting Dose
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Overview of Study Design and Key Features
(Cohort 1)

Both ESA non-users and users will start oral treatment with 
GSK1278863 at the starting dose of 4 mg once daily (Day 
1) and remain on the same regimen until the day of Week 4.
(Cohort 3)

ESA non-users
o
Baseline Hgb 8.0 g/dL and <9.0 g/dL: the 
subjects will start oral treatment with GSK1278863 
at the starting dose of 4 mg once daily (Day 1) and 
remain on the same regimen until the day of Week 
4*.
o
Baseline Hgb 9.0 g/dL and <11.0 g/dL: the 
subjects will start oral treatment with GSK1278863 
at the starting dose of 2 mg once daily (Day 1) and 
remain on the same regimen until the day of Week 
4*.

ESA users will start oral treatment with GSK1278863 at the 
starting dose of 4 mg once daily (Day 1) and remain on the 
same regimen until the day of Week 4*.
*: The HemoCue Hgb value will be measured for safety 
confirmation at Week 2 in ND subjects. When Hgb > 1.0 
g/dL increase over 2 weeks, the dose of GSK1278863 is 
decreased to the next lower dose.
(Cohort 2)

ESA non-users will start oral treatment with GSK1278863 at 
the starting dose of 4 mg once daily (Day 1) and remain on 
the same regimen until the day of Week 4. 

ESA users will start oral treatment with GSK1278863 at the 
starting dose of 4 mg once daily (Day 1) and remain on the 
same regimen until the day of Week 4.
ESA users should skip ESA on Day 1 when treatment with 
GSK1278863 is started.
Maintenance Dose

From Weeks 4 to 52, interruption of treatment or dose 
adjustments will be made within the maintenance dose 
range of 1-24 mg (Table 6 in the protocol) according to the 
dose adjustment algorithm (Table 7 in the protocol) to 
achieve and/or maintain Hgb within the target range (11.0-
13.0 g/dL) based on the HemoCue Hgb value measured 
every 4 weeks. Dose changes will be made every 4 weeks.
Epoetin Beta Pegol
Starting Dose for ESA Non-users

ESA non-users will start subcutaneous treatment with 
epoetin beta pegol at a dose of 25 μg once every 2 weeks 
(Day 1). Dose adjustments will be made within the initial 
dose range of 25-150 μg (Table 8 in the protocol) according 
to the dose adjustment criteria (Table 9 in the protocol) to 
increase Hgb to 11.0 g/dL (lower limit of the target) or more 
based on the HemoCue Hgb value measured every 4 
weeks. Dose changes will be made every 4 weeks.
Dose Conversion for ESA Users
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Overview of Study Design and Key Features

For ESA users, prior ESA will be replaced with epoetin beta 
pegol at the equivalent dose once every 4 weeks (Day 1).

At Week 2, HemoCue Hgb value will be measured for 
subjects' safety confirmation. If the measurement shows an 
Hgb increase of >1.0 g/dL over 2 weeks, the dose of 
GSK1278863 will be reduced by one step (or treatment 
interrupted) at Week 4 (Cohort 3 only).
Maintenance Dose

Epoetin beta pegol will be administered once every 4 weeks 
from dosing interval change (once every 4 weeks) with Hgb 
≥11.0 g/dL to Week 52 in ESA non-users and from Weeks 4 
to 52 in ESA users

Further details of dosing are provided in the protocol Section 6.4.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignme
nt

The randomization schedule will be generated by 
GlaxoSmithKline (GSK) using the randomization system 
(Randall NG). 

In Cohort 1 and Cohort 3 (ND subjects), subjects will be stratified 
by the current ESA therapy (ESA non-user or ESA user) and the 
Hgb level on Day 1 and randomized in a 1:1 ratio to one of the 
two treatment groups according to the randomization schedule. 

In Cohort 2 (PD subjects), all eligible subjects will start treatment 
with GSK1278863 on Day 1. 
Interim 
Analysis

No interim analysis is planned.
2.4.
Statistical Hypotheses / Statistical Analyses
The primary objective of the study is to demonstrate the non-inferiority of GSK1278863 
to epoetin beta pegol based on mean Hgb during the primary efficacy evaluation period 
(Weeks 40 to 52) in ND subjects, including Cohort 1 subjects (only ESA users) and 
Cohort 3 subjects (both ESA users and ESA non-users).
As a preliminary assessment, it will be confirmed whether the mean Hgb during the 
primary efficacy evaluation period in GSK1278863 group would be in the target range 
(11.0-13.0 g/dL) at first. And then the following non-inferiority statistical hypotheses are 
to be tested at a one-sided significance level of 2.5% (i.e. two-sided significance level of 
5%):
•
H0: Treatment difference (daprodustat – epoetin beta pegol) in mean Hgb during the 
primary efficacy evaluation period is -1.0 g/dL or less.
•
H1: Treatment difference (daprodustat – epoetin beta pegol)
in mean Hgb during 
the primary efficacy evaluation period is greater than -1.0 g/dL.
Only when the primary endpoint achieves non-inferiority, statistical testing will progress 
to the principal secondary endpoint with a focus on superiority according to the step-
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down procedure. More specifically, the superiority of GSK1278863 to epoetin beta pegol 
in terms of target Hgb control in ND subjects, including Cohort 1 subjects (only ESA 
users) and Cohort 3 subjects (both ESA users and ESA non-users), is to be demonstrated 
at a one-sided significance level of 2.5% by testing the following statistical hypotheses:
•
H0: The proportion of subjects whose mean Hgb during the primary efficacy 
evaluation period is within the target range (11.0-13.0 g/dL) is equal or less in 
GSK1278863 than epoetin beta pegol.
•
H1: The proportion of subjects whose mean Hgb during the primary efficacy 
evaluation period is within the target range (11.0-13.0 g/dL) is greater in 
GSK1278863 than epoetin beta pegol.
No hypothesis will be tested in PD subjects (Cohort 2).
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3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis is planned.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
The study has completed with the last subject’s last study visit. 
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
Randomization codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Screening

Consists of all subjects who are given subject number 
and whose data are collected, including demographics 
at screening

Study Population
Enrolled

Consists of subjects in All Screening except for screen 
failures (who never passed screening even if 
rescreened).

Study Population 
(some displays for 
EudraCT)
Randomized 

Consists of all subjects who are given randomization 
number regardless of whether they actually receive 
study treatment.

Study Population
Safety

Consists of all subjects who receive at least one dose 
of study treatment.

Subjects will be analyzed according to the treatment 
received.[1]

This population will be used for safety analyses.

Study Population

Safety
Efficacy Non-
dialysis (Efficacy 
ND)

Consists of Cohort 1 subjects (both ESA users and 
ESA non-users) and Cohort 3 subjects (both ESA users 
and ESA non-users) who are given randomization 
number with Hgb measurement at both baseline and at 
least one scheduled visits following the baseline.

Subjects will be analyzed according to randomized 
treatment.

Study Population

Efficacy
Efficacy 
Peritoneal 
Dialysis (Efficacy 
PD)

Consists of Cohort 2 subjects who are given 
randomization number with Hgb measurement at both 
baseline and at least one scheduled visits following the 
baseline.

Study Population

Efficacy
Intent-To-Treat 
(ITT)

Consists of Cohort 1 subjects (only ESA users) and 
Cohort 3 subjects (both ESA users and ESA non-users) 
who are given randomization number with Hgb 
measurement at both baseline and at least one 
scheduled visits following the baseline.

Study Population

Efficacy
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Population
Definition / Criteria
Analyses Evaluated

Subjects will be analyzed according to randomized 
treatment.

This population will be the primary population for an 
assessment of non-inferiority.
modified ITT 
(mITT)

Consist of all ITT subjects who have at least one Hgb 
measurement during the efficacy evaluation period.

Subjects will be analyzed according to randomized 
treatment.

This population will be the primary population for an 
assessment of superiority.

Study Population

Efficacy
Per-Protocol 
(PP)

Consists of all mITT subjects who are not major 
protocol violators.

This population will be used for efficacy sensitivity 
analyses.

Protocol deviations that would exclude subjects from 
the PP population are defined in Section 4.1(Protocol 
Deviations) and Appendix 1: Protocol Deviation 
Management and Definitions for Per Protocol 
Population.

Efficacy
Pharmacokinetic 
(PK)

Consists of all GSK1278863-treated subjects from 
whom PK samples are collected and analyzed.

PK
NOTES : 

Basically, enrolled population will be the same as randomized population because a subject is going to be given 
randomized number as soon as passed screening.

Refer to Appendix 10: List of Data Displays which details the population used for each display.

Refer to 15.6.2 for handling rescreened subjects.
[1]: Only subjects receiving incorrect randomized treatment for the duration of their study participation will be analyzed 
according to the treatment received. Otherwise, subjects will be analyzed according to the treatment to which they 
were randomized.
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Figure 1
Analysis Populations
NOTES : 
[1]: Subjects who never passed screening even if rescreened
[2]: Subjects who are not given randomization number
[3]: Subjects who never receive study treatment
[4]: Subjects who do not have Hgb measurement at both baseline and at least one scheduled visits following the 
baseline
[5]: ESA non-users in Cohort 1 subjects
[6]: Subjects who have no Hgb measurement during the efficacy evaluation period
[7]: Subjects who are major protocol violators (See Section 4.1 and Appendix 1)
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4.1.
Protocol Deviations
Important protocol deviations (including deviations related to the study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarized and listed.
Important deviations which resulted in exclusion from the analysis population will also 
be summarised and listed. (Please refer to Appendix 1: Protocol Deviation Management 
and Definitions for Per Protocol Population).
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
D1
GSK1278863
Daprodustat
1
D2
Epoetin beta pegol
Epoetin beta pegol
2
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
Daprodustat vs Epoetin Beta Pegol
5.2.
Baseline Definitions
The baseline Hgb value will be the value from the Day 1 visit. no derivation will be 
performed and baseline will be set to missing, even if missing at Day 1 visit. 
For all other endpoints, the baseline value will be the latest pre-dose assessment with a 
non-missing value. This is generally expected to be the pre-dose value from the Day 1 
visit, except for ECG. For ECG, screening assessment will be used as a baseline. If 
missing at Day 1 visit, screening assessment or other pre-dose assessment may be used as 
baseline. If baseline data is missing (i.e. Day 1, screening, and pre-dose assessment is all 
missing), no derivation will be performed and baseline will be set to missing.
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
For TSAT, Hepcidin, and 
Lipid Parameters
1.
Log-transform the data at both the baseline and the specified 
timepoint
2.
Calculate a change from baseline using the log-transformed data 
for each subject
3.
Calculate the mean, and 95%CI and standard error (SE) of the 
log-transformed data
4.
Exponentially back-transform to the original scale 
5.
Subtract 1, then multiply everything by 100%
So, geometric mean for percent change from baseline 
= { exp(Mean [ln(Post-Dose Visit Value) – ln(Baseline)]) – 1 }x 100
Coefficient of variation will be calculated as
CV%=[exp(Var in loge scale)-1 ]1/2 x 100
where 'Var in loge scale' represents variance of percent change from 
baseline in loge scale.
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5.3.
Multicentre Studies
It is anticipated that subject accrual will be spread thinly across centers and summaries of 
data by center would be unlikely to be informative. Therefore, data from all participating 
centers will be pooled for analysis.
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
The list of covariates and other strata will be used in statistical analyses, the strata will
also be used for subgroup analyses.
Randomization is stratified by prior ESA use and baseline Hgb in Cohort 1 and Cohort 3 
(ND subjects). Baseline Hgb will be included as a covariate in the primary efficacy 
analyses. Prior ESA use and baseline Hgb will be included as covariates in the principal 
secondary efficacy analyses. The reasons why prior ESA use will not be included in the 
primary analyses are 1) the data for the primary endpoint is longitudinal data and the visit 
effect and the interaction with visit are important. 2) if including prior ESA use in the 
analyses the model will be complicate and it will be difficult to interpret the results. 
While, the data for the principal secondary endpoint is not longitudinal data and it has no 
visit data. Thus, it will not be complicate even if including prior ESA use in the model.
Category
Details
Strata
ESA use, Baseline Hgb
Covariates
For primary efficacy analyses:

Mixed model for repeated measurements (MMRM) including covariates of treatment
group, baseline Hgb, visit, treatment-by-visit interaction, and baseline Hgb-by-visit 
interaction will be used.
For principal secondary efficacy analyses:

Logistic regression model including treatment group, baseline Hgb, and current ESA 
therapy (presence or absence) as covariates will be used.
5.4.2.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and statistical analyses.
Subgroup
Categories 
Prior ESA Use[1]
Non-user, User
Baseline Hgb (g/dL)[1][2]
ESA non-users: <=9.5, >9.5  
ESA users: <11.0, >=11.0 
Age (year)
< 65, >=65
Sex
Female, Male
Prior ESA Dose (IU/week)
<4,500, >=4,500[3][4]
Prior ESA Type
Epoetin, Epoetin beta pegol, Darbepoetin alfa
ERI [3]
< median, >= median
Baseline Iron Use[5]
Yes, No
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Subgroup
Categories 
Baseline Weight (kg) 
< 55, >=55
Baseline BMI (kg/m2)
<20, >=20 
History of Diabetes[6]
Yes, No
Dialysis[7]
ND subjects, PD subjects
CKD Stage[8]
Stage 3 (30=<eGFR<60), Stage 4 (15=<eGFR<30), Stage 5 
(eGFR<15)
NOTES:

BMI = Body Mass Index

See Section 15.6.1 for the subgroup derivations
[1] Stratum code will be used to determine category. Stratum code=1: ESA non-user, Baseline Hgb <= 9.5, 2: 
ESA non-user, Baseline Hgb > 9.5, 3: ESA user, Baseline Hgb < 11.0, 4: ESA user, Baseline Hgb >= 11.0.
[2] Hemocue Hgb at Day 1 will be used for categorization.
[3] Additional thresholds might be added in order to divide the population equally as appropriate.
[4] Standardized dose on epoetin i.v. (IU/week) will be used for subgroup.
[5] Subjects who used ferric citrate (trade name: Riona) will also be included in Baseline Iron Use group. This 
category will be used just for iron analyses. See Section 15.6.3.
[6] Past or current history of diabetes
[7] This subgroup will be used for study population analyses and safety analyses.
[8] CKD Stage will be determined by eGFR (mL/min/1.73m2) at a screening visit
For prior ESA use, the subgroup of non-users in PD subjects is small. Therefore 
endpoints summarized for PD subjects (i.e. Safety or Efficacy PD population) by prior 
ESA use will also be listed for the ESA non-users in PD subjects.
5.5.
Multiple Comparisons and Multiplicity
Adjustment for multiplicity will be applied to maintain an overall type I error rate of 
2.5% (one-sided, change from define in the protocol, see Section 2.1). After a preliminary 
assessment, the primary endpoint will be evaluated to demonstrate the non-inferiority at a 
one-sided significance level of 2.5%. Only when the primary endpoint achieves non-
inferiority, statistical testing will progress to the principal secondary endpoint with a 
focus on superiority. Since the process will follow step-down manner, a multiplicity 
adjustment for one-sided significance level of 2.5% will not be needed according to a 
closed test procedure.
Other secondary endpoints, which will be evaluated on a complementary or exploratory 
basis, will be compared at a two-sided significance level of 5% without multiplicity 
adjustment.
Since Cohort 2 is a single-arm cohort, no testing will be performed to evaluate the 
efficacy in PD subjects.
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5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
15.3
Appendix 3: Assessment Windows
15.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
15.5
Appendix 5: Data Display Standards & Handling Conventions
15.6
Appendix 6: Derived and Transformed Data
15.7
Appendix 7: Reporting Standards for Missing Data
15.8
Appendix 8: Values of Potential Clinical Importance
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the specified population. For the 
populations including both ND and PD subjects (All Screening, Enrolled, Randomized, 
Safety), the summaries will be provided by dialysis (ND and PD separately) unless 
otherwise specified. 
Study population analyses including analyses of subject’s disposition, protocol 
deviations, population analysed, demographic and baseline characteristics, medical 
conditions and concomitant medications, and exposure and treatment compliance will be 
based on GSK Core Data Standards. Analysis of dialysis will also be included. Details of 
the planned displays are presented in Appendix 10: List of Data Displays.
Endpoint / Parameter / Display Type
Population
Data Displays Generated
Table
Figure
Listing
Subject’s Disposition
Subject Status and Reason for Study Withdrawal
Randomized
Y
Reasons for Study Withdrawal
Randomized
Y
Treatment Status and Reasons for Discontinuation of 
Study Treatment
Safety
Y
Y
Screening Status and Reasons for Screen Failure
All Screening
Y
Y
Subjects Enrolled by Country and Site ID
Enrolled
Y
Planned and Actual Treatments
Safety
Y
Protocol Deviations
Important Protocol Deviations
Randomized
Y
Y
Subjects with Inclusion/Exclusion Criteria Deviations
Randomized
Y
Y
Populations Analyzed
Study Populations
Randomized
Y
Exclusions from the Per Protocol Population
mITT
Y
Y
Subjects Excluded from Any Population
Randomized
Y
Composition of Randomized Population
Randomized
Y
Demographic and Baseline Characteristics
Demographic Characteristics
ITT/Safety/Effica
cy ND/Efficacy 
PD
Y
Y
Demographic Characteristics by Prior ESA Use
ITT/Safety/Effica
cy PD
Y
Demographic Characteristics by Cohort
Efficacy ND
Y
Other Baseline Characteristics [1]
Safety
Y
Prior ESA
ITT/Safety/Effica
cy PD
Y
Y
Age Ranges
Enrolled
Y
Race and Racial Combinations
Safety
Y
Y [1]
Family History for CV Risk Factors
Safety
Y
Y
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Endpoint / Parameter / Display Type
Population
Data Displays Generated
Table
Figure
Listing
Substance Use (History of Tobacco Use, Alcohol 
Intake)
Safety
Y
Y
Dialysis
Subjects with Dialysis Initiation during the Study Period
Safety
Y
Subjects with Peritoneal Dialysis at Baseline
Safety
Y
Subjects with Vascular Therapeutic Procedures during 
the Study Period
Safety
Y
Medical Conditions and Concomitant Medications
Current/Past Medical Conditions
Safety
Y
Y
Concomitant Medications [2]
Safety
Y
Y
Other Concomitant Medications (ESA, iron, and anti-
hypertensive medication)
Safety
Y [3]
Y
Blood products and blood supportive care products
Safety
Y
Y
Exposure and Treatment Compliance
Exposure to Study Treatment
Safety
Y
Y
Treatment Compliance
Safety
Y
Y[4]
NOTES :

Y = Yes display generated.
[1] As a separate listing, include prior ESA type, standardized prior ESA dose, ERI, iron use, diabetes, and CKD 
stage.
[2] Listing of race.
[3] Concomitant medications in pre-therapy, on-therapy, and post-therapy period will be summarized separately.
[4] On-therapy ESA, on-therapy iron, and on-therapy anti-hypertensive medications will be provided. .
[5] For Daprodustat in cohort 3, compliances up to Week 2 and Week 2 to 4 will be including in the listing 
6.2.
Planned Summary Display Details
Subjects who have multiple subject numbers (i.e. rescreened subjects) will be analyzed as 
unique subjects based on the latest screening results (see Section 15.6.1 and Section 
15.6.2).
The definition of subgroup is described in Section 5.4.2.

Subject Disposition
Subject Status and Reason for Study Withdrawal
The number and percentage of subjects completing the study (see Appendix 7) or 
withdrawing early from the study will be summarized overall and by reason for 
withdrawal by treatment group and total. Reasons for withdrawal of subjects will be 
listed.
Treatment Status and Reasons for Discontinuation of Study Treatment
The number and percentage of subjects completing the treatment or discontinuing the 
treatment during the study will be summarized overall and by reason (and subreason) by 
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treatment group and total. Reasons for discontinuation of study treatment of subjects will 
be listed.
Screening Status and Reasons for Screen Failure
The number and percentage of subjects who passed screening (i.e. enrolled) and who 
failed screening and were therefore not entered into the study will be summarized 
regardless of treatment group. Note that the reasons for rescreen subjects who initially 
failed but subsequently enrolled are not included in the display (see Section 15.6.2).
Reasons for screen failure of subjects will be listed.
Subjects Enrolled by Country and Site ID
The number and percentage of subjects by Country and Site ID and Investigator name 
will be summarized by treatment group and total.

Protocol Deviations
Important Protocol Deviations
The number and percentage of subjects who had important protocol deviations defined in 
PDMP will be summarized by treatment group and total. Important protocol deviations of 
subjects will be listed.
Subjects with Inclusion/Exclusion Criteria Deviations
The number and percentage of subjects, who were randomized into the trial, but deviated 
from the inclusion or exclusion criteria, will be summarized, further classifying 
inclusion/exclusion deviations by treatment group and total. Inclusion/exclusion criteria 
deviation of subjects will be listed.

Population Analyzed
Study Populations
The number and percentage of subjects in each analysis population (defined in Section 4) 
will be summarized by treatment group and total.
Exclusion from the Per Protocol Population
The number of the exclusions from the PP population and the exclusion categories will be 
summarized by treatment group and total.
Composition of the Randomized Population
The number and percentage of subjects by dialysis, cohort, and prior ESA use will be 
summarized by treatment group and total.
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
Demographic and Baseline Characteristics
Demographic Characteristics
The number and percentage of subjects or summary statistics will be provided by 
treatment group and total for the demographic and baseline characteristics: Sex, Age 
(years), Age Group (years), Ethnicity, Race detail, Height, Weight, Body Mass Index, 
and CKD Stage. The period of time on dialysis (years) will also summarized only for PD 
subjects in Safety population and Efficacy PD population. Age Group (years) will be 
categorized into 3 ('18', '19-64', '65'). CKD Stage will be categorized into 3 by eGFR
(Stage 3 (30=<eGFR<60), Stage 4 (15=<eGFR<30), Stage 5 (eGFR <15)) at a screening visit.
Separate summaries for ITT, Safety, Efficacy ND, and Efficacy PD population will be 
produced. For Efficacy ND population, summary will also be provided by cohort. For the 
ITT, Safety, and Efficacy PD populations, summary will also be provided by Prior ESA-
use.
Prior ESA
For overall prior ESA medication, the weekly dose (standardized by IU/week) 
erythropoietin resistance index (ERI), and the number and percentage of subjects’ dosing 
route (intravenous [IV] or subcutaneous [SC]) will be summarized by treatment group 
and total. For each type of prior ESA medication (epoetin, epoetin beta pegol, and 
darbepoetin alfa), the weekly dose (IU/week or g/week), ERI and the number and 
percentage of subjects’ dosing route (IV or SC) will also be summarized by treatment 
group and total. See Section 15.6.2 for the derivation of standardized weekly dose and 
ERI. Separate summaries for ITT and Safety population will be produced.
Age Ranges
The number and percentage of subjects within each age range category will be provided
by treatment group and total. Age range will be categorized into: 18-64 years, 65-84 
years, 85 years.
Race and Racial Combinations
Summaries of race and racial combinations will be provided by treatment group and total.
Family History for CV Risk Factors
A summary of family (first degree relatives) history for CV risk factors will be provided
by treatment group and total.
Substance Use (History of Tobacco Use, Alcohol Intake)
A summary of substance use will be provided by treatment group and total.
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
Medical Conditions and Concomitant Medications
Current/Past Medical Conditions
The number and percentage of subjects with current and past medical conditions recorded 
in eCRF will be provided by treatment group and total.
Concomitant Medications
The number and percentage of subjects reporting the use of each concomitant medication 
will be summarized by treatment group and total by anatomical therapeutic chemical 
(ATC) Level 1, and Ingredient. Summaries for pre-therapy, on-therapy, and post-therapy 
medication will be provided separately. See Section 15.4.1 for the study phases.
Other Concomitant Medications (On-Therapy ESA, iron, and anti-hypertensive 
medication)
The similar summary as above will be provided by treatment group and total focusing on 
on-therapy ESA, on-therapy iron medication (see Section 15.6.2), and on-therapy anti-
hypertensive medications. See Section 15.4.1 for the study phases.
Blood Products and Blood Supportive Care Products (On-Therapy)
The number and percentage of subjects who use blood products and/or blood supportive 
care products will be provided by treatment group and total. The details for the use will 
also be summarized.

Exposure and Treatment Compliance
Exposure to Study Treatment
Full details of exposure definition are presented in Section 15.6.2.
Time on study treatment (days), subject daily dose (for daprodustat) or monthly dose (for 
epoetin beta pegol), and cumulative dose will be summarized using the number of 
subjects exposed, mean, standard deviation, median, minimum, and maximum by 
treatment groups. Time on study treatment will be categorized in different time periods (< 
3 months, 3 months to 6 months, >6 months to 12 months, >12 months; 1 month = 
30.4375 days) and the number and percentage of subjects exposed will be displayed for 
each category.
Treatment Compliance
Full details of treatment compliance definition are presented in Section 15.6.2.
The number and percentage of subjects within each category will be summarized by 
treatment groups and total for up to Week 4, Week 40 to 52, and overall. Up to Week 2 
and Week 2 to 4 will also be summarized for only cohort 3. The categories will be 
classified into under compliant, compliant, over compliant.
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7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
[Endpoint / 
Parameter/ Display 
Type]
Populati
on
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Mean Hgb based on observed Hgb during the Primary Efficacy Evaluation Period
(i.e. Individual Mean of Hgb at Week 40, 44, 48, and 52)
(Preliminary 
assessment)
Observed Case 
mITT
Y
Observed Case
Efficacy 
PD
Y
Observed Case
by Subgroup[3]
Efficacy 
PD
Y
Model based Mean Hgb during the Primary Efficacy Evaluation Period
(Primary)
MMRM 
ITT
Y
Y
MMRM 
mITT/PP
/Efficacy 
ND
Y
Y
MMRM
By Subgroup
ITT
Y
Y[1][2]
MMRM
Excluding ESA Users 
with Hgb rapid 
increase at Week 2
ITT
Y
Y
MMRM
Evaluable Hgb
ITT
Y
Y
Analysis of Covariance 
(ANCOVA)
mITT/PP
Y
ANCOVA By 
Subgroup
mITT
Y
Y[1]
Tipping Point Analysis
ITT/mITT
/PP
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Forest Plots
[2] For prior ESA use, Hgb curve over time will also be displayed.
[3] Only for prior ESA use and baseline Hgb.
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7.1.2.
Summary Measure
Mean Hgb based on observed Hgb during the Primary Efficacy Evaluation Period
The values will be summarized using mean, standard deviation, 95%CI, minimum, P25, 
median, P75, and maximum by treatment group for the mITT and Efficacy PD 
population. For the Efficacy PD population, summary will also be provided by baseline 
Hgb.
Analysis of Mean Hgb during the Primary Efficacy Evaluation Period
For ITT population, model-based mean Hgb will be estimated using a statistical model 
(Section 7.1.5). The point estimates of model-based mean Hgb for each treatment will be 
presented with standard error, and 95% CI. For non-inferiority assessment at a one-sided 
significance level of 2.5%, the estimate of treatment difference, its 95% CI, and non-
inferiority p-value will be provided. Analysis will be repeated by mITT, PP, Efficacy ND
populations in the same manner. The subgroup analysis based on the ITT population will 
be also produced using tables and forest plot (See Section 7.1.5 for the detail).
Sensitivity/Supplementary analysis for Mean Hgb during the Primary Efficacy Evaluation 
Period

Excluding ESA Users with Hgb rapid increase at Week 2
Supplementary analysis excluding the ESA users whose daprodustat dose level was 
decreased by one step at Week 2 will be performed as the same as primary efficacy 
analysis using a mixed model for repeated measures.

Evaluable Hgb (Section 7.1.6.1 for the statistical analysis specifications)
Supplementary analysis using evaluable Hgb (See Section 15.6.3) based on the ITT 
population will be performed as the same as primary efficacy analysis using a mixed 
model for repeated measures.

ANCOVA (Section 7.1.6.2 for the statistical analysis specifications)
Supplementary analysis using ANCOVA based on the mITT population will be 
summarized. Analysis will be repeated for the PP population. The subgroup analysis 
based on the mITT population will be produced using tables and a forest plot.

Tipping Point Analysis (Section 7.1.6.3 for the statistical analysis specifications)
Tipping point sensitivity analysis based on the ITT population will be summarized 
using combined treatment differences, the associated 95% CIs and non-inferiority p-
values by delta adjustments. Graphical display, the horizontal and vertical axes 
indicate values of delta for daprodustat and epoetin beta pegol, will be provided as a 
heat map that represents non-inferiority p-values obtained from the test conducted for 
each delta adjustment. The color grids which highlight non-inferiority success or not 
will be displayed.
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7.1.3.
Population of Interest
The primary efficacy analyses will be based on the ITT population, unless otherwise 
specified.
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Intercurrent events
Strategy
Study withdrawal
The following hypothetical scenario is considered; 
what would have happened if the event did not occur. 
The primary analyses using MMRM assume missing 
at random mechanism, that is the observations of 
missing depend on just observed values, not on 
unobserved values. 
Prohibited medications 
(except for commercial ESA 
medications)
Basically, the occurrence of the event is taken to be 
irrelevant. Subjects with long-term use of prohibited 
medications will be excluded from the PP population.
Blood transfusion and/or
commercial ESA medication
In primary analyses, the occurrence of the event is 
taken to be irrelevant. 
Intermittent missing
The following hypothetical scenario is considered to 
assess what would have happened; if the event did not 
occur. The hypothesis is that an intermittent missing 
would occur at at-random manner, that is the 
observations of the missing depend on just observed 
values, not on unobserved values. 
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and
listed.
As a preliminary assessment, it will be confirmed whether the mean Hgb during the 
primary efficacy evaluation period in the daprodustat group would be in the target range 
(11.0-13.0 g/dL) at first. This confirmation will be established if the lower and upper 
limit of 95% CI for the mean Hgb based on observed Hgb during the primary efficacy 
evaluation period in the daprodustat group would lie fully within the target range. After 
the stated confirmation, non-inferiority will be assessed at a one-sided significance level 
of 2.5%.
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7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Mean Hgb during the primary efficacy evaluation period (Weeks 40 to 52)
Model Specification

Analyses will be conducted by MMRM as follows:
Hgbik = β0 + βbaseline *Baselinei + βj + βk + βjk + βbaseline*k * Baselinei + εik
    Hgbi, week: Hgb measurement for subject i at visit k
    β0: Intercept
    βbaseline: baseline Hgb effect
    Baselinei: Hgb measurement for subject i
    βj: treatment effect (j= daprodustat, epoetin beta pegol)
    βk: visit effect (k = Week 4, Week 8, …, Week 52)
    βjk: treatment-by-visit interaction
    βbaseline*k: baseline-by-visit interaction
    εik: random error for subject i at visit k
    i: subject (i = 1, 2, …, N)
    N: number of subjects included in the analysis

The model parameters will be estimated using Restricted Maximum Likelihood 
(method=REML) with the Newton-Raphson algorithm. 

