Clinical trial NCT02689206
Conditions: Anaemia
Keywords: Chronic kidney disease Efficacy Erythropoiesis-stimulating agent GSK1278863 Safety Hemodialysis-dependent anemia Pharmacokinetics
Sponsor: GlaxoSmithKline
Start date: 2016-02-17; Completion date: 2017-01-25
Enrollment: 103 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
GSK1278863 is an orally available, hypoxia-inducible factor - prolyl hydroxylase inhibitor, currently being investigated as a treatment for anemia associated with chronic kidney disease. GSK1278863 has been given as a once daily regimen in clinical studies to date. However, physicians in countries that use a three-times weekly hemodialysis schedule prefer to give the anemia medicine at the same time as the dialysis session. This study will test how well GSK1278863 can maintain hemoglobin levels when given three-times weekly, for 29 days.

This study will describe the relationship between hemoglobin and GSK1278863 given three-times weekly. The data from this study will allow for conversion of once daily doses to three-times weekly doses.

Detailed description:

Arms: arm 1: Subject will receive 10 mg of GSK1278863 three-times weekly for 4 weeks (up to 29 days). arm 2: Subject will receive 15 mg of GSK1278863 three-times weekly for 4 weeks (up to 29 days). arm 3: Subject will receive 25 mg of GSK1278863 three-times weekly for 4 weeks (up to 29 days). arm 4: Subject will receive 30 mg of GSK1278863 three-times weekly for 4 weeks (up to 29 days). arm 5: Subject will receive GSK1278863 matching placebo three-times weekly for 4 weeks (up to 29 days).
Interventions: intervention 1: GSK1278863 intervention 2: GSK1278863 matching Placebo
Intervention descriptions: intervention 1: GSK1278863 will be supplied as a round, biconvex, 10 millimeter (mm) white film coated tablet with the unit dose strength of 5 mg and 25 mg. intervention 2: GSK1278863 matching placebo will be supplied as a round, biconvex, 10 mm white film coated tablet.

Protocol documents:
Prot_000.pdf: 
2015N241222_01
CONFIDENTIAL
The GlaxoSmithKline group of companies
204836
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A 29-day, randomized, double-blinded, placebo-controlled, 
parallel-group, multi-center study to evaluate the efficacy, safety 
and pharmacokinetics of three-times weekly dosing of 
GSK1278863 in hemodialysis-dependent subjects with anemia 
associated with chronic kidney disease who are switched from a 
stable dose of an erythropoiesis-stimulating agent
Compound Number:
GSK1278863
Development Phase:
IIA
Effective Date:
11-MAY-2016
Protocol Amendment Number:  01
Author (s):
 
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N241222_00
2015-OCT-16
Original
2015N241222_01
2016-MAY-11
Amendment No. 1
Inclusion criterion #5 was modified to include the complete timeframe in which this 
criterion is applicable.  Other eligibility criteria have been clarified or updated for 
consistency with project level requirements.  Minor clarifications were made throughout 
the protocol, including clarifications related to hemoglobin stopping criteria, wording of 
the AEs of special interest, visit windows and the Time and Events Table. References to 
IB Supplements 1 and 2 were added, and corresponding updates to the Risk Assessment 
Table were made. Flexible language was added to allow for subjects to be dosed outside 
of the study clinic in exceptional circumstances. The definition of the PK analysis 
population was added.
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitors and Serious Adverse Events (SAE) Contact Information:
Role
Name
Day Time Phone 
Number
Fax Number
Site Address
Primary 
Medical 
Monitor -
PPD
 M.D.
PPD, Inc.
3900 Paramount Parkway, 
Suite 353
Morrisville, NC 27560-7200
Secondary 
Medical 
Monitor -
GSK
 
M.D.
GlaxoSmithKline
1250 S. Collegeville Road, 
UP4400
Collegeville, PA 19426
SAE Contact 
Information1
PPD Hotline
1PPD Hotline for reporting of SAEs is only to be used in the event of the electronic data capture system being 
unavailable.
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee).  If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s):
IND Number: 101,291
EudraCT: 2015-004790-32
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204836:
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 204836........................................................8
2.
INTRODUCTION....................................................................................................10
2.1.
Brief Background ........................................................................................10
2.2.
Study Rationale ..........................................................................................11
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................12
4.
STUDY DESIGN ....................................................................................................12
4.1.
Overall Design ............................................................................................12
4.2.
Treatment Arms and Duration.....................................................................13
4.3.
Type and Number of Subjects.....................................................................14
4.4.
Design Justification.....................................................................................14
4.5.
Dose Justification........................................................................................15
4.6.
Benefit:Risk Assessment ............................................................................16
4.6.1.
Benefit Assessment.....................................................................16
4.6.2.
Risk Assessment .........................................................................16
4.6.3.
Overall Benefit:Risk Conclusion...................................................17
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............17
5.1.
Hemoglobin Stability Criteria.......................................................................17
5.2.
Inclusion Criteria.........................................................................................18
5.3.
Exclusion Criteria........................................................................................19
5.4.
Other Eligibility Criteria Considerations.......................................................21
5.5.
Screening/Baseline/Run-in Failures............................................................21
5.6.
Withdrawal/Stopping Criteria.......................................................................21
5.6.1.
Criteria for Permanent Discontinuation from Study 
Medication and Early Withdrawal.................................................22
5.6.2.
Hemoglobin Stopping Criteria ......................................................22
5.6.3.
Missed Clinic Visits/Lost to Follow-up ..........................................23
5.6.4.
Liver Chemistry Stopping Criteria ................................................24
5.6.4.1.
Study Treatment Restart or Rechallenge....................24
5.7.
Early Withdrawal.........................................................................................24
5.8.
Subject and Study Completion....................................................................25
6.
STUDY TREATMENT ............................................................................................25
6.1.
Investigational Product and Other Study Treatment....................................25
6.2.
Treatment Assignment................................................................................26
6.3.
Blinding.......................................................................................................26
6.4.
Packaging and Labeling..............................................................................27
6.5.
Preparation/Handling/Storage/Accountability..............................................27
6.6.
