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
Phase: PHASE3
Conditions: Anaemia
Sponsor: GlaxoSmithKline

2015N266248_04
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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 
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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 
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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, 
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)

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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.