The Kenward-Roger method for calculating the denominator degree of freedom will be used.

The variance-covariance structures for repeated measures within the individual subject will be 
unstructured (type=UN). 

LS means for treatment j at visit k will be calculated as follows.
jk = β0 + βbaseline * μbaseline + βj+ βk + βjk + βbaseline*k * μbaseline
    jk: LS mean for treatment j at visit k
    baseline: mean for baseline Hgb

Model based mean Hgb during the primary efficacy evaluation period for treatment j will be 
calculated as follows
j*evaluation = (μj*Week 40 + μj*Week 44 + μj*Week 48 + μj*Week 52)/4
= β0 + βbaseline * μbaseline + βj+ (βWeek 40 + βWeek 44 + βWeek 48 + βWeek 52)/4 + (βj*Week 40 + βj*Week 44 + 
βj*Week 48 + βj*Week 52)/4 + (βbaseline*Week 40 + βbaseline*Week 44 + βbaseline*Week 48 + βbaseline*Week 52) * 
μbaseline/4

The treatment difference for model based mean Hgb during the primary efficacy evaluation 
period will be calculated as follows
daprodustat*evaluation - epoetin*evaluation = βdaprodustat - βepoetin + (βdaprodustat*Week 40 + βdaprodustat*Week 44 + 
βdaprodustat*Week 48 + βdaprodustat*Week 52)/4 - (βepoetin*Week 40 + βepoetin*Week 44 + βepoetin*Week 48 + 
βepoetin*Week 52)/4

P-value for non-inferiority test will be based on the following t test statistic (Mascha 2011):
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t = (daprodustat*evaluation - epoetin*evaluation - )/s
   : non-inferiority margin (= -1.0 g/dL)
   s: standard error of treatment difference
The non-inferiority p-value is the probability of observing a larger value of t in a t distribution 
with degrees of freedom of the estimate of treatment difference based on the Kenward-Roger 
method.
Model Checking & Diagnostics

In case there is a problem with convergence of the unstructured (type=UN) variance-
covariance, the following strategy will be examined.
1.
Use Fisher’s scoring algorithm for the estimation method.
2.
Set Heterogeneous Toeplitz (type=TOEPH) structure for variance-covariance 
structure.

In the event of that this model still fails to converge, alternative correlation structures may be 
considered such as type=CSH or CS.
Model Results Presentation

The point estimates of LS mean Hgb during the primary efficacy evaluation period for each 
treatment will be presented with the associated standard errors and 95% CIs. For non-
inferiority assessment at a one-sided significance level of 2.5%, the estimate of the treatment 
difference, standard error, its 95% CI, and non-inferiority p-value will be provided.
Non-inferiority will be established if the lower limit of the 95% CI for the treatment difference 
(daprodustat - epoetin beta pegol) of the mean Hgb during the primary efficacy evaluation 
period is greater than -1.0 g/dL (i.e., a p-value is smaller than 0.025).
Model based Hgb curve over time with 95% confidence band will be displayed graphically for 
each treatment. 
Subgroup Analyses

Treatment differences (daprodustat - epoetin beta pegol) of the mean Hgb during the primary 
efficacy evaluation period, standard error, and the associated 95%CIs will be provided by each 
subgroup (See Section 5.4.2).

The subgroup analyses will be based on the ITT population.

The same statistical analysis method (using MMRM described as above) will be applied to 
estimate the mean Hgb during the primary efficacy evaluation period for each subgroup. If 
there is a problem with convergence for a certain subgroup, the result of the subgroup will not 
be displayed.

Graphical summaries for the treatment differences of the mean Hgb during the primary efficacy 
evaluation period and the associated 95% CIs will be produced using a forest plot.

For prior ESA use, model based Hgb curve over time with 95% confidence band will be 
displayed graphically for each treatment.
7.1.6.
Sensitivity and Supportive Analyses
To assess the robustness of the primary efficacy results, the primary efficacy analyses 
will be repeated using following sensitivity and supplementary approaches:
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
ESA Users with Hgb rapid increase at Week 2; the primary efficacy analysis will be 
repeated for the ITT population excluding the ESA users whose daprodustat dose 
level was decreased by one step at Week 2.

Efficacy ND Population; the primary efficacy analyses will be repeated for the 
Efficacy ND population (see Section 4).

mITT/PP Population; the primary efficacy analyses will be repeated for the mITT 
and PP populations as the supplementary analysis.

Evaluable Hgb; if there are Hgb values considered to be impacted by a red blood cell 
transfusion, a whole blood transfusion or marketed rhEPO/ESAs, supplementary
analysis excluding the Hgb values from the analyses of primary endpoint will be 
conducted.

Analysis of covariance (ANCOVA); it will be conducted as supplementary analysis 
to MMRM. This model includes treatment group, baseline Hgb, and prior ESA use. 
The analysis population will be the mITT population and the analysis will be repeated 
in the PP population.

Tipping point analysis; based on multiple imputation it will be conducted as 
sensitivity and supplementary analysis to missing data assumption. This analysis 
explores points where non-inferiority is not confirmed (tipping points) by changing 
assumption to missing data and repeating imputations. The analysis population will 
be ITT population and the analysis will be repeated in the mITT and PP populations.
7.1.6.1.
Evaluable Hgb
The analyses will be based on the ITT population, unless otherwise specified. In a 
strategy for intercurrent event of a red blood cell transfusion, a whole blood transfusion
and commercial ESA medication, the following hypothetical scenario is considered to 
assess what would have happened if the event did not occur. Non-evaluable Hgb 
(described in 15.6.3), which is caused by this event, will be treated as missing, and will 
be analyzed based on missing at random assumption (the observations of missing depend 
on just observed values, not on unobserved values).
Model Specification

Evaluable Hgb defined in Section 15.6.3 will be used for the analysis. Non-evaluable Hgb will 
be treated as missing.

Analyses will be conducted by MMRM. See Section 7.1.5.1 for the detail.
Model Results Presentation

The point estimates of adjusted mean Hgb during the primary efficacy evaluation period for 
each treatment will be presented with the associated standard errors and 95% CIs. The 
treatment difference, standard error, its 95% CI, and the non-inferiority p-value (described in 
Section 7.1.5.1, Model Specification) will also be presented.
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7.1.6.2.
Analysis of Covariance (ANCOVA)
The analyses will be based on the mITT and PP populations, unless otherwise specified.
In a strategy for intercurrent event of study withdrawal, a subject who has the event 
before Week 40 will not be included in analyses. If a subject has the event on or after 
Week 40, the event is taken to be irrelevant to the mean Hgb during primary efficacy 
evaluation period (i.e., observed values will be used for the analysis).
Model Specification

A subject must have at least one Hgb measurement during the primary efficacy evaluation 
period (Week 40 to Week 52) to be included in this analysis.

Analyses will be conducted by an ANCOVA model as follows:
mean(Hgbi) = β0 + βbaseline *Baselinei + βj + βl + ε
    mean(Hgbi) = (Hgbi,Week 40 + Hgbi,Week 44 + Hgbi,Week 48 + Hgbi,Week 52)/4:
    mean Hgb during the primary efficacy evaluation period for subject i
    β0: Intercept
    βbaseline: baseline Hgb effect
   Baselinei: Hgb measurement for subject i 
    βj: treatment effect (j= daprodustat, epoetin beta pegol)
    βl: prior ESA use effect (l = ESA user, ESA non user)
    ε: random error
    i: subject (i = 1, 2, …, N)
    N: number of subjects included in the analysis

LS means for treatment j will be calculated as follows:
j = β0 + βbaseline * μbaseline + βj + (βESA user + βESA non-user)/2
    j: LS mean for treatment j
    baseline: mean for baseline Hgb

The treatment difference for mean Hgb during the primary efficacy evaluation period will be 
calculated as follows:
daprodustat - epoetin = βdaprodustat – βepoetin

P-value for non-inferiority test will be based on the following t test statistic (Mascha 2011):
t = (daprodustat - epoetin - )/s
   : non-inferiority margin (= -1.0 g/dL)
   s: standard error of treatment difference
The non-inferiority p-value is the probability of observing a larger value of t in a t distribution 
with degrees of freedom of residual.
Model Checking & Diagnostics

Not applicable
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Model Results Presentation

The point estimates of adjusted mean Hgb for each treatment will be presented with the 
associated standard errors and 95% CIs. The treatment difference, standard error, its 95% CI, 
and the non-inferiority p-value (described in Section 7.1.5.1, Model Specification) will also be 
presented.
Subgroup Analyses

The subgroup analyses will be based on the modified ITT population.

The same statistical analysis method (using ANCOVA described as above) will be applied to 
estimate the mean Hgb during the primary efficacy evaluation period for each subgroup.

Graphical summaries for the treatment differences of the mean Hgb during the primary efficacy 
evaluation period and the associated 95% CIs will be produced using a forest plot
7.1.6.3.
Tipping Point Analysis
The analyses will be based on the ITT population, unless otherwise specified.
Tipping point sensitivity analyses will be conducted under a range of missing data 
assumptions to determine how extreme assumptions need to be for non-inferiority 
conclusions to change. Assumptions about missing Hgb values on the daprodustat and 
epoetin beta pegol arm will vary independently, and will include scenarios where subjects 
with missing data on daprodustat have worse outcomes than subjects with missing data 
on epoetin beta pegol. If the tipping point scenario is clinically plausible, the conclusion 
under missing at random may be questionable.
In a strategy for intercurrent event of study withdrawal, a hypothetical scenario is 
considered to assess what would have happened if the event did not occur. For this 
hypothesis, the missing data due to this event would occur at not-at-random manner, that 
is the observations of missing depend on unobserved values, which will be mimicked 
with delta-adjustment analysis in this study.
Model Specification

A tipping point is the critical point that reverses the study conclusion (i.e., non-inferiority test). 

Tipping point analysis for this study takes following steps:
1.
multiple imputation
2.
delta adjustment
3.
analyses for each imputed complete dataset.
4.
making combined results
As a reference, programming codes for tipping point analysis are described by Yuan 2014 as 
%midata macro in the appendix.
1.
Multiple Imputation Strategy

Imputations will be conducted by a multiple imputation method using the SAS PROC MI 
procedure.
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o
The number of imputations will be set to 200.
o
The seed for reproducibility is set to 201753.

The analysis will not include subjects who are in the ITT population but who don’t have any 
Hgb measurement on and after Week 4 (i.e., withdrawn at Week 2).

Initially, to obtain a monotone missing dataset from a non-monotone missing dataset, the 
imputation for intermittent missing values will be done using MCMC by treatment.

After obtaining the dataset with only the monotone missing patterns, imputation based on MAR 
assumption can be performed by treatment in a sequential manner. Assume that repeated 
measures variables Yi (i=1,…,n) are included in the imputation model (linear regression model 
with a covariate of baseline Hgb). The Y1 is imputed first based on the covariate. Then Y2
would be imputed using the covariate and Y1 and so on for each variable until Yn is imputed 
using the covariates and Y1,…,Yn-1 .
2.
Delta () Adjustment Strategy

Based on MAR assumption (=0), monotone missing data that occurred before Week 52 will 
be imputed as shown above. To mimic missing not at random manner, sequentially increasing
will be added to imputed values where represents a change in Hgb over 4-week interval.
No adjustments will be done for intermittent missing values.

Sequentially increasing adjustment is to add n*value on the imputed value of nth 
monotone missing data. The longer the period of time with monotone missing, the larger 
value will be added. Suppose a subject who has withdrawn at Week 40 visit, in other 
words, this subject has monotone missing data from Week 44 to Week 52. Imputations are 
conducted on missing data of Week 44, 48, and 52 and then is added to an imputed 
value on Week 44, 2on Week 48, and 3on Week 52.

Initially, the values will be explored for both arms and will range from -4.0 to 4.0 g/dL with a 
1.0 g/dL increment. Once the “rough” tipping point is found with the larger increment 
(=1.0 g/dL), the exploration will be done with smaller increments to find the more precise
tipping points. In order to keep clinically plausible range, if delta adjusted imputed value is 
lower than 7.0 g/dL or higher than 14.0 g/dL then the value will be replaced by 7.0 g/dL or 
14.0 g/dL respectively. To reduce computationally intensive iterations, the further worsening 
scenarios beyond a range from -4.0 to 4.0 g/dL will not be examined. 
3.
Analysis Strategy for Each Imputed Complete Dataset

The analysis using a MMRM (described in Section 7.1.5.1) will be applied and will be repeated 
for each imputed complete dataset. The calculation of the denominator degrees of freedom 
may be simplified (e.g., between-within degrees of freedom) for the imputed complete dataset. 
The mean differences between the mean Hgb during the primary efficacy evaluation period will 
be estimated for each imputed complete dataset.
4.
Combine results of m datasets

For each pair of deltas (one independently assigned delta for each treatment arm), Rubin’s 
rules (Rubin 1987) will be used to combine results of all imputed datasets, using SAS PROC 
MIANALYZE procedure. As a result, for each pair of delta values, a single estimated treatment 
difference and its standard error will be produced, with which a one-sided non-inferiority p-
value can be calculated using non-adjusted degree of freedom. 
Model Checking & Diagnostics

For the model checking & diagnostics of MMRM analyses, see the Section 7.1.5.1.
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Model Results Presentation

Graphics depicting treatment difference and non-inferiority p-value surfaces will be produced 
using an enhanced tipping point approach (Liublinska 2014); A colored heat map that 
illustrates the gradual change of non-inferiority p-values will be produced.

In a display, colored grids highlight delta combinations that result in rejecting the null 
hypothesis (i.e., non-inferiority established).
Sensitivity and Supplementary Analyses

The analysis will be repeated for mITT and PP population.
7.2.
Principal Secondary Efficacy Analyses
7.2.1.
Endpoint / Variables
[Endpoint / 
Parameter/ Display 
Type]
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Number (%) of Subjects with Mean Hgb in Target Range during the Primary Efficacy Evaluation 
Period
(Principal Secondary)
Logistic Regression
mITT Population
Y
Logistic Regression
ITT Population
Y
Logistic Regression
PP Population
Y
Logistic Regression
Efficacy ND Population
Y
Logistic Regression
mITT Population
By Subgroup
Y
Y[1]
Efficacy PD Population
Y
Efficacy PD Population
By Subgroup[2]
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Forest plots
[2] Only for prior ESA use and baseline Hgb.
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7.2.2.
Summary Measure
Number (%) of Subjects with Mean Hgb in Target Range during the Primary Efficacy 
Evaluation Period
The number and percentage of responders, who are subjects with observed mean Hgb 
within the target range during the primary efficacy evaluation period, and non-responders 
will be summarized. Odds ratio will be estimated by using a logistic regression and 
provided along with its 95% CI and superiority one-sided p-value. Analysis will be 
repeated by the ITT, PP, and Efficacy ND populations in the same manner. The subgroup 
analysis based on the mITT population will be also produced using tables and a forest 
plot. For the Efficacy PD population, the summary of the number and percentage of 
responders and non-responders will be produced and the summary by prior ESA use and 
baseline Hgb will be created.
7.2.3.
Population of Interest 
The principal secondary efficacy analyses will be based on the mITT population, unless 
otherwise specified.
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events
Intercurrent events
Strategy
Study withdrawal
The occurrence of the event is taken to be a 
component of response to treatment. If a subject has 
no available Hgb data during Week 40 to 52 due to 
early withdrawal, the subject is deemed as a non-
responder. If a subject has at least one available Hgb 
data during Week 40 to 52, a response to treatment 
will be defined by whether the mean Hgb during Week 
40 to 52 using observed Hgb values within target 
range.
Prohibited medications 
(except for commercial ESA 
medications)
Basically, the occurrence of the event is taken to be 
irrelevant. Subjects with long-term use of prohibited 
medications will be excluded from PP population. 
Blood transfusion and/or
commercial ESA medication
The occurrence of the event is taken to be irrelevant. 
Intermittent missing
The occurrence of the event is taken to be irrelevant.
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7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.2.5.1.
Statistical Methodology Specification
Endpoint / Variables

Number (%) of subjects with mean Hgb in the target range (11.0-13.0 g/dL) during the primary 
efficacy evaluation period (Week 40 to 52)
Model Specification

The percentage of subjects with observed mean Hgb during the primary efficacy evaluation 
period within target range will be derived from the mean of observed Hgb values during the 
primary efficacy evaluation period for individuals. 
Analyses will be conducted by a logistic regression model as follows:
logit() = β0 + βbaseline *Baselinei + βj + βl + ε
    i: treatment success (mean(Hgbi) is within the target range or not)
    β0: Intercept
    βbaseline: baseline Hgb effect
    Baselinei: Hgb measurement for subject i 
    βj: treatment effect (j= daprodustat, epoetin beta pegol)
    βl: Prior ESA use effect (l = ESA user, ESA non user)
    ε: random error
    i: subject (i = 
 …, N)
    N: number of subjects included in the analysis

The mean Hgb during the primary efficacy evaluation period will be calculated by individuals 
and confirmed if the values are in the target range or not. Therefore, subjects who have at 
least one Hgb measurement during the evaluation period will be included in this analysis. A 
subject who has missing data of the mean Hgb during the primary efficacy evaluation period
due to intercurrent events will be regarded as a non-responder.

The odds ratio (daprodustat/epoetin beta pegol) will be obtained as follows:
OR = exp(βdaprodustat – βepoetin)
The odds ratio, the Wald-type 95% CI. and a superiority one-sided p-value based on a z-score 
will be provided together.
Model Checking & Diagnostics

If the logistic regression cannot be applicable due to all responders or all non-responders, the 
odds ratio and the associated statistics will not be provided.

If there is a problem with quasi-complete separation, a penalized likelihood method by Firth will 
be used by specifying the FIRTH option in the MODEL statement.
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Model Results Presentation

The superiority assessment will be performed only if the primary endpoint achieved non-
inferiority.

The number and percentage of subjects with observed mean Hgb during the primary efficacy 
evaluation period within the target range (11.0-13.0 g/dL) will be presented by treatment group. 
If available, the odds ratio (daprodustat/epoetin beta pegol), the associate 95% CI, and a 
superiority one-sided p-value will also be provided, otherwise ‘NC’(not calculated) will be 
provided for odds ratios and the associated statistics. 

Superiority will be established if the lower limit of the 95% CI for the odds ratio is greater than 
1.0 (i.e. a p-value is smaller than 0.025).
Subgroup Analyses

The subgroup analyses will be based on the mITT population for all subgroup specified in 
Section 5.4.2 and the Efficacy PD population for baseline Hgb.

The statistical analysis method uses the same logistic model, unless the logistic model is not 
applicable due to all responders or all non-responders. 

Graphical summaries for odd ratios and the associated 95% CIs will be produced using a forest 
plot for the mITT population. If the logistic model is not applicable, ‘NC’(not calculated) label 
will be provided.
Sensitivity and Supplementary Analyses

The mITT Population will be used for this logistic analysis, and the supplementary analysis 
using same logistic model will be repeated in the ITT and PP Population to evaluate the 
robustness of the conclusion. In the ITT population, subjects who have no available Hgb after 
Week 40 will be considered as non-responder.

The logistic regression will be performed by a set of pre-specified subgroups (Section 5.4.2. 
These subgroup analyses are considered exploratory to assess for consistency with the overall 
results.
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7.3.
Secondary Efficacy Analyses
7.3.1.
Endpoint / Variables
[Endpoint / Parameter/ Display Type]
Absolute
Stats Analysis
Summary
Individual
T
F
T
F
F
L
Hgb
Hgb (g/dL) at each assessment visit
Y
Y
Y
Hgb (g/dL) at each assessment visit 
by Prior ESA[1] and baseline Hgb
Y
Y[9]
Change from baseline in Hgb (g/dL) at each 
assessment visit 
Y
Y
Change from baseline in Hgb (g/dL) at each 
assessment visit 
by Prior ESA[1] and baseline Hgb
Y
Y[9]
Number (%) of subjects by Hgb change from baseline 
category at Week 2 and 4 [2]
Y
Number (%) of subjects by Hgb change from baseline 
category at Week 2 and 4 
by Prior ESA[1][2] and baseline Hgb
Y
Number (%) of subjects with Hgb level within the target 
range at each assessment visit[3]
Y
Y
Time (%) in Hgb target range during the primary 
efficacy evaluation period [4][6]
Y
Y
Time (%) in Hgb target range during the primary 
efficacy evaluation period
by prior ESA use[4]{6]
Y
Time (days) to reach the lower Hgb target (11.0 g/dL)
[5][6]
Y
Y
Y
Time (days) to reach the lower Hgb target (11.0 g/dL) 
by prior ESA use[5][6]
Y
Y
Number (%) of subjects who have an Hgb level of less 
than 7.5 g/dL[6]
Y
Y
Number (%) of subjects who have an Hgb level of less 
than 7.5 g/dL 
by prior ESA use[6]
Y
Number (%) of subjects who have an Hgb increase of 
more than 2.0 g/dL over any 4 weeks
Y
Y
Number (%) of subjects who have an Hgb increase of 
more than 2.0 g/dL over any 4 weeks 
by prior ESA use
Y
Number (%) of subjects who have an Hgb level of more 
than 13.0 g/dL and number of episodes[6]
Y
Y
Number (%) of subjects who have an Hgb level of more 
than 13.0 g/dL and number of episodes 
by prior ESA use[6]
Y
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[Endpoint / Parameter/ Display Type]
Absolute
Stats Analysis
Summary
Individual
T
F
T
F
F
L
Hemocue Hgb
Y
Scatter Plot of Hgb Assessments: Central Laboratory 
vs. HemoCue
Y
Dose adjustment 
Dose (mg or g) at each assessment visit / final visit
Y
Y
Dose (mg or g) at each assessment visit / final visit
by prior ESA[1]
Y
Duration (days) of treatment interruption due to Hgb 
>13.0 g/dL
Y
Y
Duration (days) of treatment interruption due to Hgb 
>13.0 g/dL 
by prior ESA use
Y
Dose adjustment
Y
Dose adjustment
by prior ESA use
Y
Number of dose adjustment to reach the lower Hgb 
target (11.0 g/dL)
Y
Number of dose adjustment to reach the lower Hgb 
target (11.0 g/dL) 
by prior ESA use
Y
Number (%) of subjects with each dose at each 
assessment visit
Y
Y
Number(%) of subjects with each dose at each 
assessment visit 
by prior ESA[1]
Y
Y
Hgb and Dose
Profiles of Hgb and dose over time
Y
Iron Use
Dose of oral iron (mg) during the treatment period and 
the primary efficacy evaluation period (Week 40 to 52)
Y
Change from baseline in dose of oral iron (mg) during 
the treatment period and the primary efficacy 
evaluation period
Y
Dose of oral iron (mg) during the treatment period and 
the primary efficacy evaluation period (Week 40 to 52)
  by Baseline Iron Use
Y
Number (%) of subjects who use iron during the 
treatment period and the primary efficacy evaluation 
period (Week 40 to 52)
Y
Number (%) of subjects who use iron during the 
treatment period and the primary efficacy evaluation 
period (Week 40 to 52)
  by Baseline Iron Use
Y
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[Endpoint / Parameter/ Display Type]
Absolute
Stats Analysis
Summary
Individual
T
F
T
F
F
L
Iron Parameters (ferritin, TSAT, hepcidin, serum iron, TIBC)
Raw observed value at each assessment visit
Y
Y
Y
Raw observed value at each assessment visit
by Subgroup[7]
Y
Y
Change from baseline at each assessment visit
Y
Y
Y
Change from baseline at each assessment visit
by Subgroup[7]
Y
Y[8]
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] prior ESA use, prior ESA dose, prior ESA type, and ERI
[2] <=-1, >-1 to -0.5, >-0.5 to 0, >0 to 0.5, >0.5 to 1, >1 g/dL, within 0.5 g/dL and over 1 g/dL for Week 2
  <=-2, >-2 to -1, >-1 to 0, >0 to 1, >1 to 2,  >2 g/dL, within 1 g/dL and over 2 g/dL for Week 4
[3] Not only within the target range, but also with above and below target range will be assessed.
[4] Rosendaal method will be used (See Section 15.6.3).
[5] Kaplan-Meier method will be used to estimate P25, median and P75. Subjects within target range at baseline and 
subjects who could not reach lower target will be regarded as censored.
[6] On-therapy Hgb values observed at scheduled visits will be included in a summary. On-therapy Hgb values 
observed at unscheduled visits will be included if specified (See Section 7.3.2).
[7] Only baseline iron use, prior ESA use
[8] Only baseline iron use
[9] Only prior ESA use and baseline Hgb
7.3.2.
Summary Measure
Hgb at each assessment visit
The values will be summarized using mean, standard deviation, 95%CI, minimum, P25, 
median, P75, and maximum at each assessment visit by treatment group. The summary 
will also be provided by prior ESA use, prior ESA dose, prior ESA type, and ERI. 
Graphical summaries will be provided using mean and 95% CI over time. The graphical 
summaries will also be provided by prior ESA use. The value at Wk2 (only for Cohort 3) 
will be provided only in summary (not in graphical summary).
Change from baseline at each assessment visit
The values will be summarized using mean, standard deviation, 95%CI, minimum, P25, 
median, P75, and maximum at each assessment visit by treatment group. The summary 
will also be provided by prior ESA use, prior ESA dose, prior ESA type, and ERI. 
Graphical summaries will be provided using mean and 95% CI over time. The graphical 
summaries will also be provided by prior ESA use. The value at Wk2 (only for Cohort 3) 
will be provided only in summary (not in graphical summary).
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Number (%) of subjects by Hgb change from baseline category at Week 2 and 4
The number and percentage of subjects within each category will be provided by 
treatment group and the categories will be classified into 6 (i.e., -1, >-1 to -0.5, >-0.5 to 
0, >0 to 0.5, >0.5 to 1, >1 g/dL for Week 2, -2, >-2 to -1, >-1 to 0, >0 to 1, >1 to 2, >2 
g/dL for Week 4). In addition, ‘within 1 g/dL (i.e., -1 and 1)’ and ‘over 2 g/dL (i.e., <-
2 and >2)’ categories for Week 4 and ’within 0.5 g/dL (i.e., -0.5 and 0.5)’ and ‘over 1
g/dL (i.e., <-1 and >1)’ categories for Week 2 will be provided. The summary will also be 
provided by prior ESA use, prior ESA dose, prior ESA type, and ERI.
Number (%) of subjects with Hgb within the target range at each assessment visit
The number and percentage of subjects with Hgb within, above and below the target 
range will be summarized at each assessment visit by treatment group. Graphical 
summaries over time will also be produced.
Time (%) in Hgb target range during the primary efficacy evaluation period
The time (weeks and percent) within/above/below the target range will be summarized by 
treatment group using mean, standard deviation, minimum, P25, median, P75, and 
maximum. For the ITT population, the treatment differences (daprodustat – epoetin beta 
pegol) and the associated 95% CIs for the time (weeks and percentage) within the target 
range will also be provided. See Section 15.6.3 for details. The summary will also be 
provided by prior ESA use.
Time (in days) to reach the lower Hgb target (11.0 g/dL)
The time (days) to reach the lower Hgb target will be summarized by treatment group 
using P25, median, and P75 by Kaplan-Meier method. Kaplan-Meier plot of time to event 
will be provided using on-therapy Hgb values including unscheduled visits. Subjects who 
could not reach lower target will be regarded as censored. Subjects who have baseline 
central laboratory Hgb >= 11.0 g/dL will be excluded in this analysis. The summary will 
also be provided by prior ESA use.
Number (%) of subjects who have an Hgb level of less than 7.5 g/dL
The number and percentage of subjects who have an Hgb level of less than 7.5 g/dL 
during the treatment period will be summarized by treatment group. On-therapy Hgb 
values observed in both scheduled and unscheduled visits will be included in the 
summary.
Number (%) of subjects who have an Hgb increase of more than 2.0 g/dL over any 4 
weeks
The number and percentage of subjects who have an Hgb increase of more than 2.0 g/dL 
over any 4 weeks (excluding Week 2) during the treatment period will be summarized by 
treatment group. For the ITT population, the odds ratio (daprodustat/epoetin beta pegol) 
will also be provided with its 95% CI. On-therapy Hgb values will be used for the 
summary. See Section 15.6.3 for details.
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Number (%) of subjects who have an Hgb level of more than 13.0 g/dL and number of 
episodes
The number and percentage of subjects who have an Hgb level of more than 13.0 g/dL 
during the treatment period and number of episodes will be summarized by treatment 
group. On-therapy Hgb values observed in both scheduled and unscheduled visits will be 
included in the summary.
Scatter plot of Hgb assessments: Central Laboratory vs. HemoCue
A scatter plot of Hgb values measured by Central Laboratory versus Hgb values 
measured by Hemocue will be produced along with Pearson’s correlation coefficient. 
Regardless of visit and treatment group, all available pairs of Hgb (i.e. non-missing 
values in both from central laboratory and from the corresponding HemoCue 
measurement) will be used.

Dose adjustment
The dose adjustment algorithm is described in Section 15.6.3, based on HemoCue Hgb 
values.
Dose at each assessment visit / final visit
Dose at each assessment visit and final visit will be summarized by treatment group using 
mean, standard deviation, minimum, P25, median, P75, mode, and maximum at each 
assessment visit. The final visit will be the last visit of treatment exposure for each 
subject. Mean dose during Week 40 to 52 will also be summarized and includes subjects 
who has at least one exposure record during Week 40 to 52. The summary will also be 
provided by Prior ESA use, prior ESA dose, prior ESA type, and ERI.
Duration (days) of treatment interruption due to Hgb >13.0 g/dL
The number and percentage of subjects who have a period of treatment interruption due 
to Hgb >13.0 g/dL will be summarized by treatment group. On subjects who have a 
period of treatment interruption due to Hgb >13.0 g/dL, the duration (in days) of 
treatment interruption due to Hgb >13.0 g/dL per subject will be summarized by 
treatment group using mean, standard deviation, minimum, P25, median, P75, and 
maximum. On-therapy Hgb values observed in scheduled visits will be counted in the 
summary. The summary will also be provided by prior ESA use.
Dose adjustment
The number and percentage of subjects with dose adjustments will be provided. Number 
of dose adjustments will be summarized by treatment group using mean, standard 
deviation, minimum, median, mode, and maximum. For dose adjustments frequency, the 
number and percentage of subjects will be provided by the number of dose adjustments 
(i.e. zero, one, two, three, four,…, ten, eleven, and twelve or more; may be refined) by 
treatment group during the whole treatment period. For timing of dose adjustments, the 
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number and percentage of subjects with dose adjustments by each assessment visit will 
be provided by treatment group. The summary will also be provided by Prior ESA use.
Dose adjustment to reach the lower Hgb target (11.0 g/dL)
The number and percentage of subjects with dose adjustments to reach the lower Hgb 
target will be provided by treatment group on the basis of on-therapy Hgb. Number of 
dose adjustment to reach the lower Hgb target will be summarized by treatment group
using mean, standard deviation, minimum, median, mode, and maximum. For dose 
adjustments frequency, the number and percentage of subjects will be provided by the 
number of dose adjustments (i.e. zero, one, two, three, four,…, ten, eleven, and twelve or 
more) by treatment group. For timing of dose adjustments, the number and percentage of 
subjects with dose adjustments by each assessment visit will be provided by treatment 
group. Subjects who do not reach the lower Hgb target during treatment period will be 
excluded from the summary. The summary will also be provided by Prior ESA use.
Number (%) of subjects with each dose at each assessment visit
The number and percentage of subjects with each dose will be provided. Graphical 
summaries of histogram will be provided with the number of subjects in each dose.
Summary and histogram will be produced for each treatment group separately. For 
daprodustat, dose categories will be classified into 10; N/A (not available), 0 mg 
(treatment interruption), 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 12 mg, 18 mg, and 24 mg. For 
epoetin beta pegol, dose categories will be classified into 9, N/A (not available), 0 g 
(treatment interruption), 25 g, 50 g, 75 g, 100 g, 150 g, 200 g, 250 g. The final 
visit will be the last visit of treatment exposure for each subject. The summary and 
histogram will also be provided by Prior ESA use, prior ESA dose, prior ESA type, and 
ERI.