Compliance with Study Treatment Administration.......................................27
6.7.
Treatment of Study Treatment Overdose....................................................28
6.8.
Treatment after the End of the Study ..........................................................28
6.9.
Concomitant Medications and Non-Drug Therapies....................................28
6.9.1.
Permitted Medications and Non-Drug Therapies..........................28
6.9.2.
Prohibited Medications and Non-Drug Therapies.........................29
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7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................29
7.1.
Time and Events Table...............................................................................31
7.2.
Screening and Critical Baseline Assessments ............................................32
7.3.
Efficacy.......................................................................................................32
7.4.
Safety .........................................................................................................32
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........32
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................33
7.4.1.2.
Adverse Events of Special Interest.............................33
7.4.1.3.
Method of Detecting AEs and SAEs ...........................34
7.4.1.4.
Follow-up of AEs and SAEs........................................34
7.4.1.5.
Cardiovascular and Death Events ..............................34
7.4.1.6.
Regulatory Reporting Requirements for SAEs............34
7.4.2.
Pregnancy ...................................................................................35
7.4.3.
Physical Exams ...........................................................................35
7.4.4.
Vital Signs....................................................................................35
7.4.5.
Electrocardiogram (ECG).............................................................36
7.4.6.
Clinical Safety Laboratory Assessments ......................................36
7.5.
Pharmacokinetics/Pharmacodynamics .......................................................37
7.5.1.
Blood Sample Collection..............................................................37
7.5.2.
Sample Analysis ..........................................................................38
7.6.
Genetics .....................................................................................................38
8.
DATA MANAGEMENT ...........................................................................................39
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................39
9.1.
Estimation...................................................................................................39
9.2.
Sample Size Considerations.......................................................................40
9.2.1.
Sample Size Assumptions ...........................................................40
9.2.2.
Sample Size Re-estimation or Adjustment...................................41
9.3.
Data Analysis Considerations .....................................................................42
9.3.1.
Analysis Populations....................................................................42
9.3.2.
Analysis Datasets ........................................................................42
9.3.3.
Interim Analysis ...........................................................................43
9.4.
Key Elements of Analysis Plan ...................................................................43
9.4.1.
Primary Analyses.........................................................................43
9.4.1.1.
Dose Response Model ...............................................43
9.4.1.2.
Estimation of Dose Ratio ............................................45
9.4.2.
Secondary Analyses ....................................................................45
9.4.3.
Safety Analyses...........................................................................46
9.4.3.1.
Exposure....................................................................46
9.4.3.2.
Adverse Events ..........................................................46
9.4.3.3.
Other Safety Measures...............................................47
9.4.3.4.
Pharmacokinetic/Pharmacodynamic Analyses ...........47
10. STUDY GOVERNANCE CONSIDERATIONS........................................................48
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............48
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................48
10.3.
Quality Control (Study Monitoring) ..............................................................49
10.4.
Quality Assurance.......................................................................................49
10.5.
Study and Site Closure ...............................................................................49
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10.6.
Records Retention......................................................................................50
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................51
11. REFERENCES.......................................................................................................52
12. APPENDICES........................................................................................................53
12.1.
Appendix 1: Abbreviations and Trademarks................................................53
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................55
12.3.
Appendix 3: GSK1278863 Risk Assessment ..............................................58
12.4.
Appendix 4: Genetic Research ...................................................................65
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................68
12.5.1.
Definition of Adverse Events........................................................68
12.5.2.
Definition of Serious Adverse Events...........................................69
12.5.3.
Definition of Cardiovascular Events .............................................70
12.5.4.
Recording of AEs and SAEs ........................................................71
12.5.5.
Evaluating AEs and SAEs............................................................71
12.5.6.
Reporting of SAEs to GSK...........................................................73
12.6.
Appendix 6: Female Eligibility Criteria.........................................................74
12.6.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............74
12.6.2.
Collection of Pregnancy Information ............................................75
12.7.
Appendix 7: Country Specific Requirements...............................................76
12.8.
Appendix 8: Protocol Changes....................................................................77
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1.
PROTOCOL SYNOPSIS FOR STUDY 204836
Rationale
In clinical studies to date, GSK1278863 has been administered as a once daily (QD) 
regimen.  However, the preferred practice in countries that utilize a three-times weekly 
hemodialysis (HD) schedule is administration of anemia therapy at the time of the HD 
session.  In order to accommodate this preference, and to provide additional flexibility for 
administration of GSK1278863, GSK proposes to also assess the ability of GSK1278863 
to maintain hemoglobin (Hgb) levels when administered three-times weekly.  This study 
will describe the dose-Hgb response relationship of three-times weekly dosing over a 29-
day treatment period.  It is anticipated that the data generated from this study will enable 
conversion of QD starting and maintenance dose regimens to three-times weekly 
doses/regimens.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary
!
Characterize the dose-response relationship 
between GSK1278863 administered three-
times weekly and Hgb at Day 29
!
Hgb change from baseline at Day 29
Secondary
!
Characterize the pharmacodynamic (PD) 
effect of GSK1278863 dose regimens on 
EPO, vascular endothelial growth factor 
(VEGF), hepcidin and red blood cells
!
Maximum observed change from baseline in 
EPO
!
Maximum observed % change from baseline 
in VEGF
!
Change from baseline in hepcidin at Day 29
!
Change from baseline in hematocrit, red 
blood cell (RBC) count, reticulocyte count 
and reticulocyte Hgb (CHr) at Day 29
!
Characterize the steady-state PK of 
GSK1278863 and major metabolites
!
Descriptive PK summaries of GSK1278863 
and major metabolites
!
Assess the safety and tolerability of 
GSK1278863 with three-times weekly 
administration for 29 days
!
Incidence and severity of AEs and SAEs
!
Reasons for discontinuation of 
investigational product
!
Discontinuation for safety-related reasons, 
e.g., pre-specified stopping criteria or AE
!
Absolute values and changes from baseline 
over time in laboratory parameters, ECGs 
and vital signs
Exploratory
!
Evaluate exposure-response relationships 
between GSK1278863 and PD endpoints
!
Further models (as appropriate) to describe 
the GSK1278863 exposure (PK or dose)
response relationship with PD endpoints
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Overall Design
This is a randomized, double-blinded, dose-ranging, placebo-controlled, parallel group 
study.  There is a 28-day Screening period, a 29-day Treatment period, and a Follow-up 
visit 14 ±3 days after completing treatment.
Treatment Arms and Duration
The total duration of subject involvement is up to 10 weeks (Screening to Follow-up) as 
described below:
!
Screening will be for at least 28 days prior to randomization.  A window of 
±2 days will be allowed for visits during the Screening period.
!
Subjects who meet eligibility criteria will be randomized and begin dosing on Day 
1.  Subjects will discontinue their current ESA therapy and will be randomized 
1:1:1:1:1 to receive one of four three-times weekly doses (10 mg, 15 mg, 25 mg, 
30 mg), or placebo on a dialysis day.
o
This should be timed such that randomization (Day 1) occurs on the date that 
would have been the next scheduled dose of ESA (or as close as practicable).
o
For subjects with a three-times weekly dialysis schedule, Day 1 must not 
occur on the first dialysis session of the week (e.g., if Monday-Wednesday-
Friday schedule, the study visit cannot be on Monday).
o
For subjects with a four- to five-times weekly dialysis schedule, Day 1 can be 
on any hemodialysis session of the week.
!
The Treatment period will be for a total of 29 days. A window of ±2 days is 
allowed for visits during the Treatment period.
o
At Day 29, all subjects will receive their last dose of study treatment and 
should not re-start ESA therapy until after the follow-up visit (Day 43).  
However, if the Investigator has a compelling clinical reason why a subject 
should restart ESA between Day 29 and Day 43, then ESA may be restarted 
prior to Day 43.
!
A Follow-up visit will be scheduled to occur 14 ±3 days after completing 
treatment.
Type and Number of Subjects
The study will enroll subjects on HD with anemia associated with CKD switching from 
ESA treatment.  The range of Hgb values for study eligibility is 9.0 - 11.5 g/dL and the 
subjects must have received the same ESA product with total weekly doses that varied by 
no more than 50% from 4 weeks prior to the Day -28 Screening visit through to Day 1.
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Approximately 200 subjects will be screened to achieve approximately 90 randomized 
and 75 evaluable subjects, with approximately 15 evaluable subjects per treatment group.
Analysis
The primary objective of the study is to estimate the relationship between three-times 
weekly doses of GSK1278863 and Hgb response after 29 days of treatment.  To achieve 
this, a model-based dose-response analysis is planned with the primary endpoint of 
change in Hgb from baseline at Day 29.  It is anticipated that the data and the estimated 
parameters generated from this model will enable conversion of QD starting and 
maintenance dose regimens to three-times weekly doses/regimens.
Three-times weekly data from this study will be compared to the QD data from study 
PHI113633, which was a phase 2B dose-ranging study to evaluate the dose-response 
relationship of GSK1278863 over the first 4 weeks of treatment and evaluate the safety 
and efficacy of GSK1278863 over 24 weeks in hemodialysis-dependent subjects with 
anemia associated with CKD.
2.
INTRODUCTION
2.1.
Brief Background
Anemia is a common complication of chronic kidney disease (CKD).  The cause of 
anemia in this population is multi-factorial, including relative or absolute deficiency of 
erythropoietin (EPO), reduced iron availability related to chronic inflammation, and 
gastrointestinal blood loss.
Current treatments for anemia associated with CKD include supplemental iron therapy 
(intravenous and/or oral), erythropoiesis-stimulating agents (ESAs) such as recombinant 
human (rh) EPO and blood transfusions.  However, each of these treatments has 
significant limitations:
!
Iron: Poor compliance is seen with oral iron therapy due to gastrointestinal 
intolerance while intravenous (IV) iron may have an increased risk of infection 
and/or iron overload as well as an increased risk for congestive heart failure 
[Agarwal, 2015].
!
ESAs: In order to achieve target Hgb levels (which are lower than normal Hgb 
levels), treatment with ESAs markedly increases plasma EPO concentrations to 
supra-physiologic levels.  Treatment with ESAs has been associated with 
increased cancer-related morbidity and mortality and increased risk of major 
cardiovascular events (e.g., stroke, myocardial infarction and all-cause mortality) 
[FDA, 2011], as well as ESA-induced hypertension.
!
Blood transfusions: These are avoided when possible because of potential allo-
immunization, which can preclude the possibility of receiving a kidney transplant 
as well as a risk of infection.
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Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs), such as 
GSK1278863, are an emerging new class of agents under investigation for the treatment 
of anemia associated with CKD.  These molecules stimulate erythropoiesis through 
inhibition of HIF-prolyl hydroxylase domain enzymes (PHD1, PHD2, PHD3).  This 
activity results in the accumulation of HIFα transcription factors which leads to increased 
transcription of HIF-responsive genes, stimulating components of the natural response to 
hypoxia.  During hypoxia, the PHDs are inhibited, resulting in the accumulation of 
unhydroxylated HIFα subunits, which dimerize with HIFβ subunits to effect the 
transcription of HIF-responsive genes, including EPO and others involved in increasing 
oxygen availability and utilization.  Other functions regulated by HIFs include iron 
metabolism and utilization, angiogenesis, extracellular matrix metabolism, apoptosis, 
energy and glucose metabolism, vascular tone, cell adhesion, and motility [Haase, 2013].
GSK1278863 may present several important advantages over other ESAs.  It is an oral 
medication and does not require cold-chain storage as do some ESAs, thus increasing 
ease of use for patients.  Moreover, data indicate that GSK1278863 can effectively raise 
hemoglobin (Hgb) concentrations with lower EPO exposures than those observed after 
administration of ESAs [Provenzano, 2011].  Because of the increased cardiovascular 
(CV) risk associated with raising Hgb concentrations through large increases in EPO 
exposure [Pfeffer, 2009], GSK1278863 has the potential to raise Hgb with less CV risk 
than other ESAs.  Additional benefits include the potential to improve iron availability 
for erythropoiesis, the potential to successfully treat ESA-hyporesponders, and the 
potential to treat anemia without causing ESA-induced hypertension.