Hgb and Dose
Profiles over time of Hgb and dose will be plotted for each subject.

Iron Use
Dose of oral iron (mg) during the treatment period and the primary efficacy evaluation 
period
Monthly Average oral iron dose by quarter (See Section 15.6.3) will be summarized 
using mean, standard deviation, minimum, P25, median, P75, and maximum. Quarter 1 
(Day 1 to Week 12), Quarter 2 (Week 12 to Week 24), Quarter 3 (Week 24 to Week 40), 
Quarter 4 (Week 40 to Week 52), during the screening period as baseline, and whole 
treatment period will be used and Quarter 4 represents the primary efficacy evaluation 
period. This will be also summarized by baseline iron use defined in Section 5.4.2.
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Change from baseline in dose of oral iron (mg) during the treatment period and the 
primary efficacy evaluation period
Change from baseline in average oral iron dose (See Section 15.6.3) will be summarized 
using mean, standard deviation, minimum, P25, median, P75, and maximum. Quarter 1 
(Day 1 to Week 12), Quarter 2 (Week 12 to Week 24), Quarter 3 (Week 24 to Week 40), 
Quarter 4 (Week 40 to Week 52), and whole treatment period will be used and Quarter 4 
represents the primary efficacy evaluation period. For the ITT population, the treatment 
differences (daprodustat – epoetin beta pegol) and the associated 95% CIs will also be 
provided.
Number (%) of subjects who use iron during the treatment period and the primary 
efficacy evaluation period
The number and percentage of subjects who use iron during the screening period as 
baseline, the treatment period, and the primary efficacy evaluation period will be 
summarized separately. These will be also summarized by baseline iron use defined in 
Section 5.4.2

Iron Parameter (ferritin, TSAT, hepcidin, serum iron, and TIBC)
Based on literature review the distributions of TSAT and hepcidin are skewed and require 
a log-transformation (See Section 5.2).
Raw observed value at each assessment visits
Ferritin, serum iron, and TIBC values will be summarized by treatment group using mean, 
standard deviation, 95% CI, minimum, P25, median, P75, and maximum at each 
assessment visit. TSAT and hepcidin values will be summarized by treatment group 
using geometric mean, standard error, coefficient of variation, and 95% CI based on log-
transformed parameters, median, minimum, and maximum based on original scale at each 
assessment visit. Graphical summaries will also be provided for each iron parameter. 
These will be also summarized by baseline iron use, prior ESA use.
Change from baseline at each assessment visit
Change from baseline in ferritin, serum iron, and TIBC values will be summarized by 
treatment group using mean, standard deviation, 95% CI, minimum, P25, median, P75, 
and maximum at each assessment visit. Percent Change from baseline in TSAT and 
hepcidin values (Section 5.2) will be summarized by treatment group using geometric 
mean, coefficient of variation, and 95% CI based on log-transformed parameters, 
minimum, median, and maximum based on original scale at each assessment visit. 
Treatment differences (daprodustat – epoetin beta pegol) and the associated 95% CIs for 
change from baseline will be provided at each assessment (See Section 7.3.5). For ferritin,
serum iron, and TIBC change from baseline, graphical summaries will be provided by 
treatment group using the adjusted means and the associated 95% CIs over time. For 
TSAT and hepcidin percent change from baseline, graphical summaries will be provided 
using the adjusted geometric means percent change from baseline and the associated 95%
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CIs over time. For the ITT population, Except for the graphical summaries, these will be 
also summarized by baseline iron use, prior ESA use, and both them. The graphical 
summaries will also be provided by only baseline iron use.
7.3.3.
Population of Interest 
The secondary efficacy analyses will be based on the ITT and Efficacy PD population, 
unless otherwise specified.
7.3.4.
Strategy for Intercurrent (Post-Randomization) Events
Any intercurrent events are taken to be irrelevant for secondary endpoints and the 
secondary endpoints will be summarized based on available and observed data. 
Analysis of change from baseline in the respective iron parameter at each assessment 
visit will follow the strategy below.
Intercurrent events
Strategy
Study withdrawal / 
Intermittent missing
The following hypothetical scenario is considered to 
assess what would have happened if the event did not 
occur. Analysis using MMRM assume missing at 
random mechanism, that is the observations of missing 
depend on just observed values, not on unobserved 
values. 
7.3.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.3.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.3.5.1.
Statistical Methodology Specification
Endpoint / Variables

Change from baseline in the respective iron parameter at each assessment visit
Model Specification

Analyses will be repeated for each iron parameter (ferritin/TSAT/hepcidin/serum iron/TIBC)
using MMRM as follows:
Ironik = β0 + βbaseline *Baselinei + βj + βk + βjk + βbaseline*k * Baselinei + εik
    Ironi, week: change from baseline in iron measurement for subject i at visit k
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   β0: Intercept
    βbaseline: baseline effect of each iron parameter
    Baselinei: the baseline value of each iron parameter for subject i 
    βj: treatment effect (j= daprodustat, epoetin beta pegol)
    βk: visit effect (k = Week 4, Week 16, Week 28, Week 40, Week 52)
    βjk: treatment-by-visit interaction
    βbaseline*k: baseline-by-visit interaction
    εik: random error for subject i at visit k
    i: subject (i = 
 …, N)
    N: number of subjects included in the analysis

The model parameters will be estimated using Restricted Maximum Likelihood 
(method=REML) with the Newton-Raphson algorithm. 

The Kenward-Roger method for calculating the denominator degrees of freedom will be used.

The variance-covariance structures for repeated measures within the individual subject will be 
unstructured (type=UN). 

LS mean change from baseline for treatment j at visit k will be calculated as follows for each 
iron parameter.
jk = β0 + βbaseline * μbaseline + βj+ βk + βjk + βbaseline*k * μbaseline
    jk: LS mean change from baseline for treatment j at visit k
    baseline: mean for the baseline value of each iron parameter

The treatment difference at visit k for model based mean change from baseline will be 
calculated as follows for each iron parameter as adjusted treatment difference
daprodustat*k - epoetin beta pegol*k = βdaprodustat - βepoetin beta pegol + βdaprodustat*k- βepoetin beta pegol*k

Note that log-transformed values will be used for TSAT and hepcidin in the MMRM analysis. 
The LS means for treatment j at visit k and the adjusted treatment difference at visit k will be 
exponentially back-transformed to the original scale and provided as follows:
Adjusted geometric mean percent change from baseline = 100*(exp(jk) – 1)
Adjusted ratio for percent change from baseline = exp(daprodustat*k - epoetin beta pegol*k)
Model Checking & Diagnostics

In case there is a problem with convergence of the unstructured (type=UN) variance-
covariance, the following strategy will be examined.
1.
Use Fisher’s scoring algorithm for the estimation method.
2.
Set Heterogeneous Toeplitz (type=TOEPH) structure for variance-covariance 
structure.
3.
In the event of that this model still fails to converge, alternative correlation structures 
may be considered such as type=CSH or CS.
Model Results Presentation

For ferritin, serum iron, and TIBC, the adjusted mean change from baseline will be presented 
with the associated 95% CIs by treatment at each assessment visit. The adjusted treatment 
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difference (daprodustat – epoetin beta pegol) for change from baseline will also be presented 
with the associated 95% CI at each assessment visit.

For TSAT and hepcidin, the adjusted geometric mean percent change from baseline will be 
presented with the associated 95% CIs by treatment at each assessment visit. The adjusted 
ratio (daprodustat / epoetin beta pegol) for percent change from baseline will also be presented 
with the associated 95% CI at each assessment visit.
Subgroup Analyses

For all of the respective iron parameter, the above analysis will be repeated by baseline iron 
use and prior ESA use subgroup (See Section 5.4.2) in the same manner.

The subgroup analyses will be based on the ITT and Efficacy PD population.

If there is a problem with convergence for a subgroup, the result of the subgroup will not be 
displayed.
7.4.
Exploratory Efficacy Analyses
7.4.1.
Endpoint / Variables
[Endpoint / Parameter/ Display Type]
Absolute
Stats Analysis
Summary
Individual
T
F
T
F
F
L
CKD progression
(eGFR, serum creatinine, urine creatinine, urine albumin, urine albumin/creatinine ratio) 
Raw observed value at each assessment visit
Y
Y
Y
Change from baseline at each assessment visit
Y
Y
Number (%) of subjects with eGFR decrease of 30% or 
more from baseline
Y
Number (%) of subjects with serum creatinine increase 
of more than double from baseline
Y
Other
Scatter plot of change from baseline in Hgb at Week 4 
vs. covariates of interest
Y
Scatter plot of mean dose during Week 40 to 52 vs. 
covariates of interest
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
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7.4.2.
Summary Measure

CKD progression (eGFR, serum creatinine, urine creatinine, urine albumin, 
urine albumin/creatinine ratio)
Raw observed value at each assessment visits
The values will be summarized using mean, standard deviation, 95%CI, minimum, P25, 
median, P75, and maximum at each assessment visit by treatment group. Graphical 
summaries will be provided using mean and 95% CI over time.
Change from baseline at each assessment visit
The values will be summarized using mean, standard deviation, 95%CI, minimum, P25, 
median, P75, and maximum at each assessment visit by treatment group. Graphical 
summaries will be provided using mean and 95% CI over time.
Number (%) of subjects with eGFR decrease of 30% or more from baseline
The number and percentage of subjects with eGFR decrease of 30% or more from 
baseline will be summarized at each assessment visit by treatment group.
Number (%) of subjects with serum creatinine increase of more than double from 
baseline
The number and percentage of subjects with serum creatinine increase of more than 
double from baseline will be summarized at each assessment visit by treatment group.

Other
Scatter plot of change from baseline in Hgb at Week 4 vs. covariates of interest
Scatter plot of change from baseline in Hgb at Week 4 versus following covariates of 
interest, body weight, baseline Hgb, prior ESA dose will be produced for the ITT and 
Efficacy PD populations. See Section 15.6.3 for the detailed derivations.
Scatter plot of mean dose during Week 40 to 52 vs. covariates of interest
Scatter plot of mean dose during Week 40 to 52 versus following covariates of interest, 
body weight, baseline Hgb, prior ESA dose will be produced for the ITT and Efficacy PD
populations. See Section 15.6.3 for the detailed derivations.
7.4.3.
Population of Interest 
The exploratory efficacy analyses will be based on the ITT population, unless otherwise 
specified.
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7.4.4.
Strategy for Intercurrent (Post-Randomization) Events
Any intercurrent events are taken to be irrelevant for exploratory endpoints. The 
exploratory endpoints will be summarized based on available and observed data.
7.4.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables presented in Section 7.4.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed.
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8.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
The summary will be provided by dialysis (ND and PD separately) and treatment group.
8.1.
Adverse Events Analyses
Adverse event analyses including the analysis of adverse events (AEs), serious adverse 
events (SAEs), and other significant AEs will be based on GSK Core Data Standards. 
The details of the planned displays are provided in Appendix 10: List of Data Displays.
Medical device incidents fulfilling the definition of an AE/SAE will follow the same 
processes for collecting AE and SAE information and will not be summarized 
particularly. 
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
On-therapy AEs by SOC and PT
Y
Y
On-therapy AEs by SOC and PT by Prior ESA Use
Y
On-therapy AEs by SOC and PT by CKD Stage
Y
On-therapy AEs by SOC and PT and Maximum Intensity
Y
On-therapy AEs by SOC and PT and Maximum Intensity by Prior ESA Use
Y
On-therapy AEs up to Week 4 by SOC and PT
Y
On-therapy AEs up to Week 4 by SOC and PT by Prior ESA Use
Y
On-therapy AEs up to Week 4 by SOC and PT by Starting Dose of Daprodustat
Y
On-therapy AEs up to Week 4 by SOC and PT and Maximum Intensity
Y
On-therapy AEs up to Week 4 by SOC and PT and Maximum Intensity by prior 
ESA use
Y
On-therapy Common (>= 2 %) AEs by SOC and PT by onset
Y
Post-therapy AEs by SOC and PT
Y
Y
Post-therapy AEs by SOC and PT and Maximum Intensity
Y
On-therapy Drug-Related AEs by SOC and PT
Y
On-therapy Drug-Related AEs by SOC and PT by Prior ESA Use
Y
On-therapy Drug-Related AEs by SOC and PT by CKD Stage
Y
On-therapy Drug-Related AEs by SOC and PT and Maximum Intensity
Y
On-therapy Drug-Related AEs up to Week 4 by SOC and PT
Y
On-therapy Drug-Related AEs up to Week 4 by SOC and PT and Maximum 
Intensity
Y
Post-therapy Drug-Related AEs by SOC and PT
Y
Post-therapy Drug-Related AEs by SOC and PT and Maximum Intensity
Y
On-therapy Common (>= 2 %) AEs by Overall Frequency
Y
Y [1]
On-therapy Common (>= 2 %) AEs by Overall Frequency by Prior ESA Use
Y
On-therapy Common (>= 2 %) AEs by Overall Frequency by CKD Stage
Y
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Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
On-therapy Common (>= 5 %) Non-Serious AEs by SOC and PT (Subjects & 
No. of Occurrences)
Y
On-therapy Non-Serious Drug Related AEs
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT & Verbatim Text
Y
Serious and Other Significant AEs 
Fatal Serious AEs
Y
Non-Fatal Serious AEs
Y
On-therapy Serious AEs
Y
Y[3]
Post-therapy Serious AEs
Y
On-therapy Serious Drug Related AEs
Y
Serious AEs in Screening Period [2]
Y
Reasons for Considering as a Serious AE
Y
On-therapy Serious AEs by SOC and PT (Subjects & No. of Occurrences)
Y
AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study 
Treatment by SOC and PT
Y
Y
CV Events
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Plot of common AEs and relative risk will be generated by treatment.
[2] Listing will be based on All Screening Population.
[3] Prior ESA use will also be displayed in the listing.
8.1.1.
Planned Adverse Events Analyses Displays

Adverse Events
AEs by SOC and PT
The number and percentage of subjects reporting at least one AE will be provided by 
treatment group. These events will be summarized by primary system organ class and 
preferred term. On-therapy AEs, on-therapy AEs up to Week 4, and post-therapy AEs 
will be summarized separately. On-therapy AEs and On-therapy AEs up to Week 4 will 
also be summarized by prior ESA use. On-therapy AEs will also be summarized by CKD 
stage. On-therapy AEs up to Week 4 will also be summarized by starting dose of 
daprodustat (i.e. bycohort, prior ESA use, and baseline Hgb). On-therapy AEs by onset
(<=Week 4, >Week 4 to <=Week 16, >Week 16 to <=Week 28, >Week 28 to <=Week 40, 
>Week 40) will be summarized separately. The number of subjects reporting the first 
occurrence of each AE will be provided by onset time by primary system organ class and 
preferred term.
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AEs by SOC and PT and Maximum Intensity
AEs will be summarized by treatment group; by maximum intensity (not applicable, mild, 
moderate, severe), by primary system organ class, and preferred term. Subjects who 
experience the same event several times with different intensities will only be counted 
with the maximum intensity in the order of (not applicable < mild < moderate < severe). 
On-therapy AEs, on-therapy AEs up to Week 4, and post-therapy AEs will be 
summarized separately. On-therapy AEs and On-therapy AEs up to Week 4 will also be 
summarized by prior ESA use.
Drug-Related AEs by SOC and PT
The number and percentage of subjects reporting at least one drug-related AE will be 
provided by treatment group. These events will be summarized by primary system organ 
class and preferred term. On-therapy AEs, on-therapy AEs up to Week 4, and post-
therapy AEs will be summarized separately. On-therapy drug-related AEs will also be 
summarized by prior ESA use. On-therapy drug-related AEs will also be summarized by 
CKD stage.
Drug-Related AEs by SOC and PT and Maximum Intensity
Drug-related AEs will be summarized by treatment group; by maximum intensity (not 
applicable, mild, moderate, severe) by primary system organ class and preferred term. 
Subjects who experience the same event several times with different intensities will only 
be counted with the maximum intensity in the order of (not applicable < mild < moderate 
< severe). On-therapy AEs, on-therapy AEs up to Week 4, and post-therapy AEs will be 
summarized separately.
On-therapy Common (>= 2%) AEs by Overall Frequency
The number and percentage of subjects with on-therapy common (>= 2% in any 
treatment group) adverse events by overall frequency will be provided by treatment group. 
These events will be summarized by preferred term. The summary will also be provided 
by prior ESA use and CKD stage.
A graph will be produced which displays both AE incidence rates and relative risks for 
ND subjects.
On-therapy Common (>= 5%) Non-Serious AEs by SOC and PT (Subjects & No. of 
Occurrences)
The number and percentage of subjects reporting at least one on-therapy common (>= 5% 
in any treatment group) non-serious AE will be provided by treatment group. The number 
of on-therapy non-serious AE occurrences will also be provided. These events will be 
summarized by primary system organ class and preferred term.
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On-therapy Non-Serious Drug-Related AEs
The number and percentage of subjects with on-therapy non-serious drug-related AEs 
will be summarized by preferred term.

Serious and Other Significant AEs
Serious AEs
The number and percentage of subjects reporting at least one serious AE will be provided 
by treatment group. These events will be summarized by primary system organ class and 
preferred term. On- and post-therapy serious AEs will be summarized separately.
On-therapy Serious Drug-Related AEs
The number and percentage of subjects with on-therapy serious drug-related AEs will be 
summarized by preferred term.
On-therapy Serious AEs by SOC and PT (Subjects & No. of Occurrences)
The number and percentage of subjects reporting at least one on-therapy serious AE will 
be provided by treatment group. The number of on-therapy serious AE occurrences will 
also be provided. These events will be summarized by primary system organ class and 
preferred term.
AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study Treatment
by SOC and PT
The number and percentage of subjects reporting an on-therapy AE leading to 
discontinuation of study treatment will be summarized by treatment group. These events 
will be summarized by primary system organ class and preferred term.
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8.2.
Adverse Events of Special Interest Analyses
A comprehensive list based on clinical review will be used to identify each type of event. 
AEs of special interest will be manually-selected before unblinding at patient-level (i.e. 
following case-by-case review by members of the Safety Review Team (SRT) including 
representatives from the local Japan team) and not at preferred term level. The details of 
the planned displays are provided in Appendix 10: List of Data Displays.
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
AEs of special interest [1]
On-therapy AEs of special interest
Y
Y
Post-therapy AEs of special interest
Y
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Refer to Section 15.6.4
8.2.1.
Planned Adverse Events of Special Interest Analyses Displays

AEs of Special Interest (AESIs)
AEs of Special Interest
The number and percentage of subjects reporting at least one AESI will be provided by 
treatment group. These events will be summarized by each AESI term (See 
Section 15.6.4). On-therapy and post-therapy AESIs will be summarized separately.
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry/ Hematology/Other 
Laboratory tests, and liver function tests will be based on GSK Core Data Standards. The 
details of the planned displays are in Appendix 10: List of Data Displays.
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Chemistry
Chemistry Values by Visit 
Y
Y
Y
Percent change from baseline in Lipid Parameters [1]
(total cholesterol, LDL cholesterol, HDL cholesterol, 
LDL/HDL cholesterol ratio) by Visit
Y
Y
Y
Worst Case Chemistry Results Relative to Normal Range 
Post-Baseline Relative to Baseline 
Y
Worst Case Chemistry Results Relative to PCI Criteria 
Y
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Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Post-Baseline Relative to Baseline 
Hematology
Hematology Values by Visit
Y
Y
Y
Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline 
Y
Worst Case Hematology Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline 
Y
Urinalysis[3] (ND subjects only)
Urinalysis Values by Visit
Y
Y
Y
Worst Case Urinalysis Results Relative to Normal Range 
Post-Baseline Relative to Baseline 
Y
Iron Parameters
Iron Values by Visit[4]
Y
Y
Y
Worst Case Iron Results Relative to Normal Range Post-
Baseline Relative to Baseline 
Y
Worst Case Iron Results Relative to PCI Criteria Post-
Baseline Relative to Baseline
Y
Other Laboratory Tests [2]
Other Laboratory Values by Visit
Y
Y
Y
Worst Case Other Laboratory Results Relative to Normal 
Range Post-Baseline Relative to Baseline
Y
Worst Case Other Laboratory Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Hepatobiliary Laboratory Abnormalities
Y
Medical Conditions for Subjects with Liver Stopping 
Events
Y
Substance Use for Subjects with Liver Stopping Events
Y
Scatter Plot of Maximum vs. Baseline for ALT
Y
Scatter Plot of Maximum ALT vs Maximum Total Bilirubin
Y
All Laboratory
All Laboratory Data for Subjects with any Value of 
Potential Clinical Concern/PCI
Y
Laboratory Values of PCI
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Lipid parameters will be log-transformed and the percent change from baseline will be reported.
[2] iPTH and eGFR will be collected as other laboratory tests
[3] Urine creatinine, urine albumin, urine albumin/creatinine ratio
[4] Transferrin and UIBC will be included for this summary and other iron parameters will be provided as efficacy 
endpoints.
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8.3.1.
Planned Clinical Laboratory Analyses Displays
LDL/HDL cholesterol ratio will be derived from LDL and HDL cholesterol (see 
Section 15.6.4), and handled as one of chemistry laboratory tests and lipid parameters.

Chemistry/Hematology/Urinalysis/Iron Parameter/Other Laboratory Tests
Clinical Laboratory Values by Visit
The values will be summarized using mean, standard deviation, median, minimum, and 
maximum at each assessment visit and baseline by treatment group. Chemistry values, 
hematology values, iron parameters, urinalysis values, and other laboratory values will be 
summarized separately.
Percent change in Lipid Parameters
Lipid parameters will be log-transformed and the percent change from baseline will be 
reported. The percent change from baseline in each lipid parameter, including baseline 
values, will be summarized using geometric mean, 95% CI, minimum, median, and 
maximum at each assessment visit by treatment group. In baseline values, the coefficient 
of variation will also be provided.
Clinical Laboratory Changes from Baseline by Visit
The values will be summarized using mean, standard deviation, median, minimum, and 
maximum at each assessment visit. Change from baseline in chemistry, hematology, 
urinalysis, iron parameter, and other laboratory will be summarized separately.
Worst Case Laboratory Results Relative to Normal Range/PCI Criteria Post-Baseline 
Relative to Baseline 
The number and percentage of subjects with worst case laboratory results relative to 
normal range/potential clinical importance (PCI) criteria which are post-baseline relative 
to baseline, including unscheduled assessments, will be summarized by test and category 
by treatment group. Summaries for normal range and PCI will be provided separately. 
The categories for normal range are: To Low, To Normal or No Change, To High; the 
categories for PCI criteria are: To Low, To w/in Range or No Change, To High. The 
categorization is determined by comparing the baseline category to the worst case post-
baseline category. PCI Criteria is described in Appendix 8.

Hepatobiliary (Liver)
Details of liver chemistry stopping criteria are described in the protocol.
Liver monitoring/stopping events will be summarized by treatment group. 
Hepatobiliary laboratory abnormalities will be summarized by treatment group. 
A scatter plot of maximum on-therapy ALT values versus baseline ALT values will be 
produced if larger data permit.
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A scatter plot of maximum total bilirubin (xULN) versus maximum ALT (xULN) values 
on-therapy will be produced if larger data permit.
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10: List of Data Displays.
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
ECG
ECG Findings 
Y
Y
ECG Values by Visit
Y
Y
Abnormal ECG Findings
Y
Vital Signs
Vital Signs by Visit
Y
Y
Y
Worst Case Vital Sign Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline
Y
All Vital Signs for Subjects with any Values of PCI
Y
Ophthalmology
Prior-Therapy Ophthalmologic Exams
Y
Y
On-Therapy Ophthalmologic Exams
Y
Y
Change in Anti-Hypertensive Medications
Number (%) of Subjects who have any change in anti-
hypertensive medications during treatment period
Y
Y
Other
Subjects who became pregnant during the study
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.4.1.
Planned Other Safety Analyses Displays

ECG
ECG findings ('normal', 'abnormal, not clinically significant', 'abnormal, clinically 
significant') will be summarized by assessment visit for each treatment group. Change 
from baseline in ECG values will be summarized using mean, standard deviation, 
minimum, median, and maximum by assessment visit for each treatment group. Findings 
without regard to visits (labelled “Worst Case Post-Baseline”, only the worst case finding 
for each subject) will also be provided. All ECG measures (heart rate, PR interval, QRS 
duration, QT [uncorrected] interval and QTcB [calculated], result of ECG) will be 
included in listings.
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
Vital Signs
Vital sign values will be summarized using mean, standard deviation, minimum, median, 
and maximum by assessment visit for each treatment group. Separate summary statistics 
of vital signs will be provided for raw values and change from baseline. In a summary of 
change from baseline, each baseline value will be used for calculation (Section 5.2). 
The number of subjects with worst case vital sign results relative to PCI criteria which 
are post-baseline relative to baseline, including unscheduled assessments, will also be 
summarized by test and category by treatment group. The categories for PCI criteria are: 
To Low, To w/in Range or No Change, To High. The categorization is determined by 
comparing the baseline category to the worst case post-baseline category.

Ophthalmology Exams
The responses to each question and any questions will be summarized using number and 
percentage at each assessment visit by treatment group. The response will be classified 
into 'Yes' and 'No'. A summary of ophthalmology exams at screening and at on-therapy 
will be produced separately. The number and percentage of subjects with worst case 
after-screening ophthalmology exams (i.e., the response is ‘Yes’ at least once during 
whole treatment period, including unscheduled visits) will also be summarized by each 
question by treatment group.

Change in Anti-Hypertensive Medications
The number and percentage of subjects who have any change at least once in anti-
hypertensive medications (type and/or dose) due to increased blood pressure during 
whole treatment period will be summarized by treatment group.
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9.
PATIENT REPORTED OUTCOME ANALYSES
9.1.
Endpoint / Variables
Endpoint / Parameter/ Display Type
Absolute
Stats Analysis
Summary
Individual
T
F
T
F
F
L
Patient Reported Outcome
SF-36 HR-QoL Scores (PCS, MCS, 8 
subscales)
Y
Y
SF-36 HR-QoL Scores (PCS, MCS, 8 
subscales)
by Prior ESA Use
Y
Changes from Baseline in SF-36 HR-QoL 
Scores (PCS, MCS, 8 subscales)
Y
Y
Changes from Baseline in SF-36 HR-QoL 
Scores (PCS, MCS, 8 subscales) 
by Prior ESA Use
Y
Y
EQ-5D-5L Scores
Y
Y
EQ-5D-5L Scores
by Prior ESA Use
Y
EQ-5D-5L Index Values
Y
Y
EQ-5D-5L Index Values
by Prior ESA Use
Y
Changes from Baseline in EQ-5D-5L Index 
Values
Y
Y
Changes from Baseline in EQ-5D-5L Index 
Values
by Prior ESA Use
Y
Y
EQ VAS
Y
Y
EQ VAS
by Prior ESA Use
Y
Changes from Baseline in EQ VAS
Y
Y
Changes from Baseline in EQ VAS
by Prior ESA Use
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
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9.2.
Summary Measure
Scoring derivations are described in Section 15.6.7.
SF36 HR-QoL Scores and Changes from Baseline (PCS, MCS, 8 subscales)
The summary scores (PCS and MCS) and the domain scores (Physical Functioning [PF], 
Role-Physical [RP], Bodily Pain [BP], General Health [GH], Vitality [VT], Social 
Functioning [SF], Role-Emotional [RE], and Mental Health [MH]), and their changes 
from baseline will be summarized using mean, standard deviation, median, minimum, 
and maximum at each assessment visit by treatment group. For changes from baseline, 
the adjusted treatment difference and the 95% CIs will also be provided. The summary 
will also be provided by prior ESA use.
EQ-5D-5L / EQ VAS Scores and Changes from Baseline in EQ-5D-5L Index Value / EQ 
VAS
The number and percentage of subjects with each EQ-5D-5L score within each category 
will be displayed at each assessment visit by treatment group. EQ-5D-5L index values,
EQ VAS scores, and their changes from baseline will be provided using mean, standard 
deviation, median, minimum, and maximum at each assessment visit by treatment group.
The summary will also be provided by prior ESA use. For changes from baseline, the 
adjusted treatment difference and the 95% CIs will also be provided.
9.3.
Population of Interest 
The analyses will be based on the ITT and Efficacy PD population, unless otherwise 
specified.
9.4.
Strategy for Intercurrent (Post-Randomization) Events
Any intercurrent events are taken to be irrelevant for the endpoints and the endpoints will 
be summarized based on available and observed data.
Analysis of change from baseline in the respective QoL parameter at each assessment 
visit will follow the strategy below.
Intercurrent events
Strategy
Study withdrawal / 
Intermittent missing
The following hypothetical scenario is considered to 
assess what would have happened if the event did not 
occur. Analysis using MMRM assume missing at 
random mechanism, that is the observations of missing 
depend on just observed values, not on unobserved 
values. 
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9.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.1 will be 
summarized using descriptive statistics and listed.
9.5.1.
Statistical Methodology Specification
Endpoint / Variables

Change from baseline in the respective QoL parameter at each assessment visit
Model Specification

Analyses will be repeated for each QoL parameter (SF-36 HR-QoL scores/EQ-5D-5L index 
value/EQ-VAS score) using MMRM as specified in Section 7.3.5.1:

Note that the QoL parameters are no need to be log-transformed as opposed to some of the 
iron parameters.
Model Results Presentation

The adjusted mean change from baseline will be presented with the associated 95% CIs by 
treatment at each assessment visit. The adjusted treatment difference (daprodustat – epoetin 
beta pegol) for change from baseline will also be presented with the associated 95% CI at 
each assessment visit.
Subgroup Analyses

Similar to the respective QoL parameters, the above analysis will be repeated by prior ESA use 
subgroup (See Section 5.4.2) in the same manner.