GSK1278863 is a HIF-PHI currently being investigated as a treatment for anemia 
associated with CKD in both dialysis (DD) and non-dialysis (ND) subjects, with adequate 
safety and efficacy in clinical trials having been demonstrated up to 24 weeks.  Both pre-
clinical and clinical data show that GSK1278863 stimulates EPO production resulting in 
increased erythropoiesis and elevation in Hgb concentrations.  These increases in Hgb are 
achieved with peak EPO exposures substantially lower than those observed with ESAs.  
Data from completed clinical and preclinical studies are provided in the GSK1278863 
Investigator Brochure (IB) and IB Supplements [GlaxoSmithKline Document Number 
RM2008/00267/07, GlaxoSmithKline Document Number 2015N266524_00,
GlaxoSmithKline Document Number 2015N266524_01].
2.2.
Study Rationale
In clinical studies to date, GSK1278863 has been administered as a once daily (QD) 
regimen.  However, the preferred practice in countries that utilize a three-times weekly 
hemodialysis (HD) schedule is administration of anemia therapy at the time of the HD 
session.  In order to accommodate this preference, and to provide additional flexibility for 
administration of GSK1278863, GSK proposes to also assess the ability of GSK1278863 
to maintain Hgb levels when administered three-times weekly.  This study will describe 
the dose-Hgb response relationship of three-times weekly dosing over a 29-day treatment 
period.  It is anticipated that the data generated from this study will enable conversion of 
QD starting and maintenance dose regimens to three-times weekly doses/regimens.
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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary
!
Characterize the dose-response relationship 
between GSK1278863 administered three-
times weekly and Hgb at Day 29
!
Hgb change from baseline at Day 29
Secondary
!
Characterize the pharmacodynamic (PD) 
effect of GSK1278863 dose regimens on 
EPO, vascular endothelial growth factor 
(VEGF), hepcidin and red blood cells
!
Maximum observed change from baseline in 
EPO
!
Maximum observed % change from baseline 
in VEGF
!
Change from baseline in hepcidin at Day 29
!
Change from baseline in hematocrit, red 
blood cell (RBC) count, reticulocyte count 
and reticulocyte Hgb (CHr) at Day 29
!
Characterize the steady-state PK of 
GSK1278863 and major metabolites
!
Descriptive PK summaries of GSK1278863 
and major metabolites
!
Assess the safety and tolerability of 
GSK1278863 with three-times weekly 
administration for 29 days
!
Incidence and severity of AEs and SAEs
!
Reasons for discontinuation of 
investigational product
!
Discontinuation for safety-related reasons, 
e.g., pre-specified stopping criteria or AE
!
Absolute values and changes from baseline 
over time in laboratory parameters, ECGs 
and vital signs
Exploratory
!
Evaluate exposure-response relationships 
between GSK1278863 and PD endpoints
!
Further models (as appropriate) to describe 
the GSK1278863 exposure (PK or dose) 
response relationship with PD endpoints
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomized, double-blinded, dose-ranging, placebo-controlled, parallel group 
study.  There is a 28-day Screening period, a 29-day Treatment period, and a Follow-up 
visit 14 ± 3 days after completing treatment.  The study design is outlined in Figure 1.
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Figure 1
Study Design
10 mg
Three-times weekly
15 mg 
Three-times weekly
25 mg
Three-times weekly
30 mg
Three-times weekly
Treatment Period Day 1 - 29
Randomization
(1:1:1:1:1)
Follow-Up
Day 43 (+ 3 Days)
Screening
Day -28 to Day -1
Placebo
This will be a double-blinded study.  The subjects, investigator and sponsor will not be 
aware of the treatment received.
Subjects will be stratified by prior ESA dose based on the average weekly (for epoetins 
or darbepoetin) or monthly (for methoxy PEG-epoetin beta) dosing during the 12 weeks 
prior to randomization (Day 1) as follows:
!
Low ESA dose: <100 IU/kg/week epoetin OR <0.5 μg/kg/week darbepoetin OR 
<0.6 μg/kg/week methoxy PEG-epoetin beta
!
High ESA dose: ≥100 IU/kg/week epoetin OR ≥0.5 μg/kg/week darbepoetin OR 
∀0.6 μg/kg/week methoxy PEG-epoetin beta
4.2.
Treatment Arms and Duration
The total duration of subject involvement is up to 10 weeks (Screening to Follow-up) as 
described below:
!
Screening will be for at least 28 days prior to randomization.  A window of 
±2 days will be allowed for visits during the Screening period.
!
Subjects who meet eligibility criteria will be randomized and begin dosing on Day 
1.  Subjects will discontinue their current ESA therapy and will be randomized to 
receive one of four three-times weekly doses, or placebo on a dialysis day as 
listed in Table 1.  Examples of switching are provided in the Study Reference 
Manual (SRM).
o
This should be timed such that randomization (Day 1) occurs on the date that 
would have been the next scheduled dose of ESA (or as close as practicable).
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o
For subjects with a three-times weekly dialysis schedule, Day 1 must not 
occur on the first dialysis session of the week (e.g., if Monday-Wednesday-
Friday schedule, the study visit cannot be on Monday).
o
For subjects with a four- to five-times weekly dialysis schedule, Day 1 can be 
on any hemodialysis session of the week.
!
The Treatment period will be for a total of 29 days. A window of ±2 days is 
allowed for visits during the Treatment period.
o
At Day 29, all subjects will receive their last dose of study treatment and 
should not re-start ESA therapy until after the follow-up visit (Day 43).  
However, if the Investigator has a compelling clinical reason why a subject 
should restart ESA between Day 29 and Day 43, then ESA may be restarted 
prior to Day 43.
!
A Follow-up visit will be scheduled to occur 14 ±3 days after completing 
treatment.
Subjects will be randomized 1:1:1:1:1 to one of 5 treatment arms:
Table 1
Study Treatment Arm Descriptions
Treatment Arm
Description
A
10 mg GSK1278863 three-times weekly
B
15 mg GSK1278863 three-times weekly
C
25 mg GSK1278863 three-times weekly
D
30 mg GSK1278863 three-times weekly
E
Placebo three-times weekly
Stopping algorithms are provided in Section 5.6.2 if Hgb values meet protocol pre-
specified ranges.
4.3.
Type and Number of Subjects
The study will enroll subjects on HD with anemia associated with CKD switching from 
ESA treatment.  The range of Hgb values for study eligibility is 9.0 - 11.5 g/dL and the 
subjects must have received the same ESA product with total weekly doses that varied by 
no more than 50% from 4 weeks prior to the Day -28 Screening visit through to Day 1.
Approximately 200 subjects will be screened to achieve approximately 90 randomized 
and 75 evaluable subjects, with approximately 15 evaluable subjects per treatment group.
4.4.
Design Justification
The purpose of this study is to describe the Hgb dose-response relationship for three-
times weekly dosing of GSK1278863 at 29 days in order to describe the efficacy 
relationship between once-daily (QD) and three-times weekly administration.  To date, 
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GSK1278863 has been administered to the HD population only by a QD dosing regimen, 
and this study is planned to enable three-times weekly dosing to be evaluated in future 
clinical studies.  This is a randomized, double-blinded, dose-ranging, placebo-controlled, 
parallel group study with a treatment period of 29 days.
The dose-response relationship for QD dosing of GSK1278863 in the HD population has 
been established in a 24-week Phase 2 study.  In that study, the Hgb response (change 
from baseline) was determined at 4 weeks over the dose range of 4 mg to 12 mg; 
therefore, in order to make a direct comparison between the QD and three-times weekly 
regimens, a 29-day treatment period will be utilized.
This study will be placebo controlled in order to establish a no-effect dose response 
relationship.  In a previous study, for subjects on placebo, Hgb levels were observed to 
decline on average 0.72 g/dL (GSK study PHI113633; range: -2.3 to 0.9 g/dL) with no 
subjects requiring rescue medication.  Therefore, there is little risk for a subject’s Hgb to 
decline to levels requiring rescue; however, stopping criteria for Hgb are included in this 
protocol.
This will be a double-blind study with subjects, investigator, site and sponsor staff 
blinded to treatment received. Although Hgb response is an objective endpoint that is 
unlikely to be affected by knowledge of treatment received, as safety and tolerability will 
be assessed in this study, a double-blind design will decrease the likelihood of reporting 
bias.  In addition, as some subjects will be administered placebo, the knowledge of their 
study treatment may influence their study completion and/or withdrawal.
4.5.
Dose Justification
To date, GSK has conducted four clinical trials with GSK1278863 in the treatment of 
anemia associated with CKD in patients on HD.  In all of these studies, GSK1278863 has 
been administered as a QD dose regimen.  However, as clinical practice (standard of 
care) in the treatment of anemia in CKD patients on HD often utilizes a three-times a 
week regimen consistent with their hemodialysis schedule, GSK proposes to assess this 
regimen as part of our planned Phase 3 clinical program in hemodialysis patients.
In addition to administration on a three-times weekly dosing schedule, extended interval 
dosing (i.e., weekly to monthly) is also routinely used with ESAs.  Evidence with epoetin 
alfa (Epogen), with Dosing and Administration guidance for three-times weekly dosing, 
has shown that increases in dosing interval (i.e., extended time between doses) can be
achieved by a proportionate increase in the dose administered at each interval.  As 
reported in a small study, epoetin alfa was administered subcutaneously at either 
50 IU/kg three-times weekly, 10,000 IU/week, 20,000 IU every two weeks or 40,000 IU 
every 4 weeks with consistent management of Hgb levels for all 4 regimens in anemia 
patients with CKD not on dialysis [McGowan, 2008].  As GSK1278863 dose response 
with Hgb is generally linear between 4 and 24 mg QD, it is anticipated that a similar 
time-proportional efficacy relationship will exist for GSK1278863 and the management 
of Hgb levels as the dosing is extended from once every day to three-times weekly.
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These data suggest that the efficacy of PHIs is most likely related to total dose or AUC, 
rather than Cmax or Cmin.  Additionally, the time to reach the steady-state response is 
determined by the RBC lifespan which on average is 2-3 months.  These data further 
support that three-times weekly administration of GSK1278863 is feasible, and that 
three-times weekly doses may be selected based on efficacy data collected after QD 
administration.  The hypothesized three-times weekly dose ‘equivalent’ would be 
approximately 2.3 times that of the QD dose (e.g., 9 mg three-times weekly would be 
expected to result in equivalent efficacy as 4 mg QD).  To match a similar Hgb response 
range to the once daily regimen, doses of 10, 15, 25 and 30 mg three-times weekly will 
be investigated for 29 days to match the 4, 6, 10 and 12 mg QD doses.  Studying multiple 
doses allows a robust analysis of a range of three-times weekly doses to determine the 
‘equivalent’ ratio to bridge to QD dose levels.  The dose-Hgb response relationship is 
generally linear in the QD dose range of interest (4 to 24 mg) but it is not known if this 
will be maintained with the higher doses needed for three-times weekly dosing.
Based on review of available safety data received to date, no risks were identified which 
would preclude dosing patients with anemia associated with CKD on dialysis with 
GSK1278863 up to 25 mg QD as well as with an extended dosing interval of three-times 
weekly at doses up to 30 mg in clinical trials in which appropriate risk minimization and 
monitoring processes are in place.
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK1278863 can be found in the GSK1278863 Investigator’s Brochure (IB) and IB 
Supplements [GlaxoSmithKline Document Number RM2008/00267/07, 
GlaxoSmithKline Document Number 2015N266524_00, GlaxoSmithKline Document 
Number 2015N266524_01].
4.6.1.
Benefit Assessment
GSK1278863 has been shown to be generally well tolerated and effective for up to 24
weeks in a recently-completed Phase 2 study (GSK study PHI113633) in the management 
of Hgb levels in patients with anemia associated with CKD that are hemodialysis-
dependent.  However, as the present study is designed to characterize the dose-response 
relationship between GSK1278863 and the change from baseline in Hgb, it is anticipated 
that some subjects will experience a decrease, and some an increase in Hgb which may 
fall outside of target during the 29 days of treatment.  Therefore, a proportion of subjects 
enrolled in this study will not gain a benefit from participation in this study.