The subgroup analyses will be based on the ITT and Efficacy PD population.

If there is a problem with convergence for a subgroup, the result of the subgroup will not be 
displayed.
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10.
PHARMACOKINETIC ANALYSES
10.1.
Pharmacokinetic Analyses
10.1.1.
Endpoint / Variables
The details of the planned displays are presented in Appendix 10: List of Data Displays.
Endpoints
Untransformed
Log-Transformed
Summary
Individual
Summary
Individual
F
T
F
L
F
T
F
L
Plasma Concentrations of 
Daprodustat
Y [1] [2]
Y
Y [1]
Y
Derived PK Parameters
Y [3]
Y [3]
Y[3]
Y
Y[3]
Dose Normalized PK 
Parameters
Y [3]
Y [3]
Y[3]
Y
Y[3]
NOTES :

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Linear and Semi-Log plots will be created on the same display.
2.
Separate Mean (± SD) and Median plots will be generated.
3.
Individual PK parameters calculated based on less than 4-time point concentrations, or any time deviated 
concentration, or concentrations obtained in the less interval of last two treatment administrations than 12 hours
will be omitted from summaries and figures.
10.1.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 15.5.3
Reporting Standards for Pharmacokinetic)
Concentrations of daprodustat in plasma will be listed and summarized by dose group
and nominal time. Individual plasma concentration-time profiles and median/mean 
profiles by dose group will be plotted. Each of figures will contain one plot on the 
untransformed scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. a
log-linear plot).
10.1.1.2.
Derived Pharmacokinetic Parameters
Derivation of pharmacokinetic parameters will be performed by, or under the direct 
auspices of, Clinical Pharmacology Office, GlaxoSmithKline K.K.
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (version 6.3 or higher). All calculations of non-compartmental parameters 
will be based on actual sampling times. Pharmacokinetic parameters listed will be 
determined from the plasma daprodustat concentration-time data, as data permits.
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Parameter
Parameter Description
AUC(0-4)
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(last)) will be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the linear trapezoidal for each decremental trapezoid.
The concentration at 0 hr will be set to 0.
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
Tmax
Time to first occurrence of Cmax will be obtained directly from the concentration-time 
data.
NOTES:

Additional parameters may be included as required.

C(last) is expected to be the concentration observed at 4 hours after the most recent dose.
10.1.2.
Summary Measure
Refer to Section 15.5.3 for the display standards.

Plasma Daprodustat Concentrations
Non-transformed and log-transformed plasma concentration at every scheduled time 
point will be summarized at Week 12, Week 24, and all visits (i.e., pooled analysis of 
Week 12 and Week 24) by dose level. Non-transformed plasma concentration of 
daprodustat will be summarized using mean, 95% CI, standard deviation, median, 
minimum, and maximum. Log-transformed plasma concentration of daprodustat will be 
summarized using geometric mean, 95% CI of geometric mean, standard deviation of 
log-transformed data and between subject coefficient of variation (%CVb).

PK Parameters
Non-transformed and log-transformed PK parameters will be summarized at Week 12, 
Week 24, and all visits (i.e., pooled analysis of Week 12 and Week 24) by dose level. 
Non-transformed PK parameters of daprodustat (AUC(0-4), Cmax, and Tmax) will be 
summarized using mean, 95% CI, standard deviation, median, minimum, and maximum. 
Log-transformed PK parameters of daprodustat (AUC(0-4), Cmax, Tmax) will be 
summarized using geometric mean, 95% CI of geometric mean, standard deviation of 
log-transformed data and between subject coefficient of variation (%CVb).
Dose normalized PK parameters (non-transformed and log-transformed) will also be 
summarized as the same by dose level. In summary of dose normalized PK parameters, 
summary tables by tablet strength (non-transformed and log-transformed) will be 
provided.
10.1.3.
Population of Interest 
The pharmacokinetic analyses will be based on the PK population, unless otherwise 
specified.
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10.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Any intercurrent events are taken to be irrelevant for pharmacokinetic endpoints. The 
pharmacokinetic endpoints will be summarized based on available and observed data.
11.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
No population pharmacokinetics analyses are planned for this study, but the 
pharmacokinetic data may be used for a separate report.
12.
PHARMACODYNAMIC ANALYSES
No pharmacodynamics analyses are planned for this study, but the pharmacodynamic 
data may be used for a separate report.
13.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES
No pharmacokinetic / pharmacodynamic analyses are planned for this study, but the 
pharmacokinetic / pharmacodynamic data may be used for a separate report.
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14.
REFERENCES
Besarab A, Reyes CM, and Hornberger J. Meta-Analysis of Subcutaneous Versus 
Intravenous Epoetin in Maintenance Treatment of Anemia in Hemodialysis Patients. 
American Journal of Kidney Diseases. 2002; 40 (No. 3): 439-446.
Liublinska V, Rubin DB. Sensitivity analysis for a partially missing binary outcome in a 
two-arm randomized clinical trial. Statistics in Medicine 2014; 33(24): 4170-4185.
Mascha EJ, Sessler DI. Equivalence and noninferiority testing in regression models and 
repeated-measures designs. Anesth Analg. 2011;112(3):678-87
O ’Kelly, M. and Ratitch. B. Clinical Trials with Missing Data: A Guide for Practitioners. 
John Wiley & Sons Ltd. 2014.
Rosendaal FR, Cannegieter SC, Van der Meer, FJM, et al. A Method to Determine the 
Optimal Intensity of Oral Anticoagulant Therapy. Thrombosis and Haemostasis. 1993; 69 
(3): 236–239.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons, 1987.
User’s Manual for the SF-36v2 Health Survey Third Edition.
Yuan, Y. Sensitivity Analysis in Multiple Imputation for Missing Data. Paper SAS270-
2014.
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15.
APPENDICES
15.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
15.1.1.
Exclusions from Per Protocol Population
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01
Informed Consent in Deviation Category
02
Eligibility Criteria Not Met in Deviation Category
03
Not Withdrawn After Developing Withdrawal Criteria in Deviation Category
04
Wrong study treatment or assignment administered in Deviation Subcategory
05
Randomization procedures (e.g. subject assigned to wrong stratum or subject randomized 
out of order) in Deviation Subcategory
06
Less than 3 out of 4 scheduled evaluable Hgb values from the primary efficacy evaluation 
period 1]
07
Subject received prohibited medication for more than 14 days during study period [2]
08
Non-compliance with randomized medication (compliance category of under compliant or 
over compliant)[3] during the primary efficacy evaluation period, based on eCRF 
randomized medication exposure and compliance forms
NOTES:
[1] Evaluable Hgb values are described in Section 15.6.3.
[2] Prohibited mediations include strong inhibitors of CYP2C8 (e.g. gemifibrozil) and strong inducers of CYP2C8 (e.g. 
rifampin/rifampicin), not include erythropoietin (e.g., epoetin/ darbepoetin alfa/ epoetin beta pegol, excluding 
epoetin beta pegol supplied by GSK). 
[3] See Section 15.6.2; Under compliant: <80%, compliant 80% and 120%, over compliant >120%
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15.2.
Appendix 2: Schedule of Activities
15.2.1.
Protocol Defined Schedule of Events
Phase
Screening9 Treatment
Follow-up
Week
-4
Day 1
210
4
8
12
16
20
24
28
32
36
40
44
48
52
Early 
withdrawal10
4 weeks 
after 52 or 
withdrawal
Permissible range (days)
±7
-
±3
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
-
±7
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history, demography, 
height, weight
X
IWRS call
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study medication dispensing 
1,2
X
X10
X
X
X
X
X
X
X
X
X
X
X
X
Study treatment compliance
X10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
Ophthalmology 3
ECG
X
X
X
HemoCue Hgb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
Only
Hgb X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb
X
Only 
Hgb
Only 
Hgb X
Only 
Hgb
Only 
Hgb X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Urinalysis (ND subjects only)
X
X
X
X
X
Pregnancy test (urine or serum 
hCG) 4
X
X
X
X
X
X
X
X
X
Estradiol, FSH 5
X
PK 6
X
X
Ferritin, TSAT
X
X
X
X
X
X
X
X
Serum iron, TIBC, UIBC, 
serum transferrin, hepcidin
X
X
X
X
X
X
X
iPTH
X
X
X
HR-QoL
X
X
X
X
X
Genetics sample 7
X
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Phase
Screening9 Treatment
Follow-up
Week
-4
Day 1
210
4
8
12
16
20
24
28
32
36
40
44
48
52
Early 
withdrawal10
4 weeks 
after 52 or 
withdrawal
Permissible range (days)
±7
-
±3
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
-
±7
Adverse event assessment 8
Review Concomitant 
Medications
1.
In Cohort 1 and Cohort 3, ESA non-users randomized to the epoetin beta pegol group will start treatment with epoetin beta pegol at a dose of 25 μg once 
every 2 weeks. For these subjects, specified examinations will be performed at Week 2 (Cohort 3 only) and every 4 weeks after Week 4, and no study-
related assessments will be necessary at study visits only for study treatment [e.g., Week 2 (Cohort 1 only), Week 6, Week 10) (see Section 6.4.2 in 
protocol).).). It should be noted that subjects receiving epoetin beta pegol once every 2 weeks should attend study visits within a window of ±3 days.
2.
If a subject visit the study site only to receive study medication, only the IWRS call, study medication dispensing, and study medication compliance will be 
required. 
3.
Ophthalmology exams should be conducted at the following time points.

Screening: anytime after consenting and prior to first dose of study medication (Day 1)

Week 12: window from weeks 10-14 (inclusive)

End of study: window from weeks 48-52 (inclusive)

Early study medication discontinuation: withdrawal eye exam as close to the last dose as possible (the repeat exams are not required if one has been 
performed within the 2 prior weeks).
4.
Performed in females of childbearing potential: serum pregnancy test will be performed if urine pregnancy test is not feasible.
5.
Measured in female subjects only to determine the menopausal status (see Section 5.1 in the protocol).
6.
See Table 15 in protocol...
7.
Informed consent for optional Genetic research should be obtained before collecting a sample (see Section 7.6 in the protocol)..
8.
See Section 7.4.1.1 in protocol
9.
Re-screening subjects who meet all the following conditions are allowed to use the results of the latest ophthalmonogy exam and not required to undergo the 
rescreening ophthalmonogy exam, at the discretion of the investigator. 
   •
Subjects had no findings that deem re-exams within 3 months at the latest screening ophthalmology exam. 
   •
Subjects had no new eye-related symptoms or complaints until the rescreening following the latest screening ophthalmology exam. 
   •
The latest screening ophthalmology exam was performed within 3 months prior to Day 1 scheduled at the rescreening. 
10. All ND subjects randomized to Cohort 3 will undergo assessment scheduled for Week 2 visit.
11. For withdrawn subjects, specified assessments should be done wherever possible. 
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15.3.
Appendix 3: Assessment Windows
All data will be reported according to the nominal visit date for which it was reported 
(that is, no visit windows will be applied during dataset creation). Permissible range at 
each visit was specified in time & event table (See Appendix 2). Records in the eCRF 
unscheduled visit will not be slotted to a particular time point, but remain as unscheduled 
if they are either summarized or listed unless otherwise specified.
15.3.1.
Definitions of Assessment Windows for Analyses
Analysis Time Point
Definitions
Screening [1]
Data collected in Screening visit
If multiple records are present, the latest record will be used for analysis.
Day 1 [1]
Data collected in Day 1 visit
If multiple records are present, the latest record will be used for analysis.
Week 2
Data collected in Week 2 visit [2]
Week 4
Data collected in Week 4 visit
Week 8
Data collected in Week 8 visit
Week 12
Data collected in Week 12 visit
Week 16
Data collected in Week 16 visit
Week 20
Data collected in Week 20 visit
Week 24
Data collected in Week 24 visit
Week 28
Data collected in Week 28 visit
Week 32
Data collected in Week 32 visit
Week 36
Data collected in Week 36 visit
Week 40
Data collected in Week 40 visit
Week 44
Data collected in Week 44 visit
Week 48
Data collected in Week 48 visit
Week 52
Data collected in Week 52 visit
Follow-up
Data collected in Follow-up visit
Note: 
Any unscheduled visit will not be slotted to a particular time point.
[1] For rescreened subjects, data collected in screening-pass visit (i.e. screening and day 1 visit where the subject 
has passed a screening test) will be used for analysis. They may have multiple records at Screening and/or Day 1 
visit, which associates with a screening pass visit and screening failure visit(s) (see Section 15.6.1 and Section 
15.6.2)
[2] Only ND subjects randomized to Cohort 3
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15.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
15.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
randomization date and treatment stop date.
Treatment Stop Date is defined in Section 15.6.1.
15.4.1.1.
Study Phases for Hgb Data
Treatment State
Definition
Pre-therapy
Date ≤ Randomization Date
On-therapy
Randomization Date < Date ≤ Treatment Stop Date + 1 day
Post-therapy
Date > Treatment Stop Date + 1 day
NOTES: 

If randomization date is missing then the assessment will be considered to be pre-therapy
15.4.1.2.
Study Phases for AE Data
On therapy AEs will be treated as treatment emergent AEs, therefore, treatment emergent 
flag for AEs will be derived from on-therapy treatment state.
Treatment State
Definition
Pre-therapy
AE Start Date < Randomization Date
On-therapy
Randomization Date ≤ AE Start Date ≤ Treatment Stop Date + 1 day
Post-therapy
AE Start Date > Treatment Stop Date + 1 day
Duration (Days) 
AE Resolution Date – AE Onset Date + 1 day
Drug-related
If relationship is marked ‘YES’ on eCRF or value is missing.
NOTES: 

If randomization date is missing then the assessment will be considered to be pre-therapy
15.4.1.3.
Study Phases for Concomitant Medication
Treatment State
Definition
Pre-therapy
Concomitant medications that meet either following conditions will be regarded as pre-
therapy.

Concomitant Medication Start Date < Randomization Date [a, b, c, j, n]

Concomitant Medication Start Date is missing [g, h, i, m, o]

Randomization Date is missing
On-therapy
Concomitant medications that meet either following conditions will be regarded as on-
therapy.

Randomization Date ≤ Concomitant Medication Start Date ≤ Treatment Stop 
Date + 1 [d, e, k, p, q, r, s, v]

(Concomitant Medication Start Date < Randomization Date) AND (Randomization 
Date ≤ Concomitant Medication Stop Date) [b, c, n]
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Treatment State
Definition

(Concomitant Medication Start Date < Randomization Date) AND (Concomitant 
Medication Stop Date is missing) [j]

(Concomitant Medication Start Date is missing) AND (Concomitant Medication 
Stop Date Randomization Date) [h, i, o]

(Concomitant Medication Start Date is missing) AND (Concomitant Medication 
Stop Date is missing) [m]
Post-therapy
Concomitant medications that meet either following conditions will be regarded as 
post-therapy.

Concomitant Medication Stop Date > Treatment Stop Date [c, e, f, I, r, t, v]

Concomitant Medication Stop Date is missing [j, k, l, m, s, u]
NOTES: 

Data of concomitant medication includes anti-hypertensive medication, ESA, iron, and blood products and blood 
supportive care products.

Alphabets in brackets after the conditions correspond to each case in following illustrations.
Illustrations of the pre-therapy, on-therapy, and post-therapy for concomitant medications 
are included below:
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Pre-
therapy
On-therapy
Post-therapy
Pre-therapy
medication
On-therapy 
medication
Post-therapy 
medication
(a)
xx
Randomization Date
Treatment Stop Date + 1 Days
Treatment Stop Date +2 Days
Y
N
N
(b)
x
x
Y
Y
N
(c)
x

x
Y
Y
Y
(d)
xx
N
Y
N
(e)
x
x
N
Y
Y
(f)
xx
N
N
Y
(g)
?x
Y
N
N
(h)
?
x
Y*
Y
N
(i)
?

x
Y*
Y*
Y
(j)
x

?
Y
Y**
Y**
(k)
x
?
N
Y
Y**
(l)
x?
N
N
Y
(m)
?

?
Y***
Y***
Y***
(n)
x
x
Y
Y
N
(o)
?
x
Y*
Y
N
(p)
x
x
N
Y
N
(q)
x

x
N
Y
N
(r)
x

x
N
Y
Y
(s)
x

?
N
Y
Y**
(t)
x
x
N
N
Y
(u)
x
?
N
N
Y
(v)
x

x
N
Y
Y
x = start/stop date of medication
? = missing start/stop date of medication
* If a medication is stopped on-therapy or post-therapy and no start date is recorded it will be assumed that the 
medication was ongoing from the pre-therapy phase
** If a medication is started pre-therapy or on-therapy and no stop date is recorded then usage will be assumed to 
be ongoing for the remainder of the study
*** If a medication has no start or stop date it will be assumed that the medication was ongoing from the pre-
therapy phase to the post-therapy phase
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15.5.
Appendix 5: Data Display Standards & Handling 
Conventions
15.5.1.
Reporting Process
Software

The currently supported versions of SAS software and S-Plus will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Compound
: /arenv/arprod/gsk1278863/mid201753/final_01
QC Spreadsheet
: /arenv/arprod/gsk1278863/mid201753/final_01/documents
Analysis Datasets

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.1.3 & ADaM IG 
Version 1.0. If the Study Data Standardization Plan (SDSP) exists for a study, ensure the CDISC 
versions are consistent.
Generation of RTF Files

RTF files will not be generated.
15.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Scheduled visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) 
will be included in listings, figures, summaries and statistical analyses.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
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Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

If unscheduled visits are included, details of how summaries will be displayed will be provided in 
the RAP.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1: This does not apply to the output of 
statistical models or when the standard list is inappropriate.
For cases where the standard may not be applied, see the display details in Section 
6 to Section 10.
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
15.5.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
GUI_51487. 
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
The following PK parameters will be derived by the Programmer: 

Dose Normalized PK parameters
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to [Standards for Handling NQ Impacted PK Parameters].
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Each pharmacokinetic parameter (AUC(0-4), Cmax, and Tmax) will be summarized 
using the minimum set of summary statistics (IDSL statistical display principle 
6.06.1).
For each pharmacokinetic parameter (AUC(0-4), Cmax, and Tmax), the log-
transformed parameter will be summarized using the summary statistics. The 
summary statistics are: N, n, geometric mean, 95% CI of geometric mean, standard 
deviation (SD) of log-transformed data and between subject coefficient of variation 
(CVb (%)) will be reported.
[1] CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data)
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15.6.
Appendix 6: Derived and Transformed Data
15.6.1.
General
Multiple Measurements at One Analysis Time Point

Subjects having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant PCI summary tables.

For multiple measurements at Screening and/or Day 1 visit, the screening pass visit record will be used 
for analysis (See Appendix 3: Assessment Windows)
Study Day

Calculated as the number of days from Randomization Date:

Ref Date = Missing              →Study Day = Missing 

Ref Date < Randomization Date →Study Day = Ref Date – Randomization Date

Ref Data ≥ Randomization Date →Study Day = Ref Date – (Randomization Date) + 1    
Unique Subject ID

All subjects have unique subject ID for analyses even if a subject was enrolled after rescreened. 
Tables/figures/listings will be produced based on unique subject ID.

For a rescreened subject, the unique subject ID will be derived from the first-assigned subject number 
though he or she seems to have different subject numbers in eCRF by screening assessments. 
Rescreening Subjects

For rescreened subjects, data collected in screening-pass visit will be used for analysis. They may have 
multiple records at Screening and/or Day 1 visit, which associates with a screening-pass visit and 
screening failure visit(s)

Regarding a listing of SAEs in screening period, all pre-therapy SAEs captured in eCRF will be 
provided including screen failure records of rescreened subjects.
Treatment Start Date

First randomized treatment start date
Treatment Stop Date - Daprodustat

Calculated as the latest treatment stop date.
Treatment Stop Date – Epoetin Beta Pegol

Following definition will be based on “assumed” treatment stop date because the treatment stop date is 
not captured in eCRF.
Definition:

If a subject has completed the treatment period (i.e., Week 52 visit record is present), treatment stop 
date will be calculated as Week 52 visit date..
o
Week 52 visit date will be based on laboratory Hgb date. HemoCue Hgb date will be used 
when laboratory Hgb date is unavailable.

If a subject has withdrawn from the treatment period (i.e., Week 52 visit record is missing), treatment 
stop date will be calculated as the latest dosing start date + XX days (1 day before the next treatment 
start date if a subject hadn’t withdrawn)

Subjects will have every 2 weeks or every 4 weeks injection of epoetin beta pegol, therefore 
assumed treatment stop date could include “+ 13 or 27 days” to mimic every 2 weeks or every 4 
weeks dosing.
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Subgroup definition

For general considerations, see Section 5.4.2

Regarding prior ESA type, prior ESA dose, and ERI, see Section 15.6.2

Baseline iron use = use or non-use of pre-therapy iron medications (including ferric citrate (trade name
Riona), see Section 15.6.3).

History of diabetes will be derived from the current history diabetes (Yes/No) in medical history records.

CKD stage will be derived from the eGFR measurement at a screening visit

Cohort will be derived from the randomization number.
o
Cohort 1 = Randomization Number in 
o
Cohort 2 = Randomization Number in 
o
Cohort 3 = Randomization Number in 

Dialysis will be derived from the randomization number.
o
ND subjects = Cohort 1 or 3
o
PD subjects = Cohort 2
Time Definitions (per GSK standard principles)

1 week = 7 days

1 month = 30.4375 days

1 year = 365.25 days
15.6.2.
Study Population
Subject Disposition and Study Population
Rescreened Subjects

Screening status and reason for screening failure for a subject who has multiple subject numbers will be 
unique in the unique subject ID.
o
The screening status of a subject who failed screening but passed rescreening will be ‘enrolled’, and 
the reason for failure will not be counted.
o
The screening status of a subject who failed more than one screening and never passed will be 
‘failed’, and the reason for failure will be derived from the latest failure record.

Study population of subjects will be derived from the above unique screening status.
Demographics and Baseline Characteristics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
A date and month will be imputed as 
 as it will not be captured.

Randomization date will be used as reference date of calculation.
o
If randomization date is missing, screening date will be used.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)]2
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Demographics and Baseline Characteristics
Type of Prior ESA

For this study, prior ESA dose can be administered in several different ways, which are categorized by 
GSK drug codes as follows.
Prior ESA
CMDRGCOL
Epoetin
00928302
00928303
00928305
Epoetin beta pegol
53876201
Darbepoetin alfa
50520401

Dosing route (i.v. or s.c.) is captured in eCRF directly.
Prior ESA dose (IU/week) at Baseline

During screening, subjects may be receiving ESA in multiple ways, including epoetin i.v. or s.c., 
darbepoeitin alfa i.v. or s.c., or epoetin beta pegol i.v. or s.c. The dose of ESA during the period of 12 
weeks prior to randomization will be standardized to obtain a continuous single unit prior ESA dose in 
terms of epoetin i.v. (IU/week). The standardization will be carried with the following formula based on 
literature review:

For subjects taking epoetin i.v.
o
Standardized mean prior ESA dose (IU/week) = epoetin i.v. dose (IU/week)

For subjects taking epoetin s.c.
o
Standardized mean prior ESA dose (IU/week) = (161/113)*epoetin s.c. dose(IU/week): 
[Besarab 2002]

For subjects taking darbepoeitin alfa i.v. or s.c.
o
Standardized mean prior ESA dose (IU/week) = 250*darbepoeitin alfa dose (g/week)

For subjects taking epoetin beta pegol i.v. or s.c.
o
Standardized mean prior ESA dose (IU/week) = 208*epoetin beta pegol dose (g/week)

Prior ESA dose will be calculated using a weighted mean:
o
Mean prior ESA dose (g/week or IU/week) 
        = ([dose]1 * [frequency]1+ ... + [dose]n* [frequency]n) / {([duration]1+ ... + [duration]n) / 7}
where
o
[dose]n : dose at n th record
o
[frequency]n = 1 when once daily (QD)
o
[duration]n = [Prior ESA start date]n+1 – [prior ESA start date]n*
or
[Randomization date] – [prior ESA start date]n*
when nth record is the last prior ESA dose
*Using “[end date] – [start date] +1’ may be inappropriate because the start date may be 
identical with the end date in case the dose frequency is once daily or twice daily, etc.

Prior ESA dose during the period of 12 weeks prior to randomization will be used for calculation.
o
Let the latest record of earlier records than the date of 12 weeks prior to randomization date be 
the 1st record. If no earlier record than the date of 12 weeks prior to randomization date, let the 
earliest record be the 1st record.
o
If prior ESA start date of 1st record is earlier than 12 weeks prior to randomization date then 
dose and duration of 1st record for calculation of prior ESA dose are defined as follows:

[dose]1 = Original dose * [Duration]1 / Original duration

Original dose is dose recorded in 1st record
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Demographics and Baseline Characteristics

Original duration = [Prior ESA start date]2 – [prior ESA start date]1
              or
              [Randomization date] – [prior ESA start date]1 
              when 1st record is the last prior ESA dose

[Duration]1 = [Prior ESA start date]2 – [Randomization date – 84]
          or
          84
          when 1st record is the last prior ESA dose
Illustration of Standardized Mean Prior ESA calculation (ex: epoetin i.v.)
i) 1st record is not earlier than 12 weeks prior to randomization date
Record#
Visit
Start Date
Dose 
(IU)
Duration 
(days)
1
Screening
10Feb2017
750
24
2
Screening
06Mar2017
750
28
3
Screening
03Apr2017
1500
28
-
Day 1
[Randomization 
Date]
Total 
dose = 
3000
Total 
duration 
= 80
   Mean prior ESA dose (IU/week) = 3000/(80/7) = 262.5
ii) 1st record is earlier than 12 weeks prior to randomization date
Record#
Visit
Start Date
Dose 
(IU)
Duration 
(days)
Duration for 
calculation 
Dose for 
calculation
1
Screening
03Feb2017
750
30
27[1]
750*27/30 = 675
2
Screening
05Mar2017
750
29
29
750
3
Screening
03Apr2017
1500
28
28
1500
-
Day 1
[Randomization 
Date]
Total duration 
= 84
Total dose = 
2925
[1] [Prior ESA start date]2 – [Randomization date – 84] = [05Mar2017] – [06Feb2017] = 27
   Mean prior ESA dose (IU/week) = 2925/(84/7) = 243.75
Erythropoietin Resistance Index (ERI) at Baseline

Calculated as standardized mean prior ESA dose (IU/week) divided by weight (kg) at screening visit and 
then divided by the achieved Day 1 central laboratory Hgb (g/dL).

If prior ESA data is missing (e.g. ESA non-user), ERI will not be calculated.
Period of Time on Dialysis at Baseline

Period of time on dialysis (years) will be defined as follows:
o
(Randomization Date – Date of Dialysis Initiation + 1) / 365.25
o
If Date of Dialysis Initiation is partially missing, follow the same handling as concomitant 
medications in Section 15.7.2.1.
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Exposure
Prescribed Dose and Actual Dose for Daprodustat

Prescribed dose will be derived from dose level captured in eCRF.

Actual dose will be derived from dose level associated with a container number in eCRF. Note that 
unscheduled (additional) bottles will not be taken into account. If a container number is “NA” then actual 
dose is considered as 0mg.

In principle, actual dose will be the same as prescribed dose except for a case in which inconsistency 
between a prescribed dose and actual bottle(s) occurs. If such an inconsistency occurs, it may not be 
possible to determine what dose was actually taken. In these cases, the actual dose may be changed 
from the prescribed dose to a more plausible value based on the available information (e.g., IRT data).
Prescribed Dose and Actual Dose for Epoetin Beta Pegol

Prescribed dose and actual dose will be derived from dose level captured in eCRF.
Extent of Exposure of Daprodustat

Subjects who were randomized but did not report a treatment start date will be categorized as having 
zero days of exposure.

Time on study treatment will be calculated based on the formula:
o
Time on study treatment (days)
= [Treatment Stop date] – [Treatment Start date] + 1 day
The time on study treatment does not exclude dose interruptions.

Cumulative dose will be based on the formula using actual dose:
o
Cumulative Dose = Sum of ([Exposure Duration] x [Actual Dose]) at Each Visit
where Exposure duration = [Treatment Stop date] – [Treatment Start date] +1 day

Subject daily dose (= Cumulative Dose / Time on study treatment) is calculated for each subject using 
actual dose and the summary statistics are calculated based on the subject average daily dose.

Distribution of the dose level
Dose level will be classified into 9 categories; 0 mg (i.e. treatment interruption), 1 mg, 2 mg, 4 mg, 
6 mg, 8 mg, 12 mg, 18 mg, 24 mg according to actual dose.
Extent of Exposure of Epoetin beta pegol

Subjects who were randomized but did not report a treatment start date will be categorized as having 
zero days of exposure.

Time on study treatment will be calculated based on the formula:
o
Time on study treatment (days)
= [Treatment Stop date] (see Section 15.6.1)– [Treatment Start date] + 1 day
The time on study treatment does not exclude dose interruptions.

Cumulative dose will be based on the formula using actual dose:
o
Cumulative Dose = Sum of [Actual Dose] at Each Visit

Subject monthly dose (= Cumulative Dose / Time on study treatment x 30.4375 days) is calculated for 
each subject using actual dose and the summary statistics are calculated based on the subject average 
monthly dose.