4.6.2.
Risk Assessment
The potential risks of clinical significance and the mitigation strategies for this protocol
taking into account the results of clinical and nonclinical studies with GSK1278863 are 
outlined in Section 12.3.  In addition to the mitigation strategies outlined, an internal 
GSK Safety Review Team (SRT) will monitor accruing safety data in a blinded fashion 
for this trial.
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4.6.3.
Overall Benefit:Risk Conclusion
GSK1278863 demonstrates a positive benefit vs. risk based on the evidence as follows.  
In clinical trials up to 24 weeks in duration, GSK1278863 treats Hgb to target range, and 
there were no adverse events that had been identified as related to treatment with 
GSK1278863.
This protocol employs precautions to mitigate known and potential risks to enrolled 
subjects (See Section 12.3 Appendix 3).  Given these precautions, as well as the potential 
benefit that GSK1278863 holds for the treatment of anemia in CKD patients compared to 
the current standard, the overall benefit risk balance is considered to be positive.
5.
SELECTION OF STUDY POPULATION 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 Investigator’s Brochure
and IB Supplements [GlaxoSmithKline Document Number RM2008/00267/07, 
GlaxoSmithKline Document Number 2015N266524_00, GlaxoSmithKline Document 
Number 2015N266524_01].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety.  Therefore, adherence to the criteria as specified in the protocol is 
essential.
5.1.
Hemoglobin Stability Criteria
Entry into the study requires a stable Hgb between 9.0 - 11.5 g/dL.  This is confirmed 
from an average of three Hgb values obtained via a validated point-of-care device to 
measure Hgb (HemoCue) on site during the screening period at Day -28, Day -14 and 
Day 1 (randomization) as outlined in Figure 2.  Calculations to determine eligibility will 
be performed automatically by IVWRS.  For subjects with a three times weekly dialysis 
schedule, Hgb values must not be obtained on the first dialysis session of the week (e.g., 
if Monday-Wednesday-Friday schedule, the study visit cannot be on Monday).  For 
subjects with a four to five times weekly dialysis schedule, Hgb values can be obtained 
on any hemodialysis session of the week.
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Figure 2
Hemoglobin Stability Criteria
Obtain Hgb sample (HemoCue). 
Is Hgb within 9.0 – 11.5 g/dL? 
Not eligible for study; 
can be rescreened in 
2 weeks
No
Obtain Hgb sample (HemoCue). Is the absolute 
difference (max-min) <1.3 g/dL from 1st Hgb
(with no clinical evidence of overt bleeding)?
Yes
Not eligible for study; 
can be rescreened in 
2 weeks
No
Subject eligible for full 
screening
Yes
Screening Criteria Met?
Not eligible for study; 
can be rescreened as 
stated in Section 5.5
No
Subject eligible for 
randomization visit
Yes
Obtain Hgb sample (HemoCue). Are the following met for the 
3 Hgb values (Day -28, Day -14, Day 1)?
• Average in range of 9.0 – 11.5 g/dL AND
• Absolute difference (max-min) <1.3 g/dL with no clinical 
evidence of overt bleeding
Randomize Subject
Yes
Not eligible for study; 
can be rescreened in 
2 weeks
No
Hgb #1: Day -28
Hgb #2: Day -14
Hgb #3: Day 1
5.2.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. ≥18 years of age, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Hemoglobin: Stable Hgb 9.0 - 11.5 g/dL (see Section 5.1).
3. Dialysis frequency: On hemodialysis (HD, hemofiltration or hemodiafiltration) three 
to five times weekly for at least 4 weeks prior to Day -28 Screening through Day 29.
4. Dialysis adequacy: A single pool Kt/Vurea of ∀1.2 based on a historical value 
obtained within the prior three months in order to ensure the adequacy of dialysis.  If 
Kt/Vurea is not available, then an average of the last 2 values of urea reduction ratio 
(URR) of at least 65%.  NOTE: Only needs confirming at Day -28.
5. Stable ESA dose: Treated with the same ESA (epoetins or their biosimilars, or 
darbepoetin or methoxy PEG-epoetin beta) with total weekly dose varying by no 
more than 50% from 4 weeks prior to Day -28 through Day 1 (randomization).
6. Iron replacement therapy: Subjects may be on maintenance oral or IV iron 
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supplementation.  If subjects are on oral iron, then the type of iron and doses must not 
be changed for the 4 weeks prior to Day -28, during the screening phase, and through 
the 29 days of treatment.  If subjects are on IV iron, then doses must be 
≤100 mg/week, and doses must not be changed for the 4 weeks prior to Day -28, 
during the screening phase, and through the 29 days of treatment.  
INFORMED CONSENT
7. Capable of giving signed informed consent as described in Section 10.2, which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.3.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CKD-RELATED CRITERIA
1. Dialysis modality: Planned change from HD to peritoneal dialysis within the study 
time period.
2. Renal transplant: Planned for living-related or living-unrelated kidney transplant.
3. High ESA dose: An epoetin dose of ≥360 IU/kg/week IV or ≥250 IU/kg/week 
subcutaneous (SC) or darbepoetin dose of ≥1.8 μg/kg/week IV or SC or methoxy 
PEG-epoetin beta dose of ∀2.2 μg/kg/week within the prior 8 weeks through Day 1 
(randomization).
4. Mircera: Administration of Mircera (methoxy PEG-epoetin beta) within 2 weeks 
prior to Day 1 if subject is on a once-every-2-weeks schedule or within 4 weeks prior 
to Day 1 if subject is on a once-every-4-weeks schedule.  
CARDIOVASCULAR DISEASE-RELATED CRITERIA
5. Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to 
Screening through Day 1 (randomization).
6. Stroke or transient ischemic attack: Within 8 weeks prior to Screening through 
Day 1 (randomization).
7. Heart failure: Class IV heart failure, as defined by the New York Heart Association 
(NYHA) functional classification system diagnosed prior to Screening through Day 1 
(randomization).