Distribution of the dose level
Dose level will be classified into 8 categories; 0 g (i.e. treatment interruption), 25 g, 50 g, 
75 g, 100 g, 150 g, 200 g, 250 g according to actual dose.
Treatment Compliance of Daprodustat

Treatment compliance of daprodustat will be based on # of tablets and categorized as Under 
compliance, Compliant, and Over Compliant
o
Calculated compliance < 80%          Under Compliant
o
Calculated compliance 80% and 120% Compliant
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Exposure
o
Calculated compliance > 120%         Over Compliant

Treatment compliance will be calculated for daprodustat as following formula:
o
Compliance (%) = [(Total # of tablets actual taken) / (Total # of tablets planned taken)] * 100
where
Total # of tablets actual taken = Sum of (Numbers of Tablets Taken at Each Visit)
Total # of tablets planned taken = Sum of [(Dosing Stop Date – Dosing Start Date + 1 day) x 
Planned # of tablet / day in Each Visit]
Planned # of tablet/day is defined as follows according to the protocol:
o
0 mg 0 tablet/day (i.e. compliance will not be calculated)
o
1 mg 1 tablet/day
o
2 mg 1 tablet/day
o
4 mg 1 tablet/day
o
6 mg 1 tablet/day
o
8 mg 2 tablets/day
o
12 mg 2 tablets/day
o
18 mg 3 tablets/day
o
24 mg 4 tablets/day
where dose record is derived from prescribed dose.
o
Dosing Start Date and Dosing Stop Date will be defined according to the period for compliance 
calculation as below
Period for Compliance 
Calculation
Dosing Start Date
Dosing Stop Date[2]
0 – 2 Week[1]
Treatment Start Date
Day 1 Dosing Stop Date
0 – 4 Week (Cohort 1)
Treatment Start Date
Day 1 Dosing Stop Date
0 – 4 Week (Cohort 3)
Treatment Start Date
Week 2 Dosing Start Date
Day 1 Dosing Stop Date
Week 2 Dosing Stop Date
2 – 4 Week[1]
Week 2 Dosing Start Date
Week 2 Dosing Stop Date
Primary Efficacy Evaluation 
Period (40 – 52 Week)
Dosing Start Date at each visit
from Week 40 to 48
Dosing Stop Date at each visit from Week 40 
to 48
Overall
Dosing Start Date at each visit
Dosing Stop Date at each visit
[1] Compliance will not be calculated for Cohort 1.
[2] If Dosing Stop Date is missing Treatment Stop Date will be used.
Treatment Compliance of Epoetin Beta Pegol

Treatment compliance of epoetin beta pegol will be based on dosing records (dose per every 2 or 
4weeks are captured) and categorized as Under compliance, Compliant, and Over Compliant
o
Calculated compliance < 80%          Under Compliant
o
Calculated compliance 80% and 120% Compliant
o
Calculated compliance > 120%         Over Compliant

Calculated compliance will be provided to derive compliance category only, not provided for any 
displays. It will be carried using the following formula:
o
Calculated Compliance (%) = [(Total # of dosing) / (Total # of planned dosing)] x 100
o
Total # of dosing = Sum of Numbers of dosing records where Prescribed Dose equals Actual 
Dose
o
Total # of planned dosing = Sum of # of planned dosing of each dosing records
o
# of planned dosing = Duration / 14 (if Frequency = every 2 weeks and Prescribed dose 0)
                Duration / 28 (if Frequency = every 4 weeks or Prescribed dose = 0)
o
Duration = Start Date of next dosing record – Start Date

If next dosing record is missing, Treatment Stop Date (see Section 15.6.1)+ 1 day will be 
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Exposure
used. instead of Start Date of next dosing record.
o
Dosing records included in compliance calculation for each period are as below.
Period for Compliance Calculation
Dosing Records
0 – 2 Week[1]
First record of Day 1
0 – 4 Week
Day 1 to Week 2
(Day 1 for ESA users in Cohort 1)
2 – 4 Week[1]
Day 1 (ESA users)
Week 2 (ESA non-users)
Primary Efficacy Evaluation Period (40 – 52 Week)
Week 40 to 48
Overall
All records
[1] Compliance will not be calculated for Cohort 1.
15.6.3.
Efficacy
Hgb Values
Central laboratory and HemoCue Hgb Values

For reporting purposes, central laboratory Hgb values will be used, unless otherwise specified. However, 
if a central laboratory Hgb value is missing, a corresponding non-missing HemoCue Hgb value, which is 
associated with the identical subject number and visit, will be used.
Evaluable Hgb Values

It will be used for reporting sensitivity analysis results and Hgb listings.

Evaluable Hgb values will be based on on-therapy central laboratory and/or HemoCue Hgb values that 
are not taken within the 8 weeks following a red blood cell transfusion, a whole blood transfusion, or a 
non-randomized ESA medication which occurs on or after the randomization date (except protocol-
specified ESA treatment in screening period).
If an Hgb record meets at least one following criteria, the Hgb record will be regarded as non-evaluable.
o
Blood Product Administration Date < Date of Hgb data ≤Blood Product Administration Date + 
56 (days)
o
ESA Start Date < Date of Hgb data ≤ESA Stop Date + 56 (days)
Medical Conditions and Concomitant Medications
Iron Medication

Although the following iron-containing drugs are collected as iron medication data, they will not be 
included in the summary of other concomitant medications.
o
GSK drug code: 54909401 (SUCROFERRIC OXYHYDROXIDE; P-TOL).
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Hgb Values
Flowchart for Hgb analyses

This flowchart will be applicable, unless otherwise specified 

Basically, scheduled visits between Day 1 and Week 52 will be applicable to this flowchart, but analyses 
including by-visit summaries may include other schedued visits (ie. screening and follow-up visit).
[1] Regarding partially evaluated Hgb values, the following summaries of Hgb will include unscheduled visits:

Summary of Time (weeks and %) within Hgb target range during the primary efficacy evaluation 
period

Summary of Number (%) of subjects who have an Hgb level of less than 7.5 g/dL

Summary of Number (%) of subjects who have an Hgb level of more than 13.0 g/dL and number of 
episodes

Time (in days) to reach the lower Hgb target (11.0 g/dL)
Hgb increase of more than 2.0 g/dL over any 4 weeks

For this reporting purpose, Hgb values from central laboratory will be used as previously described.

A subject who has at least one record with Hgb increase of more than 2.0 g/dL over any 4 weeks will be 
counted and all episodes will be listed.

Hgb increase will be calculated for scheduled visits between Day 1 and Week 52 if available (i.e. Week 4 
Hgb - Day 1 Hgb, Week 8 Hgb - Week 4 Hgb, ...)
Illustration of calculation (example in case of Week 12 missing, until Week 24 visit)
Hgb
(g/dL)
Lab Date
Study 
Day
Visit
Hgb increase
9.1
1
Day 1
Not calculated
9.8
30
Week 4
0.7
11.9
61
Week 8
2.1
12.6
127
Week 16
Not calculated
12.7
158
Week 20
0.1
12.3
183
Week 24
-0.4

Odds ratio and its 95% CI will be obtained using the same statistical model described in Section 7.2.5.

When the odds ratio is undefined, it will not be presented.
Scatter plot of Hgb assessments: Central Laboratory vs. HemoCue

All available pairs of Hgb (i.e. non-missing values in both from central laboratory and from the 
corresponding HemoCue measurement) will be used, regardless of treatment groups and visits. The 
figure will include a linear regression line with 95% CI band, R-squared, and Pearson’s correlation 
coefficient.
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Hgb Values
Scatter plot of Change from Baseline in Hgb at Week 4 vs covariates of interest

The following scatter plot figures will be produced separately: 

Change from baseline in Hgb (g/dL) at Week 4 vs. Baseline body weight (kg)

Change from baseline in Hgb (g/dL) at Week 4 vs. Baseline Hgb (g/dL)

Change from baseline in Hgb (g/dL) at Week 4 vs. Prior ESA dose

Different displays by prior ESA use will be used to differentiate them.

Vertical axis will indicate the change from baseline in Hgb (g/dL) at Week 4, horizontal axis will indicate 
the covariates of interest, baseline body weight (kg), baseline Hgb (g/dL), or prior ESA dose (IU/week).

Only individual plots will be provided unlike the scatter plot of Hgb assessments.
Scatter plot of Mean Dose during Week 40 to 52 vs. Covariates of Interest

The following scatter plot figures will be produced for overall: 

Mean Dose during Week 40 to 52 vs. Baseline Body Weight (kg)

Mean Dose during Week 40 to 52 vs. Baseline Hgb

Mean Dose during Week 40 to 52 vs. Prior ESA dose

Different displays by prior ESA use will be used to differentiate them.

Vertical axis will indicate the mean dose (mg), horizontal axis will indicate the covariates of interest; 
baseline body weight (kg), baseline Hgb (g/dL), or prior ESA dose (IU/week).

Mean dose will be calculated from the arithmetic mean using the latest 3 exposure records (i.e., for 
completers Week 40, 44, and 48), which are based on the actual doses and the scheduled visits.

Subjects who has less than 3 dosing records will be excluded from the figures. 

Mean dose during Week 40 to 52 will also be summarized and listed.

Only individual plots will be provided unlike the scatter plot of Hgb assessments.
Time in Target Range
Time (weeks and percentage) in Target Range During the Primary Efficacy Evaluation Period

For this reporting purpose, on-therapy Hgb values of central laboratory during Week 40 to Week 52, 
including unscheduled visits, will be used. However, if a central laboratory Hgb value is missing, a 
corresponding non-missing HemoCue Hgb value, which is associated with the identical subject number 
and visit, will be used.

Number of days that a subject’s Hgb is within the analysis range of 11.0-13.0 g/dL inclusive between 
Week 40 and 52, including any on-therapy Hgb values that were taken during this time period. Linear 
interpolation is used to estimate Hgb between visits, if a subject has an intermittent missing value 
(Rosendaal1993).
Illustration of calculation
Hgb
(g/dL)
Lab Date
Visit
Ref 
Day
Hgb Shift
Total shift (%) 
within range
Time in range 
(weeks)
9.9
Week 
40
0
NC
NC
NC
11.2
Week 
44
31
1.3 (=11.2-
9.9)
total shift: 0.2
0.2/1.3=15.38%
(31-0)*0.1538/7
=4.77/7 (weeks)
missing
Week 
48
61
NA
NA
NC
13.4
Week 
52
92
2.2(=13.4-
11.2)
total shift: 1.8
1.8/2.2=81.82%
(92-31)*0.8182/7
=49.91/7 (weeks)
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Time in Target Range
Overall time in range = (4.77 + 49.91)/7 = 54.68/7 = 7.81 (weeks)
Percent time in range = 7.81/(92/7) = 59.42%
NC: Not calculated, NA: Not available

Hgb laboratory assessment date will be used to calculate a duration (Ref Day) between assessments.
o
Duration between assessments = [Hgb lab date] – [Hgb lab date of the previous measurement]
If a subject has withdrawn from the treatment before Week 40 the duration between Week 40 to Week 
52 cannot be calculated, the subject will not be included in a summary.
Basically, the duration should be [Week 52 lab date – Week 40 lab date] unless a subject has withdrawn 
before Week 52. In the case of withdraw before Week 52, Treatment Stop Date (see Section 15.6.1) will 
be used instead of Week 52.

As an above example, suppose a subject has Hgb reading 9.9 g/dL on August 1st (Week 40), then 
reading if 11.2 g/dL on September 1st. The assumption is made that the week, between these scheduled 
assessments the subjects Hgb increases from 9.9 to 11.2 g/dL in a linear manner, To following steps are 
taken to calculate the time (days) the subject’s Hgb was within target range (11.0 to 13.0 g/dL).
1.
Calculate amount of Hgb shift (9.9 to 11.2 = 1.3 shift) and Hgb shift within range (0.2 out of shift is 
within range of 11.0 – 13.0)
2.
Calculate percent of total shift (%) within range (0.2/1.3 = 15.38%)
3.
Estimate the number of weeks since last visit within range (15.38% x duration between 
assessments = 15.38% x 31/7 weeks = 0.68 weeks within range)
If a subject has an intermittent missing Hgb assessment (on-therapy), the linear interpolation will be 
done by ignoring missing Hgb data.
To calculate overall time (weeks) in Hgb target range, the total days in range for each time period are 
added together and divided by 7. 
The % of time in range between Week 40 and Week 52 for a subject will be calculated by calculating 
overall time (weeks) within range and dividing by the total duration (weeks) between Week 40 to Week 
52. Similarly, the % of time above Hgb target range and % of time above and below Hgb target range will 
be calculated,
Time (days) to reach the lower Hgb target (11.0 g/dL)

Time to reach the lower Hgb target will be determined as follows:
o
Time to reach the lower Hgb target = Date to reach the lower Hgb target – Randomization Date + 
1 day

Subjects who could not reach the lower Hgb target during on-therapy will be regarded as censored. 
Censored time will be determined as follows: 
o
Censored time = Treatment Stop Date – Randomization Date + 1
Dose Adjustment
Dose adjustment algorithm

Dose Adjustment algorithm will be based on HemoCue Hgb values at scheduled visits. No Hgb values 
measured at unscheduled visits will be included.

Dose will be derived from actual dose.

The following table illustrates the algorithm using analysis flags as below:
o (FL_A): Adjustment flags will be counted if actual dose is changed from that of the previous visit.
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Dose Adjustment
o (FL_B): Over 13 g/dL flags will be counted if HemoCue Hgb >13 g/dL is observed.
o (FL_C): Interruption flags will be counted if actual doseis zero.
Treatment durations in each visit will be calculated based on the following formula:
o Daprodustat
Duration (days) = Treatment Stop Date in the visit – Treatment Start Date in the visit + 1 day
o Epoetin beta pegol group
Treatment stop date in the visit will be derived from [treatment start date in the next visit – 1 day]. If 
there is no record of the next scheduled visit, Treatment Stop Date(see Section 15.6.1) will be 
applied for the record.
Illustration of dose adjustment algorithm (24-week case)
Visit
(Example)
Treatment 
Start date/
Stop date
Duration
HemoCue 
Hgb
(g/dL)
Dose 
(mg)
(FL_A)
(FL_B)
(FL_C)
Adjust-
ment
Over 
13 g/dL
Inter-
ruption
Day 1
29
11.1
4
N
N
N
Week 4
14
11.4
4
N
N
N
Week 8
30
11.8
2
Y
N
N
Week 12
31
13.4
0
Y
Y
Y
Week 16
30
12.6
0
N
N
Y
Week 20
31
11.7
1
Y
N
N
Week 24
-
-
12.3
-
-
N
-
For programmers, note that the flags are for the purposed of illustration, and are not intended to 
imply any type of requirement.
For summary tables, further details are described within the next items;
o 'Duration (days) of treatment interruption due to Hgb >13 g/dL'
o 'Dose adjustment'
o Number of dose adjustment to reach the lower Hgb target (11.0 g/dL)
Duration (days) of treatment interruption due to Hgb >13.0 g/dL
Calculation of duration of treatment interruption due to Hgb >13.0 g/dL will be based on the dose adjustment
algorithm specified in the protocol.

Duration (days) = Sum of [Duration]n
where
[Duration]n represents exposure duration at visit n to meet the following.

Treatment interruption is made due to HemoCue Hgb over 13 g/dL and consecutive until 
treatment is resumed. 
In the above illustration, duration = 61 (days), from Week 12 and 16 visit records.
Dose adjustment
Calculation of frequency of dose adjustment will be based on the above algorithm.

Number of dose adjustment will be counted for each subject as follows:
o
Counts of adjustment flag = 'Y'
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Dose Adjustment
Number of dose adjustment to reach the lower Hgb target (11.0 g/dL)

Reaching the lower Hgb target will be determined on the basis of central laboratory Hgb.

Subjects who has a baseline central laboratory Hgb value within target range or who does not reach the 
lower Hgb target during treatment period will be excluded from the summary.

Number of dose adjustment to reach the lower Hgb target will be counted for each subject as follows
o
Counts of adjustment flag =’Y’ at visits before Date to reach the lower Hgb target.
Iron Endpoints
Oral Iron Use

The following iron-containing drugs will not be included in the analysis of iron use.
o
GSK drug code: 54909401 (SUCROFERRIC OXYHYDROXIDE; P-TOL).
Subjects who used IV and/or oral iron

Number of subjects who used IV and/or oral iron will be summarized

Subjects who used IV and/or oral iron will be defined as follows:

Subjects with on-therapy IV and/or oral iron medication collected in a specific eCRF form 
(CONMEDS-IRON).

Regarding oral iron use, the number of subjects who used ferric citrate and other than ferric citrate
will also be counted respectively.
Oral Iron Dose by Quarter

Records of on-therapy iron medication will be used for the following calculations. 

Summary will be created for all subjects (both iron users and iron non-users) and iron users respectively. 
In a summary containing all subjects, iron dose of subjects who do not use iron medication will be 
calculated as 0 mg.

Monthly average oral iron during the treatment period = Total oral iron dose (mg) during the treatment 
period / (duration in the treatment period (days) / 30.4375 days)

Monthly average oral iron by quarter = Total oral iron dose during each quarter (mg) / (duration in a 
quarter (days) / 30.4375 days).

Total oral iron dose during each quarter (mg) will be carried with the following formula using each record. 
Duration will be derived from iron medication start/stop date:
o
Total oral iron dose during each quarter (mg) = (iron dose1*frequency1*duration1) + ... + (iron 
dosen*frequencyn*durationn)
o
Duration (days) = (stop date1 - start date1 + 1) + ... + (stop daten - start daten + 1)
Frequency is defined as follows:
o
If subject receives iron dose with once daily frequency = 1
o
If subject receives iron dose with BID frequency = 2
o
If subject receives iron dose with TID frequency = 3
o
If subject receives iron dose with QID frequency = 4
Total oral iron dose (mg) during the treatment period will be carried in the same manner.

Quarters/Duration will be defined as follows:
Start Date
End Date
baseline
Screening Date
Randomization Date - 1
Treatment 
Randomization Date
Treatment Stop Date
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Iron Use Subgroup

The baseline iron use will be defined as a subject takes a pre-therapy iron medication excluding 
sucroferric oxhydroxide (trade name: P-TOL, GSK drug code = 54909401).
period
Quarter 1
Randomization Date
Treatment Start Date at Week 12 - 1 day
Quarter 2
Treatment Start Date at Week 12
Treatment Start Date at Week 24 - 1 day
Quarter 3
Treatment Start Date at Week 24
Treatment Start Date at Week 40 - 1 day
Quarter 4[1]
Treatment Start Date at Week 40
Treatment Stop Date
NOTES:

A Quarter End Date will be replaced with Treatment Stop Date (see Section 15.6.1) when 
treatment start date at Week 12, 24, or 40 is missing (i.e. early withdrawal before Week 12, 24, or 
40). In this case, the subsequent Quarter(s) will not be generated. 

Iron medication start/stop date will be defined newly for the analyses in addition to Quarter 
start/end date to derive amount of iron dose within a specified Quarter (analysis flags may be 
used to judge which quarters the iron records should belong to).
[1] Quarter 4 represents the primary efficacy evaluation period.

If iron medication start date < screening date, the iron medication start date will be replaced with 
screening date for the analysis.

If iron medication stop date > Treatment Stop Date, the iron medication stop date will be replaced with 
Treatment Stop Date for the analysis.

If iron medication start date and stop date step over quarters, the iron medication record will be divided; 
the end date in the former of divided record and the start date in the latter of divided record will be the
former quarter end date and the latter quarter start date, respectively.

If no start or stop date is recorded on iron medication, the date will be replaced with Screening Date or 
Treatment Stop Date, respectively.

For ferric citrate (trade name: Riona, GSK drug code = 00752601), iron dose value for analyses will be 
converted as follows,
o
Iron dose for analyses (mg) = iron dose (mg) x 62 / 250
TIBC
TIBC will be calculated automatically by the central laboratory using:

TIBC = UIBC + total iron
TSAT
Based on literature review the distribution of TSAT is skewed and requires a log-transformation. 
Calculation of statistics on log-transformed data are described in Section 5.2.
TSAT will be calculated automatically by the central laboratory using:

TSAT = 100 * (Serum Iron/TIBC)
Hepcidin
Based on literature review the distribution of hepcidin is skewed and requires a log-transformation. 
Calculation of statistics on log-transformed data are described in Section 5.2
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15.6.4.
Safety
Adverse Events
AE up to Week 4

Cut-off date of Week 4 for individuals will be based on Week 4 visit date which is associated 
with the earliest date throughout Week 4 records (i.e., SDTM.SVSTDTC). 
AEs of Special Interest (AESIs)
AESIs are manually-selected at patient-level (i.e. following case-by-case review by members of the SRT 
including representatives from the local Japan team) and not at preferred term level. 
AESI categories are classified as follows:

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis

Death, myocardial infarction, stroke, heart failure, thromboembolic events, thrombosis of vascular 
access

Cardiomyopathy

Pulmonary artery hypertension

Cancer-related mortality and tumor progression and recurrence

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization

Exacerbation of rheumatoid arthritis
Following events will be programmatically identified as AESIs.
Thrombosis and tissue ischemia events will be considered to be secondary to excessive erythropoiesis if 
during the window of [AE start date – 30 days, AE start date +15 days] any one of the following 3 events 
occurs:

Any Hgb value > 13 g/dL

Hgb increase > 2 g/dL over 2 weeks (applied to only Cohort 3)

Hgb increase > 4 g/dL over 4 weeks
Note: Thrombosis and tissue ischemia events that need to be considered against the above 3 Hgb events 
will be identified by the case-by-case review.
Note: HemoCue and central laboratory values will be considered separately. Unscheduled Hgb values will 
also be used in the assessment of secondary to excessive erythropoiesis if available.
Note: All Hgb values that have an assessment date within the window of [AE start date – 58 days, AE start 
date + 15 days] will be considered.
Any SAE which outcome is fatal will be identified AESI as death.
CV Events
Patient profiles of CV events will be provided according to records captured in eCRF, except for 
Peripheral Arterial Thrombosis Embolism (PAT) form.
CV events in PAT form will be provided only when a related AE sequence number is not present. 
This is because several records in PAT form are captured just for AESI information instead of CV 
events. 
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Laboratory Parameters

LDL/HDL cholesterol ratio will be derived from the following equation.
o
LDL/HDL cholesterol ratio = LDL cholesterol (mmol/L)/ HDL cholesterol (mmol/L)
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Laboratory Parameters
Imputation

If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits
= ‘< x‘ becomes x – 0.01
o
Example 2: 1 Significant Digit
= ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits
= ‘< x’ becomes x – 1

The following laboratory values will not be applicable for this imputation:
o
Hgb, serum iron, serum ferritin, serum transferrin, TIBC, UIBC, TSAT, and Hepcidin

The default convention for reporting of clinical laboratory units will be the international system of units (SI 
units).
Log-transformation

Lipid parameters will be log-transformed and the percent change from baseline will be reported. Based 
on literature review the distributions of hepcidin and TSAT are skewed and require a log-transformation. 
Other endpoints may also be log-transformed if deemed appropriate (See Section 5.2).
Others

For summaries of, the absolute neutrophils and lymphocytes count, PCI cutoffs will be calculated by 
multiplying the percentages given for each subject by the absolute white blood count.
15.6.5.
Pharmacokinetic
General
Dose level

Summaries by dose level and used tablet strength will be based on an actual dose associated with a 
container number (See Section 15.6.2). Tablet strength is defined as follows:
oActual dose = 1 mg 1 mg tablet strength
oActual dose = 2 mg 2 mg tablet strength
oActual dose = 4 mg 4 mg tablet strength
oActual dose = 6 mg 6 mg tablet strength
oActual dose = 8 mg 4 mg tablet strength
oActual dose = 12 mg 6 mg tablet strength
oActual dose = 18 mg 6 mg tablet strength
oActual dose = 24 mg 6 mg tablet strength

Dose level which is actually provided to subjects will be derived from an actual dose of the visit 
(including unscheduled visit) which meets the following:
o
Treatment Start Date Date of last dose taken prior to PK sampling Treatment Stop Date
Others

Dose normalized PK parameters will be derived from the PK parameters dividing by actual dose (mg).

In aggregated analyses, data collected in Week 12 and Week 24 will be aggregated.

For the PK parameters calculation, the concentration at 0 hr will be set to 0 and assign zero to NQ 
values.

Individual’s PK parameters calculated less than 4-time point concentrations, or any time deviated 
(beyond 30 min of scheduled visits) concentrations, or concentrations obtained in the less interval of 
last two treatment administrations than 12 hours will be omitted from summaries and figures. but 
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General
presenting in a listing.
15.6.6.
Exploratory Endpoint
CKD Progression
Equation for eGFR
eGFR is estimated by the following Japanese Society of Nephrology-Chronic Kidney Disease Initiatives 
(JSN-CKDI) equation.
Male: eGFR (mL/min/1.73m2) = 194 * Serum creatinine-1.094 * Age-0.287
Female: eGFR (mL/min/1.73m2) = 194 * Serum creatinine-1.094 * Age-0.287 * 0.739
eGFR decrease of 30% or more from baseline
eGFR decrease of 30% or more from baseline is defined as follows.
At each assessment visit,
eGFR change (%) = (eGFR – Baseline eGFR) / Baseline eGFR * 100
If eGFR change (%) < -30 then let the eGFR at the visit be decrease of 30% or more from 
baseline.
Serum creatinine increase of more than double from baseline
Serum creatinine increase of more than double from baseline is defined as follows.
At each assessment visit,
Serum creatinine change (%) = (Serum creatinine – Baseline serum creatinine) / Baseline serum 
creatinine * 100
If Serum creatinine change (%) > 200 then let the Serum creatinine at the visit be increase of more 
than double from baseline.
15.6.7.
Patient Reported Outcome
The original version of instructions and questionnaire items for the study are written in 
Japanese. In displays, the items will be translated into English version (can be found at 
http://www.qualitymetric.com for SF-36v2, EuroQol products for EQ-5D-5L).
SF-36v2
Overview of Scoring Algorithm

Scores will be calculated by Optum PRO CoRE (version 1.2). Refer to “User’s Manual for the SF-36v2 
Health Survey Third Edition” for further details.

Three sets of summary scores will be calculated based on responses to each item on the SF-36:

Physical Component Summary (PCS) score

Mental Component Summary (MCS) score

Domain scores based on the following eight domains
Physical Functioning
Role-Physical (i.e., role limitations due to physical health)
Bodily Pain
General Health
Vitality
Social Functioning
Role-Emotional (i.e., role limitations due to mental/emotional health)
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SF-36v2
Mental Health
The scoring process is summarized in the following figure (Refer to Figure 5.1 in User’s Manual for the SF-
36v2 Health Survey Third Edition).
Before submitting an SF-36v2 response set for scoring, the following points will be ensured.

SF-36v2 Acute is being used for this study. [Acute (1 Week)]

Missing values will be estimated using the Maximum Data Recovery Mode.

2009 U.S. general population will be set for scoring. [2009 US Norms]
EQ-5D-5L / EQ-VAS
Scoring Algorithm

EQ-VAS scores will be summarized based on the numbers subjects have written in the box.

Index values will be calculated based on responses to each item on the EQ-5D-5L:

Mobility (level 1 to 5; e.g., level 1 = “I have no problems in waling about”)

Self-Care (level 1 to 5; e.g., level 1 = “I have no problems washing or dressing myself”)

Usual Activities (level 1 to 5; e.g., level 1 = “I have no problems doing my usual activities”)

Pain / Discomfort (level 1 to 5; e.g., level 1 = “I have no pain or discomfort”)

Anxiety / Depression (level 1 to 5; e.g., level 1 = “I am not anxious or depressed”)

Based on the EQ-5D-5L profile, the index value will be carried out using “EQ-5D-
5L_Crosswalk_Index_Value_Calculator.v2” (can be downloaded from the EuroQol website). Japan 
specific value sets will be used.
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15.7.
Appendix 7: Reporting Standards for Missing Data
15.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as follows: A 
completed subject is one who has completed all periods of the study including the 
follow-up visit.

Withdrawn subjects were not replaced in the study.

All available data from subjects who were withdrawn from the study will be listed and all 
available planned data will be included in summary tables and figures, unless otherwise 
specified.