8. QTcB: QTcB >500 msec or QTcB >530 msec in subjects with Bundle Branch Block.  
There is no QTc exclusion for subjects with a predominantly paced rhythm.
OTHER DISEASE-RELATED CRITERIA
9. Inflammatory disease: Active chronic inflammatory disease that could impact 
erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, 
celiac disease) diagnosed prior to Screening through Day 1 (randomization).
10. Hematological disease: Any hematological disease including those affecting 
platelets, white or red blood cells (e.g., sickle cell anemia, myelodysplastic 
syndromes, hematological malignancy, myeloma, hemolytic anemia and thalassemia), 
coagulation disorders (e.g., antiphospholipid syndrome, Protein C or S deficiency), or 
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any other cause of anemia of chronic disease other than renal disease diagnosed prior 
to Screening through Day 1 (randomization).
11. Liver disease: Current liver disease, known hepatic or biliary abnormalities (with the 
exception of Gilbert’s syndrome or asymptomatic gallstones) or evidence at 
Screening of abnormal liver function tests [alanine transaminase (ALT) or aspartate 
transaminase (AST) >2x upper limit of normal (ULN) or total bilirubin >1.5xULN]; 
or other hepatic abnormalities that in the opinion of the investigator would preclude 
the subject from participating in the study.
NOTE: Those with Hepatitis B or Hepatitis C are eligible provided these exclusions 
are not met.
12. Major surgery: Major surgery (excluding vascular access surgery) within the 8 
weeks prior to Screening, during the Screening phase, or planned during the study.
13. Transfusion: Blood transfusion within the 8 weeks prior to Screening, during the 
Screening phase or an anticipated need for blood transfusion during the study.
14. GI Bleeding: Evidence of actively bleeding peptic, duodenal, or esophageal ulcer 
disease OR clinically significant GI bleeding within the 8 weeks prior to Screening 
through Day 1 (randomization).
15. Acute Infection: Clinical evidence of acute infection or history of infection requiring 
intravenous (IV) antibiotic therapy within the 4 weeks prior to Screening through Day 
1 (randomization).  NOTE: IV antibiotics as prophylaxis are allowed.
16. Malignancy: History of malignancy within the two years prior to Day -28 through to 
Day 1 (randomization) or currently receiving treatment for cancer, or has a known 
complex kidney cyst (i.e. Bosniak Category II F, III of IV) > 3cm.  NOTE: The 
ONLY exception is squamous cell or basal cell carcinoma of the skin that has been 
definitively treated ∀8 weeks prior to Screening.
CONCOMITANT MEDICATIONS
17. Severe allergic reactions: History of severe allergic or anaphylactic reactions or 
hypersensitivity to excipients in the investigational product.
18. Drugs and supplements: Use of any prescription or non-prescription drugs or 
dietary supplements that are prohibited (see Section 6.9.2 for details) from Screening 
until the Follow-up Visit.
19. Prior investigational product exposure: The Subject has participated in a clinical 
trial and has received an experimental investigational product within the prior 30 days 
from Screening through Day 1 (randomization).
GENERAL HEALTH RELATED CRITERIA
20. Other conditions: Any other condition, clinical or laboratory abnormality, or 
examination finding that the investigator 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.
21. Females ONLY: Does not meet the female eligibility criteria (Section 12.6 Appendix 
6), is pregnant [as confirmed by a positive serum human chorionic gonadotrophin 
(hCG) test for females of reproductive potential (FRP) only], breastfeeding, and if of 
reproductive potential does not agree to follow one of the options listed in Section 
12.6.1.
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DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
(To be verified on Day -28 only)
22. Vitamin B12: At or below the lower limit of the reference range (may rescreen in a 
minimum of 8 weeks).
23. Folate: <2.0 ng/mL (4.5 nmol/L) (may rescreen in a minimum of 4 weeks).
24. Ferritin: <100 ng/mL (<100 μg/L).
25. Transferrin saturation (TSAT): <20%.
5.4.
Other Eligibility Criteria Considerations
Laboratory eligibility criteria will be assessed according to the central laboratory results 
from the Screening visit samples.  See Section 7.4.6 for a listing of Clinical Laboratory 
Assessments.
5.5.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized.  In this study, a subject can become a screen failure 
at any time from the Day -28 visit to the Day 1 visit, prior to randomization.  In order to 
ensure transparent reporting of screen failure subjects, meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements, and respond to queries from 
Regulatory authorities, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and Serious Adverse Events (see 
Section 7.4.1.6).
Subjects who fail screening may be rescreened as soon as the investigator feels they may 
have become eligible.  However, an individual subject may not rescreen more than twice.  
There is no predetermined amount of time that the investigator needs to wait to rescreen a 
previously ineligible subject, except those excluded for Hgb or folate who may only 
rescreen in 2 and 4 weeks, respectively, and those excluded for Vitamin B12 who may 
rescreen in 8 weeks.
5.6.
Withdrawal/Stopping Criteria
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral or 
administrative reasons.  If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records.
The reason for discontinuation of study treatment and/or withdrawal from the study must 
be recorded in the eCRF.
Refer to the Time and Events Table (Section 7.1) for the assessments to complete in the 
event of discontinuation of study medication and early withdrawal.
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5.6.1.
Criteria for Permanent Discontinuation from Study Medication 
and Early Withdrawal
Subjects must permanently discontinue study medication for the following reasons:
!
Meeting Hgb stopping criteria (Section 5.6.2).
!
Receiving blood transfusions.
!
Receiving kidney transplant.
!
Subject becomes pregnant or intends to become pregnant during the study.
!
Active GI bleeding.
!
Diagnosis of cancer, with the exception of squamous cell and basal cell 
carcinoma.
!
Liver chemistry abnormalities exceeding the threshold criteria (Section 5.6.4).
!
Missing 2 consecutive dialysis sessions.
!
Need for chronic (more than 14 days) use of prohibited medication (Section 
6.9.2).
The subject should attend the clinic as soon as possible to complete the Early Withdrawal 
assessments and return for a Follow-up visit as described in Section 7.1, Time and 
Events.
The reason for discontinuation of study medication and date of last dose will be recorded 
in the eCRF.
5.6.2.