15.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report, if 
applicable.
15.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
When only the start year is provided, a '01' will be used for the day and 'Jan' will be 
used for the month
o
When only the start month and year is provided, a ‘01’ will be used for the day.
o
When only the stop year is provided, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.
o
When only the stop month and year is provided, a '28/29/30/31' will be used for the 
day (dependent on the month and year)

The recorded partial date will be displayed in listings.
Adverse 
Events

The eCRF does not allow for the possibility of partial dates.
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15.8.
Appendix 8: Values of Potential Clinical Importance
15.8.1.
Laboratory Values
Chemistry
Laboratory Parameter
Units
Clinical Concern Range
Low Flag
High Flag
Albumin (serum)
g/L
< 30 g/L
>55 g/L
Aspartate Aminotransferase
IU/L
N/A
3x ULRR
Alanine Aminotransferase
IU/L
N/A
3x ULRR
Bilirubin (total)
mol/L
N/A
2x ULRR
Calcium (albumin-adjusted)
mmol/L
< 1.87 mmol/L
> 2.56 mmol/L
Bicarbonate (total)
mmol/L
< 20 mmol/L
> 32 mmol/L
Inorganic phosphate
mmol/L
< 0.81 mmol/L
> 1.77 mmol/L
Potassium (serum)
mmol/L
> 0.5 mmol/L below 
LLRR
> 1.0 mmol/L above 
ULRR
Sodium (serum)
mmol/L
< 130 mmol/L
> 150 mmol/L
Hemotology
Laboratory Parameter
Units
Clinical Concern Range
Low Flag
High Flag
Platelet Count 
GI/L
< 80 GI/L
> 500 GI/L
WBC Count
GI/L
> 1x LLRR
>5x ULRR
   Neutrophils
GI/L
< 1.0 GI/L
N/A
   Lymphocytes
GI/L
< 0.5 GI/L
N/A
Iron Parameters
Laboratory Parameter
Units
Clinical Concern Range
Low Flag
High Flag
Ferritin
g/L
< 100 g/L
> 1200 g/L
TSAT
%
<15 %
>40 %
Urinalysis Parameters
Laboratory Parameter
Units
Clinical Concern Range
Low Flag
High Flag
Urine albumin/creatinine ratio
g/mol
> 3.4 g/mol
Other Parameters
Laboratory Parameter
Units
Clinical Concern Range
Low Flag
High Flag
iPTH
ng/L
N/A
> 9x ULRR
eGFR
mL/min/1
.73m2
40% decrease from 
baseline
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15.8.2.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85 mmHg
> 180 mmHg
Diastolic Blood Pressure
mmHg
< 45 mmHg
> 110 mmHg
Heart Rate
beats/min
< 40 beats/min
> 110 beats/min
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15.9.
Appendix 9 Abbreviations & Trade Marks
15.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
ANCOVA
Analysis of Covariance
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
Hgb
Hemoglobin
HRQoL
Health-Related Quality of Life
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
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Abbreviation
Description
SOP
Standard Operation Procedure
SRT
Safety Review Team
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TIBC
Total Iron Binding Capacity
TSAT
Transferrin Saturation
UIBC
Unsaturated Iron Binding Capacity
UN
Unstructured
VAS
Visual Analog Scale
WBC
White Blood Cell
15.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
None
HemoCue
OptumOptum PRO CoRE
P-TOL
Riona
SAS
WinNonlin
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15.10.
Appendix 10: List of Data Displays
15.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.59
Not Applicable
Efficacy
2.1 to 2.133
2.1 to 2.91
Safety
3.1 to 3.126
3.1 to 3.3
Patient Reported Outcome
4.1 to 4.34
Not Applicable
Pharmacokinetic
5.1 to 5.8
5.1 to 5.15
Section
Listings
ICH Listings
1 to 49
Other Listings
50 to 90
Patient Profile Listings
91 to 100
15.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
display provided: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Patient Reported Outcome
PRO_Fn
PRO_Tn
PRO_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
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15.10.3.
Table of Contents for Headline Results Deliverable
The numbering of displays will match with that of final statistical analysis.
Headline Results Analysis
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Headline Tables
Study Population
1.1
Randomized
ES8
Summary of Subject Status and Reason for Study Withdrawal – ND 
Subjects
1.19
ITT
DM1
Summary of Demographic Characteristics - ITT
Efficacy
2.1
ITT
EFF_T1
Summary of Hgb (g/dL) by Visit – ITT
2.3
ITT
EFF_T1
Summary of Hgb (g/dL) by Visit by Prior ESA and baseline Hgb– ITT
2.7
ITT
EFF_T1
Summary of Change from Baseline in Hgb (g/dL) by Visit by Prior ESA and 
baseline Hgb- ITT
2.9
mITT
EFF_T2
Summary of Mean Hgb (g/dL) Based on Observed Cases During the 
Primary Efficacy Evaluation Period – mITT
2.10
Efficacy PD
EFF_T2
Summary of Mean Hgb (g/dL) Based on Observed Cases During the 
Primary Efficacy Evaluation Period - Efficacy PD
2.12
ITT
EFF_T3
Analysis of Mean Hgb (g/dL) During the Primary Efficacy Evaluation Period 
– ITT
2.16
ITT
EFF_T3
Analysis of Mean Hgb (g/dL) During the Primary Efficacy Evaluation Period 
– Subgroup
Only subgroup of prior ESA use
2.25
mITT
EFF_T5
Analysis of Number (%) of Subjects with Mean Hgb in Target Range 
During the Primary Efficacy Evaluation Period - mITT
2.58
ITT
EFF_T11
Summary of Dose by Visit – ITT
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Headline Results Analysis
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Safety
3.1
Safety
AE1
Summary of On-Therapy AEs by SOC and PT – ND Subjects
3.2
Safety
AE1
Summary of On-Therapy AEs by SOC and PT – PD Subjects
ICH E3
3.55
Safety
AE1
Summary of On-Therapy Serious AEs – ND Subjects
3.65
Safety
SAFE_T2
Summary of On-Therapy AEs of Special Interest – ND Subjects
3.66
Safety
SAFE_T2
Summary of On-Therapy AEs of Special Interest – PD Subjects
3.121
Safety
SAFE_T6
Summary of Ophthalmologic Exams at Screening – ND Subjects
3.122
Safety
SAFE_T6
Summary of Ophthalmologic Exams at Screening – PD Subjects
3.123
Safety
SAFE_T7
Summary of On-Therapy Ophthalmologic Exams – ND Subjects
3.124
Safety
SAFE_T7
Summary of On-Therapy Ophthalmologic Exams – PD Subjects
44
Safety
SAFE_L1
Listing of Adverse Events of Special Interest
ICH E3
Displays will be produced with AESI category in 
addition of AE8 template.
82
Safety
SAFE_L2
Listing of Ophthalmologic Exams
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15.10.4.
Table of Contents for SAC Deliverable
15.10.4.1. Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Subject’s Disposition
1.1.
Randomized
ES8
Summary of Subject Status and Reason for Study Withdrawal –
ND Subjects
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.2.
Randomized
ES8
Summary of Subject Status and Reason for Study Withdrawal –
PD Subjects
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.3.
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment – ND Subjects
ICH E3
Y
1.4.
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment – PD Subjects
ICH E3
Y
1.5.
All Screening
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
Y
1.6.
Enrolled
NS1
Summary of Subjects Enrolled by Country and Site ID – ND 
Subjects
EudraCT/clinical operations
Y
1.7.
Enrolled
NS1
Summary of Subjects Enrolled by Country and Site ID – PD 
Subjects
EudraCT/clinical operations
Y
Protocol Deviations
1.8.
Randomized
DV1
Summary of Important Protocol Deviations – ND Subjects
ICH E3
Y
1.9.
Randomized
DV1
Summary of Important Protocol Deviations – PD Subjects
ICH E3
Y
1.10.
Randomized
IE1
Summary of Inclusion/Exclusion Criteria Deviations – ND 
Subjects
ICH E3
Y
1.11.
Randomized
IE1
Summary of Inclusion/Exclusion Criteria Deviations – PD 
Subjects
ICH E3
Y
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Population Analyzed
1.12.
Randomized
SP1
Summary of Study Populations – ND Subjects
IDSL
Y
1.13.
Randomized
SP1
Summary of Study Populations – ND Subjects, Cohort 1
IDSL
Y
1.14.
Randomized
SP1
Summary of Study Populations – ND Subjects, Cohort 3
IDSL
Y
1.15.
Randomized
SP1
Summary of Study Populations – PD Subjects
IDSL
Y
1.16.
mITT
SP2
Summary of Exclusions from the Per Protocol Population 
IDSL
Y
1.17.
Randomized
POP_T1
Summary of Composition of the Randomized Population
Y
Demographic and Baseline Characteristics
1.18.
ITT
DM1
Summary of Demographic Characteristics - ITT
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.19.
ITT
DM1
Summary of Demographic Characteristics by Prior ESA Use –
ITT
Y
1.20.
Safety
DM1
Summary of Demographic Characteristics – Safety, ND Subjects
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.21.
Safety
DM1
Summary of Demographic Characteristics by Prior ESA Use –
Safety, ND Subjects
Y
1.22.
Safety
DM1
Summary of Demographic Characteristics – Safety, PD Subjects
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.23.
Safety
DM1
Summary of Demographic Characteristics by Prior ESA Use –
Safety, PD Subjects
Y
1.24.
Efficacy ND
DM1
Summary of Demographic Characteristics – Efficacy ND
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.25.
Efficacy PD
DM1
Summary of Demographic Characteristics – Efficacy PD
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.26.
Efficacy PD
DM1
Summary of Demographic Characteristics by Prior ESA Use –
Efficacy PD
Y
1.27.
Efficacy ND
DM1
Summary of Demographic Characteristics – Efficacy ND, Cohort 
1
ICH E3, GSK CTR, FDAAA, EudraCT
Y
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
1.28.
Efficacy ND
DM1
Summary of Demographic Characteristics – Efficacy ND, Cohort 
3
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.29.
Safety
POP_T1
Summary of Prior ESA Medication – Safety, ND Subjects
Y
1.30.
Safety
POP_T1
Summary of Prior ESA Medication – Safety, PD Subjects
Y
1.31.
ITT
POP_T1
Summary of Prior ESA Medication – ITT
Y
1.32.
Efficacy PD
POP_T1
Summary of Prior ESA Medication – Efficacy PD
Y
1.33.
Enrolled
DM11
Summary of Age Ranges – ND Subjects
EudraCT
Y
1.34.
Enrolled
DM11
Summary of Age Ranges – PD Subjects
EudraCT
Y
1.35.
Safety
DM5
Summary of Race and Racial Combinations – Safety, ND 
Subjects
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.36.
Safety
DM5
Summary of Race and Racial Combinations – Safety, PD 
Subjects
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.37.
Safety
FH1
Summary of Family History for CV Risk Factors – ND Subjects
IDSL
Y
1.38.
Safety
FH1
Summary of Family History for CV Risk Factors – PD Subjects
IDSL
Y
1.39.
Safety
SU1
Summary of Substance Use (History of Tobacco Use, Alcohol 
Intake) – ND Subjects
IDSL
Y
1.40.
Safety
SU1
Summary of Substance Use (History of Tobacco Use, Alcohol 
Intake) – PD Subjects
IDSL
Y
Medical Conditions and Concomitant Medications
1.41.
Safety
MH4
Summary of Current Medical Conditions – ND Subjects
ICH E3
Y
1.42.
Safety
MH4
Summary of Current Medical Conditions – PD Subjects
ICH E3
Y
1.43.
Safety
MH4
Summary of Past Medical Conditions – ND Subjects
ICH E3
Y
1.44.
Safety
MH4
Summary of Past Medical Conditions – PD Subjects
ICH E3
Y
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
1.45.
Safety
CM1
Summary of Concomitant Medications (Pre-Therapy) – ND 
Subjects
ICH E3
Y
1.46.
Safety
CM1
Summary of Concomitant Medications (Pre-Therapy) – PD 
Subjects
ICH E3
Y
1.47.
Safety
CM1
Summary of Concomitant Medications (On-Therapy) – ND 
Subjects
ICH E3
Y
1.48.
Safety
CM1
Summary of Concomitant Medications (On-Therapy) – PD 
Subjects
ICH E3
Y
1.49.
Safety
CM1
Summary of Concomitant Medications (Post-Therapy) – ND 
Subjects
ICH E3
Y
1.50.
Safety
CM1
Summary of Concomitant Medications (Post-Therapy) – PD 
Subjects
ICH E3
Y
1.51.
Safety
CM1
Summary of Other Concomitant Medications (On-Therapy) – ND 
Subjects
Y
1.52.
Safety
CM1
Summary of Other Concomitant Medications (On-Therapy) – PD 
Subjects
Y
1.53.
Safety
POP_T2
Summary of Blood Products and Blood Supportive Care 
Products – ND Subjects
Y
1.54.
Safety
POP_T2
Summary of Blood Products and Blood Supportive Care 
Products – PD Subjects
Y
Exposure and Treatment Compliance
1.55.
Safety
EX1
Summary of Exposure to Study Treatment – ND Subjects
Y
1.56.
Safety
EX1
Summary of Exposure to Study Treatment – PD Subjects
Y
1.57.
Safety
POP_T4
Summary of Treatment Compliance – ND Subjects
Y
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
1.58.
Safety
POP_T4
Summary of Treatment Compliance – PD Subjects
Y
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15.10.4.2. Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
Hgb [general]
2.1.
ITT
EFF_T1
Summary of Hgb (g/dL) by Visit - ITT
Y
2.2.
Efficacy PD
EFF_T1
Summary of Hgb (g/dL) by Visit – Efficacy PD
Y
2.3.
ITT
EFF_T1
Summary of Hgb (g/dL) by Visit by Prior ESA and baseline Hgb–
ITT
Y
2.4.
Efficacy PD
EFF_T1
Summary of Hgb (g/dL) by Visit by Prior ESA and baseline Hgb–
Efficacy PD
Y
2.5.
ITT
EFF_T1
Summary of Change from Baseline in Hgb (g/dL) by Visit - ITT
Y
2.6.
Efficacy PD
EFF_T1
Summary of Change from Baseline in Hgb (g/dL) by Visit –
Efficacy PD
Y
2.7.
ITT
EFF_T1
Summary of Change from Baseline in Hgb (g/dL) by Visit by 
Prior ESA and baseline Hgb- ITT
Y
2.8.
Efficacy PD
EFF_T2
Summary of Change from Baseline in Hgb (g/dL) by Visit by 
Prior ESA and baseline Hgb – Efficacy PD
Y
Mean Hgb Based on Observed Hgb During the Primary Efficacy Evaluation Period
2.9.
mITT
EFF_T2
Summary of Mean Hgb (g/dL) Based on Observed Cases During 
the Primary Efficacy Evaluation Period – mITT
Y
2.10.
Efficacy PD
EFF_T2
Summary of Mean Hgb (g/dL) Based on Observed Cases During 
the Primary Efficacy Evaluation Period - Efficacy PD
Y
2.11.
Efficacy PD
EFF_T2
Summary of Mean Hgb (g/dL) Based on Observed Cases During 
the Primary Efficacy Evaluation Period by prior ESA use and by 
Baseline Hgb – Efficacy PD
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
Primary Efficacy Analyses: Model based Mean Hgb During the Primary Efficacy Evaluation Period
2.12.
ITT
EFF_T3
Analysis of Mean Hgb (g/dL) During the Primary Efficacy 
Evaluation Period - ITT
Y
2.13.
mITT
EFF_T3
Analysis of Mean Hgb (g/dL) During the Primary Efficacy 
Evaluation Period – mITT
Y
2.14.
PP
EFF_T3
Analysis of Mean Hgb (g/dL) During the Primary Efficacy 
Evaluation Period – PP
Y
2.15.
Efficacy ND
EFF_T3
Analysis of Mean Hgb (g/dL) During the Primary Efficacy 
Evaluation Period – Efficacy ND
Y
2.16.
ITT
EFF_T3
Analysis of Mean Hgb (g/dL) During the Primary Efficacy 
Evaluation Period – Subgroup
Y
Sensitivity Analyses
2.17.
ITT
EFF_T3
Sensitivity Analysis of Mean Hgb (g/dL) During the Primary 
Efficacy Evaluation Period Excluding ESA Users with Hgb Rapid 
Increase at Week 2
Y
2.18.
ITT
EFF_T3
Sensitivity Analysis of Mean Hgb (g/dL) During the Primary 
Efficacy Evaluation Period Using Evaluable Hgb
Y
2.19.
mITT
EFF_T3
Sensitivity Analysis of Mean Hgb (g/dL) During the Primary 
Efficacy Evaluation Period Using ANCOVA - mITT
Y
2.20.
PP
EFF_T3
Sensitivity Analysis of Mean Hgb (g/dL) During the Primary 
Efficacy Evaluation Period Using ANCOVA – PP
Y
2.21.
mITT
EFF_T3
Sensitivity Analysis of Mean Hgb (g/dL) During the Primary 
Efficacy Evaluation Period Using ANCOVA - Subgroup
Y
2.22.
ITT
EFF_T4
Tipping Point Summary for Non-Inferiority Test (Daprodustat vs 
Epoetin Beta Pegol) – ITT
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
2.23.
mITT
EFF_T4
Tipping Point Summary for Non-Inferiority Test (Daprodustat vs 
Epoetin Beta Pegol) – mITT
Y
2.24.
PP
EFF_T4
Tipping Point Summary for Non-Inferiority Test (Daprodustat vs 
Epoetin Beta Pegol) - PP
Y
Number (%) of Subjects with Mean Hgb in Target Range during the Primary Efficacy Evaluation Period
2.25.
mITT
EFF_T5
Analysis of Number (%) of Subjects with Mean Hgb in Target 
Range During the Primary Efficacy Evaluation Period - mITT
Y
2.26.
ITT
EFF_T5
Analysis of Number (%) of Subjects with Mean Hgb in Target 
Range During the Primary Efficacy Evaluation Period – ITT
Y
2.27.
PP
EFF_T5
Analysis of Number (%) of Subjects with Mean Hgb in Target 
Range During the Primary Efficacy Evaluation Period - PP
Y
2.28.
Efficacy ND
EFF_T5
Analysis of Number (%) of Subjects with Mean Hgb in Target 
Range During the Primary Efficacy Evaluation Period – Efficacy 
ND
Y
2.29.
mITT
EFF_T5
Analysis of Number (%) of Subjects with Mean Hgb in Target 
Range During the Primary Efficacy Evaluation Period -
Subgroup
Y
2.30.
Efficacy PD
EFF_T5
Summary of Number (%) of Subjects with Mean Hgb in Target 
Range During the Primary Efficacy Evaluation Period – Efficacy 
PD
Y
2.31.
Efficacy PD
EFF_T5
Summary of Number (%) of Subjects with Mean Hgb in Target 
Range During the Primary Efficacy Evaluation Period by 
Baseline Hgb – Efficacy PD
Y
Hgb
2.32.
ITT
EFF_T6
Summary of Number (%) of Subjects by Hgb Change from 
Baseline Category at Week 2 and 4 - ITT
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
2.33.
Efficacy PD
EFF_T6
Summary of Number (%) of Subjects by Hgb Change from 
Baseline Category at Week 4 – Efficacy PD
Y
2.34.
ITT
EFF_T6
Summary of Number (%) of Subjects by Hgb Change from 
Baseline Category at Week 2 and 4 by Prior ESA – ITT
Y
2.35.
Efficacy PD
EFF_T6
Summary of Number (%) of Subjects by Hgb Change from 
Baseline Category at Week 4 by Prior ESA – Efficacy PD
Y
2.36.
ITT
EFF_T7
Summary of Number (%) of Subjects with Hgb within the Target 
Range by Visit - ITT
Y
2.37.
Efficacy PD
EFF_T7
Summary of Number (%) of Subjects with Hgb within the Target 
Range by Visit – Efficacy PD
Y
2.38.
ITT
EFF_T8
Summary of Time (%) in Hgb Target Range During the Primary 
Efficacy Evaluation Period – ITT
Y
2.39.
Efficacy PD
EFF_T8
Summary of Time (%) in Hgb Target Range During the Primary 
Efficacy Evaluation Period – Efficacy PD
Y
2.40.
ITT
EFF_T8
Summary of Time (%) in Hgb Target Range During the Primary 
Efficacy Evaluation Period by Prior ESA Use - ITT
Y
2.41.
Efficacy PD
EFF_T8
Summary of Time (%) in Hgb Target Range During the Primary 
Efficacy Evaluation Period by Prior ESA Use – Efficacy PD
Y
2.42.
ITT
EFF_T8A
Summary of Time (days) to Reach the Lower Hgb Target 
(11.0 g/dL) – ITT
Y
2.43.
Efficacy PD
EFF_T8A
Summary of Time (days) to Reach the Lower Hgb Target 
(11.0 g/dL) – Efficacy PD
Y
2.44.
ITT
EFF_T8A
Summary of Time (days) to Reach the Lower Hgb Target 
(11.0 g/dL) by Prior ESA Use - ITT
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
2.45.
Efficacy PD
EFF_T8A
Summary of Time (days) to reach the Lower Hgb Target 
(11.0 g/dL) by Prior ESA Use – Efficacy PD
Y
2.46.
ITT
EFF_T9
Summary of Number (%) of Subjects Who Have Hgb Level of 
Less than 7.5 g/dL - ITT
Y
2.47.
Efficacy PD
EFF_T9
Summary of Number (%) of Subjects Who Have Hgb Level of 
Less than 7.5 g/dL – Efficacy PD
Y
2.48.
ITT
EFF_T9
Summary of Number (%) of Subjects Who Have Hgb Level of 
Less than 7.5 g/dL by Prior ESA Use - ITT
Y
2.49.
Efficacy PD
EFF_T9
Summary of Number (%) of Subjects Who Have Hgb Level of 
Less than 7.5 g/dL by Prior ESA Use – Efficacy PD
Y
2.50.
ITT
EFF_T9
Summary of Number (%) of Subjects Who Have Hgb Increase of 
More than 2.0 g/dL over Any 4 weeks - ITT
Y
2.51.
Efficacy PD
EFF_T9
Summary of Number (%) of Subjects Who Have Hgb Increase of 
More than 2.0 g/dL over Any 4 weeks – Efficacy PD
Y
2.52.
ITT
EFF_T9
Summary of Number (%) of Subjects Who Have Hgb Increase of 
More than 2.0 g/dL over Any 4 weeks by Prior ESA Use - ITT
Y
2.53.
Efficacy PD
EFF_T9
Summary of Number (%) of Subjects Who Have Hgb Increase of 
More than 2.0 g/dL over Any 4 weeks by Prior ESA Use –
Efficacy PD
Y
2.54.
ITT
EFF_T10
Summary of Number (%) of Subjects Who Have Hgb Level of 
More than 13.0 g/dL and Number of Episodes - ITT
Y
2.55.
Efficacy PD
EFF_T10
Summary of Number (%) of Subjects Who Have Hgb Level of 
More than 13.0 g/dL and Number of Episodes – Efficacy PD
Y
2.56.
ITT
EFF_T10
Summary of Number (%) of Subjects Who Have Hgb Level of 
More than 13.0 g/dL and Number of Episodes by Prior ESA Use
- ITT
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
2.57.
Efficacy PD
EFF_T10
Summary of Number (%) of Subjects Who Have Hgb Level of 
More than 13.0 g/dL and Number of Episodes by Prior ESA Use
– Efficacy PD
Y
Dose Adjustment
2.58.
ITT
EFF_T11
Summary of Dose by Visit – ITT
Y
2.59.
Efficacy PD
EFF_T11
Summary of Dose by Visit – Efficacy PD
Y
2.60.
ITT
EFF_T11
Summary of Dose by Visit by Prior ESA- ITT
Y
2.61.
Efficacy PD
EFF_T11
Summary of Dose by Visit by Prior ESA– Efficacy PD
Y
2.62.
ITT
EFF_T14
Summary of Duration (days) of Treatment Interruption due to 
Hgb >13.0 g/dL - ITT
Y
2.63.
Efficacy PD
EFF_T14
Summary of Duration (days) of Treatment Interruption due to 
Hgb >13.0 g/dL – Efficacy PD
Y
2.64.
ITT
EFF_T14
Summary of Duration (days) of Treatment Interruption due to 
Hgb >13.0 g/dL by Prior ESA Use - ITT
Y
2.65.
Efficacy PD
EFF_T14
Summary of Duration (days) of Treatment Interruption due to 
Hgb >13.0 g/dL by Prior ESA Use – Efficacy PD
Y
2.66.
ITT
EFF_T15
Summary of Dose Adjustment - ITT
Y
2.67.
Efficacy PD
EFF_T15
Summary of Dose Adjustment – Efficacy PD
Y
2.68.
ITT
EFF_T15
Summary of Dose Adjustment by Prior ESA Use - ITT
Y
2.69.
Efficacy PD
EFF_T15
Summary of Dose Adjustment by Prior ESA Use – Efficacy PD
Y
2.70.
ITT
EFF_T15
Summary of Dose Adjustment to Reach the Lower Hgb Target 
(11.0 g/dL) – ITT
Y
2.71.
Efficacy PD
EFF_T15
Summary of Dose Adjustment to Reach the Lower Hgb Target 
(11.0 g/dL) – Efficacy PD
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
2.72.
ITT
EFF_T15
Summary of Dose Adjustment to Reach the Lower Hgb Target 
(11.0 g/dL) by Prior ESA Use - ITT
Y
2.73.
Efficacy PD
EFF_T15
Summary of Dose Adjustment to Reach the Lower Hgb Target 
(11.0 g/dL) by Prior ESA Use – Efficacy PD
Y
2.74.
ITT
EFF_T12
Summary of Number (%) of Subjects with Each Dose for 
Daprodustat by Visit - ITT
Y
2.75.
ITT
EFF_T13
Summary of Number (%) of Subjects with Each Dose for Epoetin 
Beta Pegol by Visit - ITT
Y
2.76.
Efficacy PD
EFF_T12
Summary of Number (%) of Subjects with Each Dose for 
Daprodustat by Visit – Efficacy PD
Y
2.77.
ITT
EFF_T12
Summary of Number (%) of Subjects with Each Dose for 
Daprodustat by Visit by Prior ESA- ITT
Y
2.78.
ITT
EFF_T13
Summary of Number (%) of Subjects with Each Dose for Epoetin 
Beta Pegol by Visit by Prior ESA- ITT
Y
2.79.
Efficacy PD
EFF_T12
Summary of Number (%) of Subjects with Each Dose for 
Daprodustat by Visit by Prior ESA– Efficacy PD
Y
Iron Use
2.80.
ITT
EFF_T16
Summary of Dose of Oral Iron (mg) During the Treatment Period
– ITT
Y
2.81.
Efficacy PD
EFF_T16
Summary of Dose of Oral Iron (mg) During the Treatment Period
– Efficacy PD
Y
2.82.
ITT
EFF_T16
Summary of Dose of Oral Iron (mg) Change from Baseline 
During the Treatment Period - ITT
Y
2.83.
Efficacy PD
EFF_T16
Summary of Dose of Oral Iron (mg) Change from Baseline 
During the Treatment Period – Efficacy PD
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
2.84.
ITT
EFF_T16
Summary of Dose of Oral Iron (mg) During the Treatment Period 
by Baseline Iron Use – ITT
Y
2.85.
Efficacy PD
EFF_T16
Summary of Dose of Oral Iron (mg) During the Treatment Period 
by Baseline Iron Use – Efficacy PD
Y
2.86.
ITT
EFF_T17
Summary of Number (%) of Subjects with Iron Use During the 
Treatment Period – ITT
Y
2.87.
Efficacy PD
EFF_T17
Summary of Number (%) of Subjects with Iron Use During the 
Treatment Period – Efficacy PD
Y
2.88.
ITT
EFF_T17
Summary of Number (%) of Subjects with Iron Use During the 
Treatment Period by Baseline Iron Use – ITT
Y
2.89.
Efficacy PD
EFF_T17
Summary of Number (%) of Subjects with Iron Use During the 
Treatment Period by Baseline Iron Use – Efficacy PD
Y
Iron Parameters (ferritin, TSAT, hepcidin, serum iron, and TIBC)
2.90.
ITT
LB1
Summary of Ferritin (ug/L) by Visit – ITT
Y
2.91.
Efficacy PD
LB1
Summary of Ferritin (ug/L) by Visit – Efficacy PD
Y
2.92.
ITT
LB1
Summary of Ferritin (ug/L) Change from Baseline by Visit - ITT
Y
2.93.
Efficacy PD
LB1
Summary of Ferritin (ug/L) Change from Baseline by Visit –
Efficacy PD
Y
2.94.
ITT
EFF_T18
Summary of Transferrin Saturation (%) by Visit - ITT
Y
2.95.
Efficacy PD
EFF_T18
Summary of Transferrin Saturation (%) by Visit – Efficacy PD
Y
2.96.
ITT
EFF_T19
Summary of Transferrin Saturation (%) Percent Change from 
Baseline by Visit - ITT
Y
2.97.
Efficacy PD
EFF_T19
Summary of Transferrin Saturation (%) Percent Change from 
Baseline by Visit – Efficacy PD
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
2.98.
ITT
EFF_T18
Summary of Hepcidin (nmol/L) by Visit - ITT
Y
2.99.
Efficacy PD
EFF_T18
Summary of Hepcidin (nmol/L) by Visit – Efficacy PD
Y
2.100.
ITT
EFF_T19
Summary of Hepcidin (nmol/L) Percent Change from Baseline 
by Visit – ITT
Y
2.101.
Efficacy PD
EFF_T19
Summary of Hepcidin (nmol/L) Percent Change from Baseline 
by Visit – Efficacy PD
Y
2.102.
ITT
LB1
Summary of Serum Iron (umol/L) by Visit - ITT
Y
2.103.
Efficacy PD
LB1
Summary of Serum Iron (umol/L) by Visit – Efficacy PD
Y
2.104.
ITT
LB1
Summary of Serum Iron (umol/L) Change from Baseline by Visit
- ITT
Y
2.105.
Efficacy PD
LB1
Summary of Serum Iron (umol/L) Change from Baseline by Visit 
– Efficacy PD
Y
2.106.
ITT
LB1
Summary of Total Iron Binding Capacity (umol/L) by Visit - ITT
Y
2.107.
Efficacy PD
LB1
Summary of Total Iron Binding Capacity (umol/L) by Visit –
Efficacy PD
Y
2.108.
ITT
LB1
Summary of Total Iron Binding Capacity (umol/L) Change from 
Baseline by Visit - ITT
Y
2.109.
Efficacy PD
LB1
Summary of Total Iron Binding Capacity (umol/L) Change from 
Baseline by Visit – Efficacy PD
Y
2.110.
ITT
LB1
Summary of Ferritin (ug/L) by Visit by Subgroup - ITT
baseline iron use, prior ESA use
Y
2.111.
Efficacy PD
LB1
Summary of Ferritin (ug/L) by Visit by Subgroup – Efficacy PD
baseline iron use, prior ESA use
Y
2.112.
ITT
LB1
Summary of Ferritin (ug/L) Change from Baseline by Visit by 
Subgroup - ITT
baseline iron use, prior ESA use
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
2.113.
Efficacy PD
LB1
Summary of Ferritin (ug/L) Change from Baseline by Visit by 
Subgroup – Efficacy PD
baseline iron use, prior ESA use
Y
2.114.
ITT
EFF_T18
Summary of Transferrin Saturation (%) by Visit by Subgroup -
ITT
baseline iron use, prior ESA use
Y
2.115.
Efficacy PD
EFF_T18
Summary of Transferrin Saturation (%) by Visit by Subgroup –
Efficacy PD
baseline iron use, prior ESA use
Y
2.116.
ITT
EFF_T19
Summary of Transferrin Saturation (%) Percent Change from 
Baseline by Visit by Subgroup - ITT
baseline iron use, prior ESA use
Y
2.117.
Efficacy PD
EFF_T19
Summary of Transferrin Saturation (%) Percent Change from 
Baseline by Visit by Subgroup – Efficacy PD
baseline iron use, prior ESA use
Y
2.118.
ITT
EFF_T18
Summary of Hepcidin (nmol/L) by Visit by Subgroup - ITT
baseline iron use, prior ESA use
Y
2.119.
Efficacy PD
EFF_T18
Summary of Hepcidin (nmol/L) by Visit by Subgroup – Efficacy 
PD
baseline iron use, prior ESA use
Y
2.120.
ITT
EFF_T19
Summary of Hepcidin (nmol/L) Percent Change from Baseline 
by Visit by Subgroup –– ITT
baseline iron use, prior ESA use
Y
2.121.
Efficacy PD
EFF_T19
Summary of Hepcidin (nmol/L) Percent Change from Baseline 
by Visit by Subgroup – Efficacy PD
baseline iron use, prior ESA use
Y
2.122.
ITT
LB1
Summary of Serum Iron (umol/L) by Visit by Subgroup - ITT
baseline iron use, prior ESA use
Y
2.123.
Efficacy PD
LB1
Summary of Serum Iron (umol/L) by Visit by Subgroup – Efficacy 
PD
baseline iron use, prior ESA use
Y
2.124.
ITT
LB1
Summary of Serum Iron (umol/L) Change from Baseline by Visit
by Subgroup - ITT
baseline iron use, prior ESA use
Y
2.125.
Efficacy PD
LB1
Summary of Serum Iron (umol/L) Change from Baseline by Visit
by Subgroup – Efficacy PD
baseline iron use, prior ESA use
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
2.126.
ITT
LB1
Summary of Total Iron Binding Capacity (umol/L) by Visit by 
Subgroup - ITT
baseline iron use, prior ESA use
Y
2.127.
Efficacy PD
LB1
Summary of Total Iron Binding Capacity (umol/L) by Visit by 
Subgroup – Efficacy PD
baseline iron use, prior ESA use
Y
2.128.
ITT
LB1
Summary of Total Iron Binding Capacity (umol/L) Change from 
Baseline by Visit by Subgroup - ITT
baseline iron use, prior ESA use
Y
2.129.
Efficacy PD
LB1
Summary of Total Iron Binding Capacity (umol/L) Change from 
Baseline by Visit by Subgroup – Efficacy PD
baseline iron use, prior ESA use
Y
CKD Progression
2.130.
ITT
LB1
Summary of CKD Progression by Visit
Y
2.131.
ITT
LB1
Summary of CKD Progression Change from Baseline by Visit
Y
2.132.
ITT
EFF_T20T20
Summary of Number (%) of Subjects with eGFR Decrease of 
30% or More from Baseline
Y
2.133.
ITT
EFF_T20T20
Summary of Number (%) of Subjects with Serum Creatinine 
Increase of More Than Double from Baseline
Y
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15.10.4.3. Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Raw Mean Hgb During the Primary Efficacy Evaluation Period
2.1.
ITT
EFF_F1
Plot of Mean Change from Baseline in Hgb (g/dL) and 95% CIs 
over Time by Treatment – ITT
Y
2.2.
Efficacy PD
EFF_F1
Plot of Mean Change from Baseline in Hgb (g/dL) and 95% CIs 
over Time by Treatment – Efficacy PD
Y
2.3.
ITT
EFF_F1
Plot of Mean Change from Baseline in Hgb (g/dL) and 95% CIs 
over Time by Treatment by Prior ESA Use and Baseline Hgb –
ITT
Y
2.4.
Efficacy PD
EFF_F1
Plot of Mean Change from Baseline in Hgb (g/dL) and 95% CIs 
over Time by Treatment by Prior ESA Use and Baseline Hgb–
Efficacy PD
Y
2.5.
ITT
EFF_F1
Plot of Mean Hgb (g/dL) and 95% CIs over Time by Treatment –
ITT
Y
2.6.
Efficacy PD
EFF_F1
Plot of Mean Hgb (g/dL) and 95% CIs over Time by Treatment –
Efficacy PD
Y
2.7.
ITT
EFF_F1
Plot of Mean Hgb (g/dL) and 95% CIs over Time by Treatment 
by Prior ESA Use and Baseline Hgb – ITT
Y
2.8.
Efficacy PD
EFF_F1
Plot of Mean Hgb (g/dL) and 95% CIs over Time by Treatment 
by Prior ESA Use and Baseline Hgb – Efficacy PD
Y
Model-Based Mean Hgb During the Primary Efficacy Evaluation Period
2.9.
ITT
EFF_F2
Hgb Curve over Time (with 95% Confidence Band) by Mixed 
Model for Repeated Measures by Treatment – ITT
Y
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
2.10.
mITT
EFF_F2
Sensitivity Hgb Curve over Time (with 95% Confidence Band) by 
Mixed Model for Repeated Measures by Treatment - mITT
Y
2.11.
PP
EFF_F2
Sensitivity Hgb Curve over Time (with 95% Confidence Band) by 
Mixed Model for Repeated Measures by Treatment - PP
Y
2.12.
Efficacy ND
EFF_F2
Sensitivity Hgb Curve over Time (with 95% Confidence Band) by 
Mixed Model for Repeated Measures by Treatment – Efficacy 
ND
Y
2.13.
ITT
EFF_F2
Sensitivity Hgb Curve over Time (with 95% Confidence Band) by 
Mixed Model for Repeated Measures by Treatment – Excluding 
ESA Users with Hgb Rapid Increase at Week 2
Y
2.14.
ITT
EFF_F2
Sensitivity Hgb Curve over Time (with 95% Confidence Band) by 
Mixed Model for Repeated Measures by Treatment – Evaluable 
Hgb
Y
2.15.
ITT
EFF_F3
Forest Plot of Model-Adjusted Treatment Difference 
(Daprodustat vs Epoetin Beta Pegol) for Mean Hgb (g/dL) 
During the Primary Efficacy Evaluation Period by Subgroup -
MMRM
Y
2.16.
ITT
EFF_F2
Hgb Curve over Time (with 95% Confidence Band) by Mixed 
Model for Repeated Measures by Treatment by Prior ESA Use –
ITT
Y
2.17.
mITT
EFF_F3
Sensitivity Forest Plot of Model-Adjusted Treatment Difference 
(Daprodustat vs Epoetin Beta Pegol) for Mean Hgb (g/dL) 
During the Primary Efficacy Evaluation Period by Subgroup -
ANCOVA
Y
2.18.
ITT
EFF_F4
Tipping Point Display for Non-Inferiority Test (Daprodustat vs 
Epoetin Beta Pegol) – ITT
Y
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
2.19.
mITT
EFF_F4
Tipping Point Display for Non-Inferiority Test (Daprodustat vs 
Epoetin Beta Pegol) – mITT
Y
2.20.
PP
EFF_F4
Tipping Point Display for Non-Inferiority Test (Daprodustat vs 
Epoetin Beta Pegol) - PP
Y
Number (%) of Subjects with Mean Hgb in Target Range During the Primary Efficacy Evaluation Period
2.21.
mITT
EFF_F5
Forest Plot of Model-Adjusted Odds Ratio (Daprodustat / 
Epoetin Beta Pegol) for Proportion of Subjects with Mean Hgb in 
the Target Range During the Primary Efficacy Evaluation Period 
by Subgroup
Y
Hgb
2.22.
ITT
EFF_F6
Figure of Number (%) of Subjects with Hgb within the Target 
Range over Time - ITT
Like Fig. 2.7.6.2.3.1-2 in NESP CTD 2.7.6
Y
2.23.
Efficacy PD
EFF_F6
Figure of Number (%) of Subjects with Hgb within the Target 
Range over Time – Efficacy PD
Like Fig. 2.7.6.2.3.1-2 in NESP CTD 2.7.6
Y
2.24.
ITT
AE11
Cumulative Distribution of Time (days) to Reach the Lower Hgb 
Target (11.0 g/dL) - ITT
Y
2.25.
Efficacy PD
AE11
Cumulative Distribution of Time (days) to Reach the Lower Hgb 
Target (11.0 g/dL) – Efficacy PD
Y
2.26.
ITT
AE11
Cumulative Distribution of Time (days) to Reach the Lower Hgb 
Target (11.0 g/dL) by Prior ESA Use - ITT
Y
2.27.
Efficacy PD
AE11
Cumulative Distribution of Time (days) to Reach the Lower Hgb 
Target (11.0 g/dL) by Prior ESA Use – Efficacy PD
Y
2.28.
ITT
EFF_F7
Scatter Plot of Hgb Assessments: Central Laboratory vs. 
HemoCue - ITT
Y
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
2.29.
Efficacy PD
EFF_F7
Scatter Plot of Hgb Assessments: Central Laboratory vs. 
HemoCue – Efficacy PD
Y
Dose Adjustment
2.30.
ITT
EFF_F8
Histogram of Daprodustat Dose (mg) by Visit - ITT
Y
2.31.
ITT
EFF_F8
Histogram of Epoetin Beta Pegol Dose (ug) by Visit - ITT
Y
2.32.
Efficacy PD
EFF_F8
Histogram of Daprodustat Dose (mg) by Visit – Efficacy PD
Y
2.33.
ITT
EFF_F8
Histogram of Daprodustat Dose (mg) by Visit by Prior ESA – ITT
Y
2.34.
ITT
EFF_F8
Histogram of Epoetin Beta Pegol Dose (mg) by Visit by Prior 
ESA – ITT
Y
2.35.
Efficacy PD
EFF_F8
Histogram of Daprodustat Dose (ug) by Visit by Prior ESA –
Efficacy PD
Y
Subject Listing
2.36.
ITT
EFF_F9
Subject Profiles of Hgb and Dose over Time - ITT
Y
2.37.
Efficacy PD
EFF_F9
Subject Profiles of Hgb and Dose over Time – Efficacy PD
Y
Iron Parameters
2.38.
ITT
EFF_F1
Plot of Mean Ferritin (ug/L) Change from Baseline and 95% 
CIover Time – ITT
Y
2.39.
Efficacy PD
EFF_F1
Plot of Mean Ferritin (ug/L) Change from Baseline and 95% CI 
over Time – Efficacy PD
Y
2.40.
ITT
EFF_F1
Plot of Geometric Mean Transferrin Saturation Percent Change 
from Baseline and 95% CI over Time – ITT
Y
2.41.
Efficacy PD
EFF_F1
Plot of Geometric Mean Transferrin Saturation Percent Change 
from Baseline and 95% CI over Time – Efficacy PD
Y
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
2.42.
ITT
EFF_F1
Plot of Geometric Mean Hepcidin Percent Change from Baseline 
and 95% CI over Time – ITT
Y
2.43.
Efficacy PD
EFF_F1
Plot of Geometric Mean Hepcidin Percent Change from Baseline
and 95% CI over Time – Efficacy PD
Y
2.44.
ITT
EFF_F1
Plot of Mean Serum Iron (umol/L) Change from Baseline and 
95% CI over Time - ITT
Y
2.45.
Efficacy PD
EFF_F1
Plot of Mean Serum Iron (umol/L) Change from Baseline and 
95% CI over Time – Efficacy PD
Y
2.46.
ITT
EFF_F1
Plot of Mean Total Iron Binding Capacity (umol/L) Change from 
Baseline and 95% CI over Time – ITT
Y
2.47.
Efficacy PD
EFF_F1
Plot of Mean Total Iron Binding Capacity (umol/L) Change from 
Baseline and 95% CI over Time – Efficacy PD
Y
2.48.
ITT
EFF_F1
Plot of Mean Ferritin (ug/L) Change from Baseline and 95% CI 
over Time by Baseline Iron Use – ITT
Y
2.49.
Efficacy PD
EFF_F1
Plot of Mean Ferritin (ug/L) Change from Baseline and 95% CI 
over Time by Baseline Iron Use – Efficacy PD
Y
2.50.
ITT
EFF_F1
Plot of Geometric Mean Transferrin Saturation Percent Change 
from Baseline and 95% CI over Time by Baseline Iron Use – ITT
Y
2.51.
Efficacy PD
EFF_F1
Plot of Geometric Mean Transferrin Saturation Percent Change 
from Baseline and 95% CI over Time by Baseline Iron Use –
Efficacy PD
Y
2.52.
ITT
EFF_F1
Plot of Geometric Mean Hepcidin Percent Change from Baseline 
over Time and 95% CI by Baseline Iron Use - ITT
Y
2.53.
Efficacy PD
EFF_F1
Plot of Geometric Mean Hepcidin Percent Change from Baseline 
over Time and 95% CI by Baseline Iron Use – Efficacy PD
Y
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
2.54.
ITT
EFF_F1
Plot of Mean Serum Iron (umol/L) Change from Baseline and 
95% CI over Time by Baseline Iron Use – ITT
Y
2.55.
Efficacy PD
EFF_F1
Plot of Mean Serum Iron (umol/L) Change from Baseline and 
95% CI over Time by Baseline Iron Use – Efficacy PD
Y
2.56.
ITT
EFF_F1
Plot of Mean Total Iron Binding Capacity (umol/L) Change from 
Baseline and 95% CI over Time by Baseline Iron Use – ITT
Y
2.57.
Efficacy PD
EFF_F1
Plot of Mean Total Iron Binding Capacity (umol/L) Change from 
Baseline and 95% CI over Time by Baseline Iron Use – Efficacy 
PD
Y
2.58.
ITT
EFF_F1
Plot of Mean Ferritin (ug/L) and 95% CI over Time - ITT
Y
2.59.
Efficacy PD
EFF_F1
Plot of Mean Ferritin (ug/L) and 95% CI over Time - Efficacy PD
Y
2.60.
ITT
EFF_F1
Plot of Geometric Mean Transferrin Saturation (%) and 95% CI 
over Time – ITT
Y
2.61.
Efficacy PD
EFF_F1
Plot of Geometric Mean Transferrin Saturation (%) and 95% CI 
over Time – Efficacy PD
Y
2.62.
ITT
EFF_F1
Plot of Geometric Mean Hepcidin (nmol/L) and 95% CI over 
Time – ITT
Y
2.63.
Efficacy PD
EFF_F1
Plot of Geometric Mean Hepcidin (nmol/L) and 95% CI over 
Time – Efficacy PD
Y
2.64.
ITT
EFF_F1
Plot of Mean Serum Iron (umol/L) and 95% CI over Time – ITT
Y
2.65.
Efficacy PD
EFF_F1
Plot of Mean Serum Iron (umol/L) and 95% CI over Time –
Efficacy PD
Y
2.66.
ITT
EFF_F1
Plot of Mean Total Iron Binding Capacity (umol/L) and 95% CI 
over Time – ITT
Y
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
2.67.
Efficacy PD
EFF_F1
Plot of Mean Total Iron Binding Capacity (umol/L) and 95% CI 
over Time – Efficacy PD
Y
2.68.
ITT
EFF_F1
Plot of Mean Ferritin (ug/L) and 95% CI over Time by Baseline 
Iron Use – ITT
Y
2.69.
Efficacy PD
EFF_F1
Plot of Mean Ferritin (ug/L) and 95% CI over Time by Baseline 
Iron Use – Efficacy PD
Y
2.70.
ITT
EFF_F1
Plot of Geometric Mean Transferrin Saturation (%) and 95% CI 
over time by Baseline Iron Use – ITT
Y
2.71.
Efficacy PD
EFF_F1
Plot of Geometric Mean Transferrin Saturation (%) and 95% CI 
over time by Baseline Iron Use – Efficacy PD
Y
2.72.
ITT
EFF_F1
Plot of Geometric Mean Hepcidin (nmol/L) and 95% CI over 
Time by Baseline Iron Use – ITT
Y
2.73.
Efficacy PD
EFF_F1
Plot of Geometric Mean Hepcidin (nmol/L) and 95% CI over 
Time by Baseline Iron Use – Efficacy PD
Y
2.74.
ITT
EFF_F1
Plot of Mean Serum Iron (umol/L) and 95% CI over Time by 
Baseline Iron Use – ITT
Y
2.75.
Efficacy PD
EFF_F1
Plot of Mean Serum Iron (umol/L) and 95% CI over Time by 
Baseline Iron Use – Efficacy PD
Y
2.76.
ITT
EFF_F1
Plot of Mean Total Iron Binding Capacity (umol/L) and 95% CI 
over Time by Baseline Iron Use – ITT
Y
2.77.
Efficacy PD
EFF_F1
Plot of Mean Total Iron Binding Capacity (umol/L) and 95% CI 
over Time by Baseline Iron Use – Efficacy PD
Y
Other
2.78.
ITT
EFF_F1
Plot of Mean and 95% CI for CKD Progression by Visit
Y
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
2.79.
ITT
EFF_F1
Plot of Mean and 95% CI for CKD Progression Change from 
Baseline over Time
Y
2.80.
ITT
EFF_F10
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. Body 
Weight - ITT
Y
2.81.
ITT
EFF_F10
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. 
Baseline Hgb - ITT
Y
2.82.
ITT
EFF_F10
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. Prior 
ESA Dose - ITT
Y
2.83.
ITT
EFF_F10
Scatter Plot of Mean Dose During Week 40 to 52 vs. Body 
Weight – ITT
Y
2.84.
ITT
EFF_F10
Scatter Plot of Mean Dose During Week 40 to 52 vs. Baseline 
Hgb – ITT
Y
2.85.
ITT
EFF_F10
Scatter Plot of Mean Dose During Week 40 to 52 vs. Prior ESA 
Dose - ITT
Y
2.86.
Efficacy PD
EFF_F10
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. Body 
Weight – Efficacy PD
Y
2.87.
Efficacy PD
EFF_F10
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. 
Baseline Hgb – Efficacy PD
Y
2.88.
Efficacy PD
EFF_F10
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. Prior 
ESA Dose – Efficacy PD
Y
2.89.
Efficacy PD
EFF_F10
Scatter Plot of Mean Dose During Week 40 to 52 vs. Body 
Weight – Efficacy PD
Y
2.90.
Efficacy PD
EFF_F10
Scatter Plot of Mean Dose During Week 40 to 52 vs. Baseline 
Hgb – Efficacy PD
Y
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
2.91.
Efficacy PD
EFF_F10
Scatter Plot of Mean Dose During Week 40 to 52 vs. Prior ESA 
Dose – Efficacy PD
Y
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15.10.4.4. Safety Tables
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Adverse Events (AEs)
3.1.
Safety
AE1
Summary of On-Therapy AEs by SOC and PT – ND Subjects
ICH E3
Y
3.2.
Safety
AE1
Summary of On-Therapy AEs by SOC and PT – PD Subjects
ICH E3
Y
3.3.
Safety
AE1
Summary of On-Therapy AEs by SOC and PT by Prior ESA Use
– ND Subjects
Y
3.4.
Safety
AE1
Summary of On-Therapy AEs by SOC and PT by Prior ESA Use 
– PD Subjects
Y
3.5.
Safety
AE1
Summary of On-Therapy AEs by SOC and PT by CKD Stage –
ND Subjects
Y
3.6.
Safety
AE1
Summary of On-Therapy AEs by SOC and PT by CKD Stage –
PD Subjects
Y
3.7.
Safety
AE5
Summary of On-Therapy AEs by SOC and PT and Maximum 
Intensity – ND Subjects
ICH E3
Y
3.8.
Safety
AE5
Summary of On-Therapy AEs by SOC and PT and Maximum 
Intensity – PD Subjects
ICH E3
Y
3.9.
Safety
AE5
Summary of On-Therapy AEs by SOC and PT and Maximum 
Intensity by Prior ESA Use – ND Subjects
Y
3.10.
Safety
AE5
Summary of On-Therapy AEs by SOC and PT and Maximum 
Intensity by Prior ESA Use – PD Subjects
Y
3.11.
Safety
AE1
Summary of On-Therapy AEs up to Week 4 by SOC and PT –
ND Subjects
Y
3.12.
Safety
AE1
Summary of On-Therapy AEs up to Week 4 by SOC and PT –
PD Subjects
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
3.13.
Safety
AE1
Summary of On-Therapy AEs up to Week 4 by SOC and PT by 
Prior ESA Use – ND Subjects
Y
3.14.
Safety
AE1
Summary of On-Therapy AEs up to Week 4 by SOC and PT by 
Prior ESA Use – PD Subjects
Y
3.15.
Safety
AE1
Summary of On-Therapy AEs up to Week 4 by SOC and PT by 
Starting Dose of Daprodustat – ND Subjects
Y
3.16.
Safety
AE1
Summary of On-Therapy AEs up to Week 4 by SOC and PT by 
Starting Dose of Daprodustat – PD Subjects
Y
3.17.
Safety
AE5
Summary of On-Therapy AEs up to Week 4 by SOC and PT and 
Maximum Intensity – ND Subjects
Y
3.18.
Safety
AE5
Summary of On-Therapy AEs up to Week 4 by SOC and PT and 
Maximum Intensity – PD Subjects
Y
3.19.
Safety
AE5
Summary of On-Therapy AEs up to Week 4 by SOC and PT and 
Maximum Intensity by Prior ESA Use – ND Subjects
Y
3.20.
Safety
AE5
Summary of On-Therapy AEs up to Week 4 by SOC and PT and 
Maximum Intensity by Prior ESA Use – PD Subjects
Y
3.21.
Safety
SAFE_T1
Summary of On-Therapy Common (>= 2 %) AEs by SOC and 
PT by Onset – ND Subjects
Not cumulative summary
Y
3.22.
Safety
SAFE_T1
Summary of On-Therapy Common (>= 2 %) AEs by SOC and 
PT by Onset – PD Subjects
Not cumulative summary
Y
3.23.
Safety
AE1
Summary of Post-Therapy AEs by SOC and PT – ND Subjects
ICH E3
Y
3.24.
Safety
AE1
Summary of Post-Therapy AEs by SOC and PT – PD Subjects
ICH E3
Y
3.25.
Safety
AE5
Summary of Post-Therapy AEs by SOC and PT and Maximum 
Intensity – ND Subjects
ICH E3
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
3.26.
Safety
AE5
Summary of Post-Therapy AEs by SOC and PT and Maximum 
Intensity – PD Subjects
ICH E3
Y
3.27.
Safety
AE1
Summary of On-Therapy Drug-Related AEs by SOC and PT –
ND Subjects
ICH E3
Y
3.28.
Safety
AE1
Summary of On-Therapy Drug-Related AEs by SOC and PT –
PD Subjects
ICH E3
Y
3.29.
Safety
AE1
Summary of On-Therapy Drug-Related AEs by SOC and PT by 
Prior ESA Use – ND Subjects
Y
3.30.
Safety
AE1
Summary of On-Therapy Drug-Related AEs by SOC and PT by 
Prior ESA Use – PD Subjects
Y
3.31.
Safety
AE1
Summary of On-Therapy Drug-Related AEs by SOC and PT by 
CKD Stage – ND Subjects
Y
3.32.
Safety
AE1
Summary of On-Therapy Drug-Related AEs by SOC and PT by 
CKD Stage – PD Subjects
Y
3.33.
Safety
AE5
Summary of On-Therapy Drug-Related AEs by SOC and PT and 
Maximum Intensity – ND Subjects
ICH E3
Y
3.34.
Safety
AE5
Summary of On-Therapy Drug-Related AEs by SOC and PT and 
Maximum Intensity – PD Subjects
ICH E3
Y
3.35.
Safety
AE1
Summary of On-Therapy Drug-Related AEs up to Week 4 by 
SOC and PT – ND Subjects
Y
3.36.
Safety
AE1
Summary of On-Therapy Drug-Related AEs up to Week 4 by 
SOC and PT – PD Subjects
Y
3.37.
Safety
AE1
Summary of On-Therapy Drug-Related AEs up to Week 4 by 
SOC and PT by Prior ESA Use – ND Subjects
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
3.38.
Safety
AE1
Summary of On-Therapy Drug-Related AEs up to Week 4 by 
SOC and PT by Prior ESA Use – PD Subjects
Y
3.39.
Safety
AE5
Summary of On-Therapy Drug-Related AEs up to Week 4 by 
SOC and PT and Maximum Intensity – ND Subjects
Y
3.40.
Safety
AE5
Summary of On-Therapy Drug-Related AEs up to Week 4 by 
SOC and PT and Maximum Intensity – PD Subjects
Y
3.41.
Safety
AE1
Summary of Post-Therapy Drug-Related AEs by SOC and PT –
ND Subjects
Y
3.42.
Safety
AE1
Summary of Post-Therapy Drug-Related AEs by SOC and PT –
PD Subjects
Y
3.43.
Safety
AE5
Summary of Post-Therapy Drug-Related AEs by SOC and PT 
and Maximum Intensity – ND Subjects
Y
3.44.
Safety
AE5
Summary of Post-Therapy Drug-Related AEs by SOC and PT 
and Maximum Intensity – PD Subjects
Y
3.45.
Safety
AE3
Summary of On-Therapy Non-Serious Drug-Related AEs – ND 
Subjects
Required for Plain Language Summary
Y
3.46.
Safety
AE3
Summary of On-Therapy Non-Serious Drug-Related AEs – PD 
Subjects
Required for Plain Language Summary
Y
3.47.
Safety
AE3
Summary of On-Therapy Common (>= 2 %) AEs by Overall 
Frequency – ND Subjects
ICH E3
Y
3.48.
Safety
AE3
Summary of On-Therapy Common (>= 2 %) AEs by Overall 
Frequency – PD Subjects
ICH E3
Y
3.49.
Safety
AE3
Summary of On-Therapy Common (>= 2 %) AEs by Overall 
Frequency by Prior ESA Use – ND Subjects
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
3.50.
Safety
AE3
Summary of On-Therapy Common (>= 2 %) AEs by Overall 
Frequency by Prior ESA Use – PD Subjects
Y
3.51.
Safety
AE3
Summary of On-Therapy Common (>= 2 %) AEs by Overall 
Frequency by CKD Stage – ND Subjects
Y
3.52.
Safety
AE3
Summary of On-Therapy Common (>= 2 %) AEs by Overall 
Frequency by CKD Stage – PD Subjects
Y
3.53.
Safety
AE15
Summary of On-Therapy Common (>=5%) Non-Serious AEs by 
SOC and PT (Subjects & No. of Occurrences) – ND Subjects
FDAAA, EudraCT
Y
3.54.
Safety
AE15
Summary of On-Therapy Common (>=5%) Non-Serious AEs by 
SOC and PT (Subjects & No. of Occurrences) – PD Subjects
FDAAA, EudraCT
Y
Serious and Other Significant AEs
3.55.
Safety
AE1
Summary of On-Therapy Serious AEs – ND Subjects
GSK CTR
Y
3.56.
Safety
AE1
Summary of On-Therapy Serious AEs – PD Subjects
GSK CTR
Y
3.57.
Safety
AE1
Summary of Post-Therapy Serious AEs – ND Subjects
GSK CTR
Y
3.58.
Safety
AE1
Summary of Post-Therapy Serious AEs – PD Subjects
GSK CTR
Y
3.59.
Safety
AE3
Summary of On-Therapy Serious Drug-Related AEs – ND 
Subjects
Required for Plain Language Summary
Y
3.60.
Safety
AE3
Summary of On-Therapy Serious Drug-Related AEs – PD 
Subjects
Required for Plain Language Summary
Y
3.61.
Safety
AE16
Summary of On-Therapy Serious AEs by SOC and PT (Subjects 
& No. of Occurrences) – ND Subjects
FDAAA, EudraCT
Y
3.62.
Safety
AE16
Summary of On-Therapy Serious AEs by SOC and PT (Subjects 
& No. of Occurrences) – PD Subjects
FDAAA, EudraCT
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
3.63.
Safety
AE1
Summary of AEs Leading to Withdrawal from Study / Permanent 
Discontinuation of Study Treatment by SOC and PT – ND 
Subjects
IDSL
Y
3.64.
Safety
AE1
Summary of AEs Leading to Withdrawal from Study / Permanent 
Discontinuation of Study Treatment by SOC and PT – PD 
Subjects
IDSL
Y
AEs of Special Interest
3.65.
Safety
SAFE_T2
Summary of On-Therapy AEs of Special Interest – ND Subjects
Y
3.66.
Safety
SAFE_T2
Summary of On-Therapy AEs of Special Interest – PD Subjects
Y
3.67.
Safety
SAFE_T2
Summary of Post-Therapy AEs of Special Interest – ND 
Subjects
Y
3.68.
Safety
SAFE_T2
Summary of Post-Therapy AEs of Special Interest – PD 
Subjects
Y
Laboratory: Chemistry
3.69.
Safety
LB1
Summary of Chemistry Values by Visit – ND Subjects
ICH E3
Includes Baseline values
Y
3.70.
Safety
LB1
Summary of Chemistry Values by Visit – PD Subjects
ICH E3
Includes Baseline values
Y
3.71.
Safety
LB1
Summary of Chemistry Changes from Baseline by Visit – ND 
Subjects
ICH E3
Y
3.72.
Safety
LB1
Summary of Chemistry Changes from Baseline by Visit – PD 
Subjects
ICH E3
Y
3.73.
Safety
SAFE_T3
Summary of Percent Change from Baseline in Lipid Parameters 
(Total Cholesterol, LDL Cholesterol, HDL Cholesterol, and 
LDL/HDL Cholesterol Ratio) by Visit – ND Subjects
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
3.74.
Safety
SAFE_T3
Summary of Percent Change from Baseline in Lipid Parameters 
(Total Cholesterol, LDL Cholesterol, HDL Cholesterol, LDL/HDL 
Cholesterol Ratio) by Visit – PD Subjects
Y
3.75.
Safety
LB15
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline – ND Subjects
ICH E3
Y
3.76.
Safety
LB15
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline – PD Subjects
ICH E3
Y
3.77.
Safety
LB17
Summary of Worst Case Chemistry Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline – ND Subjects
ICH E3
Y
3.78.
Safety
LB17
Summary of Worst Case Chemistry Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline – PD Subjects
ICH E3
Y
Hematology
3.79.
Safety
LB1
Summary of Hematology Values by Visit – ND Subjects
ICH E3
Includes Baseline values
Y
3.80.
Safety
LB1
Summary of Hematology Values by Visit – PD Subjects
ICH E3
Includes Baseline values
Y
3.81.
Safety
LB1
Summary of Hematology Changes from Baseline by Visit – ND 
Subjects
ICH E3
Y
3.82.
Safety
LB1
Summary of Hematology Changes from Baseline by Visit – PD 
Subjects
ICH E3
Y
3.83.
Safety
LB15
Summary of Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline – ND Subjects
ICH E3
Y
3.84.
Safety
LB15
Summary of Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline – PD Subjects
ICH E3
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
3.85.
Safety
LB17
Summary of Worst Case Hematology Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline – ND Subjects
ICH E3
Y
3.86.
Safety
LB17
Summary of Worst Case Hematology Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline – PD Subjects
ICH E3
Y
Urinalysis
3.87.
Safety
LB1
Summary of Urinalysis Values by Visit – ND Subjects
ICH E3
Includes Baseline values
Y
3.88.
Safety
LB1
Summary of Urinalysis Changes from Baseline by Visit – ND 
Subjects
ICH E3
Y
3.89.
Safety
LB15
Summary of Worst Case Urinalysis Results Relative to Normal 
Range Post-Baseline Relative to Baseline – ND Subjects
ICH E3
Y
3.90.
Safety
LB17
Summary of Worst Case Urinalysis Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline – ND Subjects
ICH E3
Y
Iron Parameters
3.91.
Safety
LB1
Summary of Iron Values by Visit – ND Subjects
ICH E3
Includes Baseline values
Y
3.92.
Safety
LB1
Summary of Iron Values by Visit – PD Subjects
ICH E3
Includes Baseline values
Y
3.93.
Safety
LB1
Summary of Iron Changes from Baseline by Visit – ND Subjects
ICH E3
Y
3.94.
Safety
LB1
Summary of Iron Changes from Baseline by Visit – PD Subjects
ICH E3
Y
3.95.
Safety
LB15
Summary of Worst Case Iron Results Relative to Normal Range 
Post-Baseline Relative to Baseline – ND Subjects
ICH E3
Y
3.96.
Safety
LB15
Summary of Worst Case Iron Results Relative to Normal Range 
Post-Baseline Relative to Baseline – PD Subjects
ICH E3
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
3.97.
Safety
LB17
Summary of Worst Case Iron Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline – ND Subjects
ICH E3
Y
3.98.
Safety
LB17
Summary of Worst Case Iron Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline – PD Subjects
ICH E3
Y
Other Laboratory Tests
3.99.
Safety
LB1
Summary of Other Laboratory Values by Visit – ND Subjects
ICH E3
Includes Baseline values
Y
3.100.
Safety
LB1
Summary of Other Laboratory Values by Visit – PD Subjects
ICH E3
Includes Baseline values
Y
3.101.
Safety
LB1
Summary of Other Laboratory Changes from Baseline by Visit –
ND Subjects
ICH E3
Y
3.102.
Safety
LB1
Summary of Other Laboratory Changes from Baseline by Visit –
PD Subjects
ICH E3
Y
3.103.
Safety
LB15
Summary of Worst Case Other Laboratory Results Relative to 
Normal Range Post-Baseline Relative to Baseline – ND 
Subjects
ICH E3
Y
3.104.
Safety
LB15
Summary of Worst Case Other Laboratory Results Relative to 
Normal Range Post-Baseline Relative to Baseline – PD Subjects
ICH E3
Y
3.105.
Safety
LB17
Summary of Worst Case Other Laboratory Results Relative to 
PCI Criteria Post-Baseline Relative to Baseline – ND Subjects
ICH E3
Y
3.106.
Safety
LB17
Summary of Worst Case Other Laboratory Results Relative to 
PCI Criteria Post-Baseline Relative to Baseline – PD Subjects
ICH E3
Y
Hepatobiliary (Liver)
3.107.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting – ND 
Subjects
IDSL
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
3.108.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting – PD 
Subjects
IDSL
Y
3.109.
Safety
LIVER10
Summary of Subjects Meeting Emergent Hepatobiliary 
Laboratory Abnormality Criteria – ND Subjects
IDSL
Y
3.110.
Safety
LIVER10
Summary of Subjects Meeting Emergent Hepatobiliary 
Laboratory Abnormality Criteria – PD Subjects
IDSL
Y
ECG
3.111.
Safety
EG1
Summary of ECG Findings – ND Subjects
IDSL
Y
3.112.
Safety
EG1
Summary of ECG Findings – PD Subjects
IDSL
Y
3.113.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit – ND 
Subjects
IDSL
Y
3.114.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit – PD 
Subjects
IDSL
Y
Vital Signs
3.115.
Safety
VS1
Summary of Vital Signs by Visit – ND Subjects
Y
3.116.
Safety
VS1
Summary of Vital Signs by Visit – PD Subjects
Y
3.117.
Safety
VS1
Summary Change from Baseline in Vital Signs by Visit – ND 
Subjects
Y
3.118.
Safety
VS1
Summary Change from Baseline in Vital Signs by Visit – PD 
Subjects
Y
3.119.
Safety
VS7
Summary of Worst Case Vital Sign Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline – ND Subjects
Y
3.120.
Safety
VS7
Summary of Worst Case Vital Sign Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline – PD Subjects
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Ophthalmology
3.121.
Safety
SAFE_T6
Summary of Ophthalmologic Exams at Screening – ND Subjects
Y
3.122.
Safety
SAFE_T6
Summary of Ophthalmologic Exams at Screening – PD Subjects
Y
3.123.
Safety
SAFE_T7
Summary of On-Therapy Ophthalmologic Exams – ND Subjects
Y
3.124.
Safety
SAFE_T7
Summary of On-Therapy Ophthalmologic Exams – PD Subjects
Y
Change in Anti-Hypertensive Medications
3.125.
Safety
SAFE_T8
Summary of Change in Anti-Hypertensive Medications Due to 
Increased Blood Pressure – ND Subjects
Y
3.126.
Safety
SAFE_T8
Summary of Change in Anti-Hypertensive Medications Due to 
Increased Blood Pressure – PD Subjects
Y
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15.10.4.5. Safety Figures
Safety Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Adverse Events
3.1.
Safety
AE10
Common (>=2%) On-therapy AEs Sorted by Relative Risk – ND 
Subjects
IDSL
Y
Clinical Laboratory Analyses
3.2.
Safety
SAFE_F1
Plot of Percent Change from Baseline in Lipid Parameters
(Total Cholesterol, LDL Cholesterol, HDL Cholesterol, and 
LDL/HDL Cholesterol Ratio) over Time – ND Subjects
Y
3.3.
Safety
SAFE_F1
Plot of Percent Change from Baseline in Lipid Parameters
(Total cholesterol, LDL Cholesterol, HDL Cholesterol, and 
LDL/HDL Cholesterol Ratio) over Time – PD Subjects
Y
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15.10.4.6. Patient Reported Outcome Tables
Patient Reported Outcome: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
Patient Reported Outcome
4.1.
ITT
SF2
Summary of SF-36 HR-QoL Scores (PCS, MCS, 8 Subscales) –
ITT
including PCS and MCS
Y
4.2.
Efficacy PD
SF2
Summary of SF-36 HR-QoL Scores (PCS, MCS, 8 Subscales) -
Efficacy PD
including PCS and MCS
Y
4.3.
ITT
SF2
Summary of SF-36 HR-QoL Scores (PCS, MCS, 8 Subscales) 
by Prior ESA Use – ITT
including PCS and MCS
Y
4.4.
Efficacy PD
SF2
Summary of SF-36 HR-QoL Scores (PCS, MCS, 8 Subscales) 
by Prior ESA Use - Efficacy PD
including PCS and MCS
Y
4.5.
ITT
SF4
Summary of Changes from Baseline in SF-36 HR-QoL Scores 
(PCS, MCS, 8 Subscales) – ITT
including PCS and MCS
Y
4.6.
Efficacy PD
SF4
Summary of Changes from Baseline in SF-36 HR-QoL Scores 
(PCS, MCS, 8 Subscales) - Efficacy PD
including PCS and MCS
Y
4.7.
ITT
SF4
Summary of Changes from Baseline in SF-36 HR-QoL Scores 
(PCS, MCS, 8 Subscales) by Prior ESA Use – ITT
including PCS and MCS
Y
4.8.
Efficacy PD
SF4
Summary of Changes from Baseline in SF-36 HR-QoL Scores 
(PCS, MCS, 8 Subscales) by Prior ESA Use - Efficacy PD
including PCS and MCS
Y
4.9.
ITT
PRO_T1
Summary of EQ-5D-5L Score - ITT
Y
4.10.
Efficacy PD
PRO_T1
Summary of EQ-5D-5L Score - Efficacy PD
Y
4.11.
ITT
PRO_T1
Summary of EQ-5D-5L Score by Prior ESA Use - ITT
Y
4.12.
Efficacy PD
PRO_T1
Summary of EQ-5D-5L Score by Prior ESA Use - Efficacy PD
Y
4.13.
ITT
PRO_T2
Summary of EQ-5D-5L Index Value - ITT
Y
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Patient Reported Outcome: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
4.14.
Efficacy PD
PRO_T2
Summary of EQ-5D-5L Index Value - Efficacy PD
Y
4.15.
ITT
PRO_T2
Summary of EQ-5D-5L Index Value by Prior ESA Use - ITT
Y
4.16.
Efficacy PD
PRO_T2
Summary of EQ-5D-5L Index Value by Prior ESA Use - Efficacy 
PD
Y
4.17.
ITT
PRO_T2
Summary of Changes from Baseline in EQ-5D-5L Index Value –
ITT
Y
4.18.
Efficacy PD
PRO_T2
Summary of Changes from Baseline in EQ-5D-5L Index Value -
Efficacy PD
Y
4.19.
ITT
PRO_T2
Summary of Changes from Baseline in EQ-5D-5L Index Value 
by Prior ESA Use – ITT
Y
4.20.
Efficacy PD
PRO_T2
Summary of Changes from Baseline in EQ-5D-5L Index Value 
by Prior ESA Use - Efficacy PD
Y
4.21.
ITT
PRO_T3
Summary of EQ Visual Analog Scale (VAS) - ITT
Y
4.22.
Efficacy PD
PRO_T3
Summary of EQ Visual Analog Scale (VAS) - Efficacy PD
Y
4.23.
ITT
PRO_T3
Summary of EQ Visual Analog Scale (VAS) by Prior ESA Use -
ITT
Y
4.24.
Efficacy PD
PRO_T3
Summary of EQ Visual Analog Scale (VAS) by Prior ESA Use -
Efficacy PD
Y
4.25.
ITT
PRO_T3
Summary of Changes from Baseline in EQ Visual Analog Scale 
(VAS) – ITT
Y
4.26.
Efficacy PD
PRO_T3
Summary of Changes from Baseline in EQ Visual Analog Scale 
(VAS) - Efficacy PD
Y
4.27.
ITT
PRO_T3
Summary of Changes from Baseline in EQ Visual Analog Scale 
(VAS) by Prior ESA Use – ITT
Y
4.28.
Efficacy PD
PRO_T3
Summary of Changes from Baseline in EQ Visual Analog Scale 
Y
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Patient Reported Outcome: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
(VAS) by Prior ESA Use - Efficacy PD
4.29.
ITT
PRO_T4
Analysis of Changes from Baseline in Changes from Baseline in 
SF-36 HR-QoL Scores (PCS, MCS, 8 Subscales) - ITT
Y
4.30.
ITT
PRO_T4
Analysis of Changes from Baseline in Changes from Baseline in 
SF-36 HR-QoL Scores (PCS, MCS, 8 Subscales) by Prior ESA 
Use - ITT
Y
4.31.
ITT
PRO_T5
Analysis of Changes from Baseline in EQ-5D-5L Index Value -
ITT
Y
4.32.
ITT
PRO_T5
Analysis of Changes from Baseline in EQ-5D-5L Index Value by 
Prior ESA Use - ITT
Y
4.33.
ITT
PRO_T5
Analysis of Changes from Baseline in EQ Visual Analog Scale 
(VAS) - ITT
Y
4.34.
ITT
PRO_T5
Analysis of Changes from Baseline in EQ Visual Analog Scale 
(VAS) by Prior ESA Use - ITT
Y
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15.10.4.7. Pharmacokinetic Tables
Pharmacokinetic Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Plasma Daprodustat Concentrations
5.1.
PK
PK01
Summary of Daprodustat Plasma Concentration by Dose Level
(non-transformed)
Y
5.2.
PK
PK_T1
based on PK05
Summary of Daprodustat Plasma Concentration by Dose Level
(loge-transformed)
Y
PK parameters
5.3.
PK
PK03
Summary of Daprodustat Pharmacokinetic Parameters by Dose 
Level (non-transformed)
Y
5.4.
PK
PK05
Summary of Daprodustat Pharmacokinetic Parameters by Dose 
Level (loge-transformed)
Y
5.5.
PK
PK03
Summary of Dose Normalized Daprodustat Pharmacokinetic 
Parameters by Dose level (non-transformed)
Y
5.6.
PK
PK05
Summary of Dose Normalized Daprodustat Pharmacokinetic 
Parameters by Dose level (loge-transformed)
Y
5.7.
PK
PK03
Summary of Dose Normalized Daprodustat Pharmacokinetic 
Parameters by Used Tablet Strength (non-transformed)
Y
5.8.
PK
PK05
Summary of Dose Normalized Daprodustat Pharmacokinetic 
Parameters by Used Tablet Strength (loge-transformed)
Y
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15.10.4.8. Pharmacokinetic Figures
Pharmacokinetic Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Plasma Daprodustat Concentrations
5.1.
PK
PK24
Individual Daprodustat Plasma Concentration-Time Plots
(Linear and Semi-Log) (by Dose)
Y
5.2.
PK
PK17
Mean Daprodustat Plasma Concentration-Time Plots
(Linear and Semi-Log) (by Dose)
Y
5.3.
PK
PK19
Mean (+SD) Daprodustat Plasma Concentration-Time Plots
(Linear and Semi-Log) (by Dose)
Y
5.4.
PK
PK20
Median Daprodustat Plasma Concentration-Time Plots
(Linear and Semi-Log) (by Dose)
Y
PK parameters
5.5.
PK
PK_F1
Individual Plot of Daprodustat Dose Level and PK Parameters (AUC 
(0-4) and Cmax)
will provide only pooled data 
Y
5.6.
PK
PK_F2
Mean (+SD) Plot of Daprodustat Dose Level and PK Parameters 
(AUC (0-4) and Cmax)
will provide only pooled data
Y
5.7.
PK
PK_F3
Median Plot of Daprodustat Dose Level and PK Parameters (AUC 
(0-4) and Cmax)
will provide only pooled data
Y
5.8.
PK
PK_F1
Individual Plot of Daprodustat Dose Level and Dose Normalized PK 
Parameters (AUC (0-4) and Cmax)
will provide only pooled data
Y
5.9.
PK
PK_F2
Mean (+SD) Plot of Daprodustat Dose Level and Dose Normalized 
PK Parameters (AUC (0-4) and Cmax)
will provide only pooled data
Y
5.10.
PK
PK_F3
Median Plot of Daprodustat Dose Level and Dose Normalized PK 
Parameters (AUC (0-4) and Cmax)
will provide only pooled data
Y
5.11.
PK
PK_F4
Box Plot of Daprodustat Dose Level and Dose Normalized PK 
Parameters (AUC (0-4) and Cmax)
will provide only pooled data
Y
5.12.
PK
PK_F1
Individual Plot of Daprodustat Used Tablet Strength and Dose 
Normalized PK Parameters (AUC (0-4) and Cmax)
will provide only pooled data
Y
5.13.
PK
PK_F2
Mean (+SD) Plot of Daprodustat Used Tablet Strength and Dose 
will provide only pooled data
Y
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Pharmacokinetic Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Normalized PK Parameters (AUC (0-4) and Cmax)
5.14.
PK
PK_F3
Median Plot of Daprodustat Used Tablet Strength and Dose 
Normalized PK Parameters (AUC (0-4) and Cmax)
will provide only pooled data
Y
5.15.
PK
PK_F4
Box Plot of Daprodustat Used Tablet Strength and Dose Normalized 
PK Parameters (AUC (0-4) and Cmax)
will provide only pooled data
Y
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15.10.4.9. ICH Listings
ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Study Population
Subject Disposition
1.
Randomized
ES2
Listing of Reasons for Subject Withdrawal
ICH E3
Y
2.
Safety
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
Y
3.
All 
Screening
ES7
Listing of Reasons for Screen Failure
CONSORT Diagram 
Y
4.
Safety
TA1
Listing of Planned and Actual Treatments
GSK CSR
Y
Protocol Deviations
5.
Randomized
DV2
Listing of Important Protocol Deviations
Y
6.
Randomized
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
Y
Population Analyzed
7.
Randomized
SP3
Listing of Subjects Excluded from Any Population
Y
8.
mITT
SP3
Listing of Subjects Excluded from Per Protocol Population
Include the exclusion categories
Y
Demographic and Baseline Characteristics
9.
Safety
DM2
Listing of Demographic Characteristics
ICH E3
Y
10.
Safety
POP_L1
Listing of Other Baseline Characteristics
Y
11.
Safety
CM2
Listing of Prior ESA
Y
12.
Safety
DM9
Listing of Race
ICH E3
Y
Exposure and Treatment Compliance
13.
Safety
POP_L2
Listing of Exposure Data - Daprodustat
ICH E3
Y
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ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
14.
Safety
POP_L3
Listing of Exposure Data - Epoetin Beta Pegol
ICH E3
Y
15.
Safety
POP_L4
Listing of Study Medication Compliance
ICH E3
Y
Efficacy
Hgb
16.
ITT
EFF_L1
Listing of Hgb Data – ITT
Y
17.
Efficacy PD
EFF_L1
Listing of Hgb Data – Efficacy PD
Y
18.
Efficacy PD
EFF_L1
Listing of Hgb Data – PD, ESA Non-Users
ESA non-users only
Y
19.
ITT
EFF_L2
Listing of Subjects Who Have Hgb Level of Less than 7.5 g/dL –
ITT
Y
20.
Efficacy PD
EFF_L2
Listing of Subjects Who Have Hgb level of Less than 7.5 g/dL –
Efficacy PD
Y
21.
Efficacy PD
EFF_L2
Listing of Subjects Who Have Hgb level of Less than 7.5 g/dL –
PD, ESA Non-Users
ESA non-users only
Y
22.
ITT
EFF_L2
Listing of Subjects Who Have Hgb Increase of More than 
2.0 g/dL over Any 4 Weeks – ITT
Y
23.
Efficacy PD
EFF_L2
Listing of Subjects Who Have Hgb Increase of More than 
2.0 g/dL over Any 4 Weeks – Efficacy PD
Y
24.
Efficacy PD
EFF_L2
Listing of Subjects Who Have Hgb Increase of More than 
2.0 g/dL over Any 4 Weeks – PD, ESA Non-Users
ESA non-users only
Y
25.
ITT
EFF_L2
Listing of Subjects Who Have Hgb Level of More than 13.0 g/dL 
– ITT
Y
26.
Efficacy PD
EFF_L2
Listing of Subjects Who Have Hgb Level of More than 13.0 g/dL 
– Efficacy PD
Y
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ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
27.
Efficacy PD
EFF_L2
Listing of Subjects Who Have Hgb Level of More than 13.0 g/dL
– PD, ESA Non-Users
ESA non-users only
Y
28.
ITT
EFF_L3
Listing of Subjects with Treatment Interruption due to Hgb > 
13 g/dL – ITT
Y
29.
Efficacy PD
EFF_L3
Listing of Subjects with Treatment Interruption due to Hgb > 
13 g/dL- Efficacy PD
Y
30.
Efficacy PD
EFF_L3
Listing of Subjects with Treatment Interruption due to Hgb > 
13 g/dL- PD, ESA Non-Users
ESA non-users only
Y
31.
ITT
EFF_L7
Listing of Subjects Who Reach the Lower Hgb Target - ITT
Y
32.
Efficacy PD
EFF_L7
Listing of Subjects Who Reach the Lower Hgb Target – Efficacy 
PD
Y
33.
Efficacy PD
EFF_L7
Listing of Subjects Who Reach the Lower Hgb Target – PD, ESA 
Non-Users
ESA non-users only
Y
Dose Adjustment
34.
Efficacy PD
EFF_L4
Listing of Dose Level – PD, ESA Non-Users
ESA non-users only
Y
35.
Efficacy PD
EFF_L5
Listing of Dose Adjustment – PD, ESA Non-Users
ESA non-users only
Y
Safety
Adverse Events
36.
Safety
AE8
Listing of All Adverse Events
ICH E3
Y
37.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
Y
38.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
Y
Serious and Other Significant Adverse Events
39.
Safety
AE8
Listing of Fatal Serious Adverse Events
ICH E3
Y
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ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
40.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
Y
41.
All 
Screening
AE8
Listing of Serious AEs in Screening Period
Y
42.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
Y
43.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
Y
44.
Safety
SAFE_L1
Listing of Adverse Events of Special Interest
ICH E3
Displays will be produced with AESI category in 
addition of AE8 template.
Y
All Laboratory
45.
Safety
LB5
Listing of All Chemistry Data for Subjects with Any Value 
Outside of Normal Range/of PCI
ICH E3
Y
46.
Safety
LB5
Listing of All Hematology Data for Subjects with Any Value 
Outside of Normal Range/of PCI
ICH E3
Y
47.
Safety
LB5
Listing of All Urinalysis Laboratory Data for Subjects with Any 
Value Outside of Normal Range
ICH E3
Y
48.
Safety
LB5
Listing of All Iron Parameters Laboratory Data for Subjects with 
Any Value Outside of Normal Range/of PCI
ICH E3
Y
49.
Safety
LB5
Listing of All Other Laboratory Data for Subjects with Any Value 
Outside of Normal Range/of PCI
ICH E3
Y
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15.10.4.10. Other Listings
Other Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Study Population
Demographic and Baseline Characteristics
50.
Safety
FH4
Listing of Family Members with History of Cardiovascular Risk 
Factors
Y
51.
Safety
SU2
Listing of Substance Use History
Y
Dialysis
52.
Safety
POP_L8
Listing of Dialysis Initiation During the Study Period
Y
53.
Safety
POP_L8
Listing of Peritoneal Dialysis at Baseline
Y
54.
Safety
POP_L9
Listing of Subjects with Vascular Therapeutic Procedures During 
the Study Period
Y
Medical Conditions and Concomitant Medication
55.
Safety
MH2
Listing of Medical Conditions
Y
56.
Safety
CM2
Listing of Concomitant Medications
Y
57.
Safety
POP_L5
Listing of ESA Concomitant Medications
Y
58.
Safety
POP_L6
Listing of Iron Concomitant Medications
Y
59.
Safety
POP_L7
Listing of Anti-Hypertensive Concomitant Medications
Y
60.
Safety
POP_L8
Listing of Blood Products and Blood Supportive Care Products
Y
Efficacy
Iron Parameters
61.
ITT
LB5
Listing of Iron Parameter Data - ITT
All iron parameters will be included.
Y
62.
Efficacy PD
LB5
Listing of Iron Parameter Data – Efficacy PD
All iron parameters will be included.
Y
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Other Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
CKD Progression
63.
ITT
EFF_L6
Listing of CKD Progression
Y
Safety
Suicidality-Related Adverse Event
64.
Safety
IDSL standard
Listing of Possible Suicidality-Related Adverse Event Data:
Event and Description (Section 1-Section 2)
Y
65.
Safety
IDSL standard
Listing of Possible Suicidality-Related Adverse Event Data: 
Possible Cause(s) (Section 3)
Y
66.
Safety
IDSL standard
Listing of Possible Suicidality-Related Adverse Event Data: 
(Section 4)
Y
67.
Safety
IDSL standard
Listing of Possible Suicidality-Related Adverse Event Data: 
(Section 5 - Section 8)
Y
Clinical Laboratory, ECG, Vital Sign, and Ophthalmology Exam
68.
Safety
LB5
Listing of Chemistry Data
Y
69.
Safety
LB5
Listing of Hematology Data
Y
70.
Safety
LB5
Listing of Other Laboratory Data
Y
71.
Safety
LB5
Listing of Urinalysis Data
Y
72.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
This listing is required for medical review of 
subjects with liver stopping events.
Y
73.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
This listing is required for medical review of 
subjects with liver stopping events.
Y
74.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
Y
75.
Safety
LIVER6
Listing of Liver Stopping Event Information for RUCAM Score
Y
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Other Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
76.
Safety
LIVER7
Listing of Liver Biopsy Details
Y
77.
Safety
LIVER8
Listing of Liver Imaging Details
Y
78.
Safety
EG3
Listing of ECG Values
Y
79.
Safety
EG5
Listing of ECG Findings
Delete column of ‘Clinically Significant Change 
from Baseline?’ from EG5 template
Y
80.
Safety
VS4
Listing of Vital Signs
Y
81.
Safety
VS4
Listing of All Vital Signs for Subjects with Values of PCI
Y
82.
Safety
SAFE_L2
Listing of Ophthalmologic Exams
Y
83.
Safety
SAFE_L3
Listing of Subjects Who Have Any Change in Anti-Hypertensive 
Medications Due to Increased Blood Pressure
Y
Other
84.
Safety
PREG1a
Listing of Subjects Who Became Pregnant During the Study
Y
Patient Reported Outcome
85.
ITT
PRO_L1
Listing of SF-36v2 Summary Scores and Domain Scores – ITT
Including PCS and MCS
Y
86.
Efficacy PD
PRO_L1
Listing of SF-36v2 Summary Scores and Domain Scores –
Efficacy PD
Including PCS and MCS
Y
87.
ITT
PRO_L2
Listing of Individual Scores of EQ-5D-5L VAS – ITT
Including index value
Y
88.
Efficacy PD
PRO_L2
Listing of Individual Scores of EQ-5D-5L VAS – Efficacy PD
Including index value
Y
Pharmacokinetic Parameters
89.
PK
PK07
Listing of Daprodustat Pharmacokinetic Concentration-Time 
Data by Dose Level
Y
90.
PK
PK13
Listing of Derived Daprodustat Pharmacokinetic Parameters by 
Dose Level
Y
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15.10.4.11. Patient Profile Listings
Patient Profile Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Safety
91.
Safety
IDSL standard
Patient Profile Listing of Arrhythmias
Y
92.
Safety
IDSL standard
Patient Profile Listing of Congestive Heart Failure
Y
93.
Safety
IDSL standard
Patient Profile Listing of Cerebrovascular Events/Stroke/ 
Transient Ischemic Attack
Y
94.
Safety
IDSL standard
Patient Profile Listing of Deep Venous Thrombosis/ Pulmonary 
Embolism
Y
95.
Safety
IDSL standard
Patient Profile Listing of Myocardial Infarction /Unstable Angina
Y
96.
Safety
IDSL standard
Patient Profile Listing of Peripheral Arterial Thrombosis 
Embolism
Y
97.
Safety
IDSL standard
Patient Profile Listing of Pulmonary Hypertension
Y
98.
Safety
IDSL standard
Patient Profile Listing of Revascularization
Y
99.
Safety
IDSL standard
Patient Profile Listing of Valvulopathy
Y
100.
Safety
IDSL standard
Patient Profile Listing of Deaths
Y
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15.11.
Appendix 11: Example Mock Shells for Data Displays
Example mock shells for data displays are developed as separate documents.
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16.
REVISION HISTORY
Note that minor wording changes are not included in below.
Reporting and Analysis Plan_201753_Amendment 1 [19-NOV-2018]
Section # and Name
Description of Change
Brief Rationale
Cover page
Approvers were changed.
Changed according to INS_689064 (1.0)
5.4.2
Examination of 
Subgroups
Cutoff values of baseline Hgb for ESA non-users and ERI were changed.
Cutoff value of baseline Hgb is aligned with 
stratification factor in randomization.
Cutoff value of ERI was reconsidered.
6.1
Overview of Planned 
Study Population Analyses
15.10.4
Table of Contents for 
SAC Deliverable
Listing of Other Baseline Characteristics including prior ESA type, standardized prior ESA 
dose, ERI, iron use, diabetes, and CKD stage was added.
Required information was added.
6.2
Planned Summary 
Display Details
15.6.2
Study Population
Added the period of time on dialysis for PD subjects in demographic characteristics.
PD subjects are on peritoneal dialysis.
6.2
Planned Summary 
Display Details
Added compliance up to week 2 and week 2 to 4 for only cohort 3
Subjects in cohort 3 have week 2 visit.
7.1
Primary Efficacy 
Analyses
15.10.4
Table of Contents for 
SAC Deliverable
Added tables of the tipping point analysis
It would facilitate review of tipping point results.
7.1.6.1
Evaluable Hgb
Blood transfusion impacting Hgb values was clarified as red blood cell transfusion and 
whole blood transfusion.
Clarification
7.1.6.3
Tipping Point Analysis
Added statement of subjects who do not have Hgb on and after week 4 will be excluded in 
the tipping point analysis
The subjects are not included in the primary 
analysis.
7.1.6.3
Tipping Point Analysis
The number of imputations was reconsidered and a text was updated.
Modifications
7.2
Principal Secondary 
Efficacy Analyses
A method to construct 95% CI and one-sided p-value for odds ratio has been specified in
Section 7.2.5.1 Statistical Methodology Specification
Clarification
7.2.5.1
Statistical Methodology 
Specification
Added handling to a problem with quasi-complete separation.
The problem with quasi-complete separation may 
occur.
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Reporting and Analysis Plan_201753_Amendment 1 [19-NOV-2018]
Section # and Name
Description of Change
Brief Rationale
7.3.1
Endpoint / Variables
Subgroup analyses by baseline Hgb for Hgb raw value, change from baseline in Hgb, 
number of subjects with Hgb within target range were added. 
Analyses required from PMDA consultation
7.3.1
Endpoint / Variables
7.3.2
Summary Measure
15.10.4
Table of Contents for 
SAC Delivrable
Figures of the raw observed values for each iron parameter were added.
It would facilitate review of iron parameters results
7.3.2
Summary Measure
Added categories for Hgb change from baseline at week 2
Change we would like to confirm at week 2 is half 
of change at week 4.
7.3.2
Summary Measure
Added subgroup analyses by prior ESA dose, prior ESA type, and ERI for following 
analyses.
Dose at each assessment visit / final visit
Duration of treatment interruption due to Hgb > 13.0 g/dL
Number of subjects with each dose at each assessment visit
Reconsidered required subgroup analysis
7.3.2
Summary Measure
Added summarizing oral iron dose in screening period as baseline.
Some subjects use oral iron at screening. It is 
useful for comparing change from baseline.
7.3.2
Summary Measure
Treatment difference and 95% CI for change from baseline of iron parameters were added.
It would facilitate review of iron parameters results
7.3.4
Strategy for Intercurrent 
(Post-Randomization) Events
The strategy for analysis of change from baseline in iron parameters was added.
The analysis was added.
7.3.5.1
Statistical Methodology 
Specification
The statistical methodology specification for analysis of change from baseline in iron 
parameters was added.
The analysis was added.
7.4.2
Summary Measure
15.10.4
Table of Contents for 
SAC Delivrable
Figures of the raw observed value for CKD progression were added.
It would facilitate review of CKD progression 
results.
8.1.1
Planned Adverse 
Events Analyses Displays
Clarification has been made to a summary of AEs by onset, i.e., the first occurrences for 
each subject will be used for the summary.
Clarification according to PMDA requirement
8.4.1
Planned Other Safety 
Analyses Displays
Update has been made to the ophthalmology exam to add the response (Y/N) to any 
questions.
Clarification
9
PATIENT REPORTED 
OUTCOME ANALYSES
Clarification has been made to the terminology of EQ-5D-5L scores and the index value.
Clarification
9
PATIENT REPORTED 
OUTCOME ANALYSES
Statistical methodology specification using a mixed model for repeated measures has been 
added for the change from baseline in the respective QoL parameter in Section 9.5.1
A model-based approach would be effectively 
estimate the results of the QoL parameters more 
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Reporting and Analysis Plan_201753_Amendment 1 [19-NOV-2018]
Section # and Name
Description of Change
Brief Rationale
Statistical Methodology Specification. Also, the strategy for intercurrent events was added 
as appropriate.
effectively
15.1.1
Exclusions from Per 
Protocol Population
It has been clarified that the exclusion criteria 07 does not include ESA medications.
Clarification
15.6.2
Study Population
Clarification has been made to prior ESA dose at baseline.
Clarification
15.6.2
Study Population
Clarification has been made to treatment compliance of daprodustat and epoetin beta 
pegol
Clarification
15.6.2
Study Population
Excluded P-TOL in iron medication summary although P-TOL is collected as iron 
medication.
Clarification
15.6.2
Study Population
Added a linear regression line with 95% CI band and R-squared for scatter plot of Hgb 
assessment
Clarification
15.6.3
Efficacy
Added statement of using different displays by prior ESA use for the following scatter plots.
Change from baseline in Hgb at week 4 vs covariates of interest
Mean dose during week 40 to 52 vs covariates of interest
Clarification
15.6.3
Efficacy
Clarification has been made to dose adjustment algorithm.
Clarification
15.6.3
Efficacy
Clarification has been made to duration of treatment interruption due to Hgb > 13.0 g/dL.
Clarification
15.6.3
Efficacy
Clarification has been made to oral iron dose by quarter.
Clarification
15.6.3
Efficacy
Excluded P-TOL for Iron use subgroup.
Clarification
15.6.4
Safety
Specified AESIs to be programmatically identified.
Some AESIs are not manually-selected by SRT.
15.6.5
Pharmacokinetic
Added a following condition omitted from summaries.
concentrations obtained in the less interval of last two treatment administrations than 12 
hours
Added according to the protocol.
15.6.6
Exploratory Endpoint
Added equation of eGFR.
Clarification
15.6.7
Patient Reported 
Outcome
Changed overview of scoring algorithm in SF-36v2.
Removed inaccurate information
15.8
Appendix 8: Values of 
Potential Clinical Importance
Added PCI value of eGFR
Addition
2018N378935_00