Hemoglobin Stopping Criteria
GSK will supply a point-of-care Hgb analyzer (HemoCue) to each site for rapid and 
convenient monitoring of Hgb levels and to ensure consistency of Hgb measurements 
across sites participating in the study.
Blood samples for measurement of Hgb concentrations via HemoCue from the screening 
visits and throughout the treatment period will be collected as specified in Section 7 and 
recorded in the eCRF.  
Subjects must permanently discontinue study medication if:
!
Confirmed Hgb (2 measurements by HemoCue pre-dialysis) <7.5 g/dL
!
Confirmed Hgb increases ∀1.0 g/dL over the previous 2 weeks
For Hgb ∀13.0 g/dL, withdrawal will be in consultation with the GSK Medical Monitor.  
The table below summarizes the Hgb values and corresponding action to be taken:
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Hgb (g/dL) 
at visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, permanently discontinue study drug.
∀7.5-<13.0
∀2.0 decrease in Hgb over 2 
weeks
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  
If confirmed, permanently discontinue study drug.
<1.0 increase or <2.0 decrease
in Hgb over 2 weeks
Continue study drug.
∀1.0 increase in Hgb over 2 
weeks
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  
If confirmed, permanently discontinue study drug.
∀13.0
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, consider permanently discontinuing study drug in 
consultation with GSK Medical Monitor.
In cases where the Hgb values from the central laboratory meet any of the Hgb stopping 
criteria in the above table, but the Hgb values from the HemoCue device do not, then the 
Investigator and the GSK Medical Monitor should discuss this situation before 
potentially discontinuing study medication.
If a subject is permanently discontinued from study medication, then the subject should
attend the clinic as soon as possible to complete the Early Withdrawal assessments and 
Follow-up visit (see Section 7.1, Time and Events) as described in Section 5.7.
The reason for discontinuation of study medication and date of last dose will be recorded 
in the eCRF.
5.6.3.
Missed Clinic Visits/Lost to Follow-up
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:
!
The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible
!
The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study
!
In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods).  These contact attempts 
should be documented in the subject’s medical record
!
Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”
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5.6.4.
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).  Drug-Induced Liver Injury Guidance
Phase II 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≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
 If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
 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 12.2 Appendix 2.
5.6.4.1.
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.
5.7.
Early Withdrawal
If a subject is withdrawn from the study, for any reason, they will be considered to be an 
Early Withdrawal.  The reason for the early withdrawal will be recorded in the eCRF.  
The Early Withdrawal assessments, as detailed in Section 7.1 Time and Events Table, 
should be performed as soon as possible following withdrawal.  Subjects should also
attend a Follow-up visit according to the timing and assessments in Section 7.1 Time and 
Events Table.
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5.8.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
Follow-up visit.
The end of the study is defined as the last subject’s last visit (LSLV).
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design.  Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment
Product name:
GSK1278863
Placebo
Dosage form:
Tablet
Tablet
Unit dose 
strength(s)/Dosage 
level(s):
5 mg and 25 mg tablet 
strengths/10 mg, 15 mg, 25 mg, 
30 mg dosage levels
0 mg
Route of Administration:
Oral
Oral
Physical description:
A round, biconvex, 10 mm white 
film coated tablet.
A round, biconvex, 10 mm white film 
coated tablet.
All eligible subjects will discontinue their current ESA therapy and will be randomized to 
receive either GSK1278863 or matching placebo on a dialysis day.  This should be timed 
such that randomization (Day 1) occurs on the date that would have been the next 
scheduled dose of ESA (or as close as practicable).  In addition, for subjects with a three 
times weekly dialysis schedule, Day 1 must not occur on the first dialysis session of the 
week (e.g., if Monday-Wednesday-Friday schedule, the study visit cannot be on 
Monday).  For subjects with a four to five times weekly dialysis schedule, Day 1 can be 
on any hemodialysis session of the week.  Examples of switching are provided in the 
SRM.
To maintain the blind, subjects will have study treatment dispensed from three bottles of 
study medication.  This combination of tablets will provide the appropriate dose of study 
medication, and will include a combination of tablet strengths, active and placebo, to 
correspond to the appropriate dose.
Subjects will be dispensed one tablet from each bottle (all subjects will take three tablets 
in total) and take with a glass of water on a dialysis day, and this should be prior to 
dialysis; however, on Day 1 it is acceptable for the subject to take study medication after 
dialysis.  All study medication should be taken in the clinic EXCEPT prior to the PK day 
(Day 15 study visit), or on other days only if the Investigator and GSK Medical Monitor 
agree that it will not interfere with the study procedures or affect the subject’s compliance
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with the protocol.  The study site must ensure that the date and time the subject took each 
dose of study treatment is documented.
On the PK day, subjects will be instructed to take their dose of study medication at home 
and arrive for clinic visit approx. 6-10 hr post-dose.  Subjects may take their Day 15 dose 
the evening prior to the study visit to accommodate the 6-10 hr PK/PD sampling window.  
Additional instructions can be found in the SRM.
Subjects can take their tablets without regard to food.  For all study visits, it is 
recommended for subjects not to eat a heavy meal before coming to the clinic in order to 
avoid lipemia of the blood sample collected for the analysis of transferrin, iron and TIBC.
6.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedule generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.
The randomization schedule will be computer generated by PPD using the randomization 
system Prism.  Subjects will be stratified as outlined in Section 4.1 and assigned a 
randomization number by IVWRS managed by PPD.  Once a randomization number has 
been assigned, it must not be reassigned.
6.3.
Blinding
This will be double-blind study, with the subject, investigator and site staff, and GSK 
study team all unaware of the study treatment received.  The following will apply 
concerning unblinding:
!
The investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
investigator.
!
Investigators have direct access to the subject’s individual study treatment.
!
It is preferred (but not required) that the investigator first contacts the GSK 
Medical Monitor or appropriate GSK study personnel to discuss options before 
unblinding the subject’s treatment assignment.
!
If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study.
!
The date and reason for the unblinding must be fully documented in the eCRF.
A subject may continue in the study if that subject’s treatment assignment is unblinded.
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!
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any subject with an SAE.  If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of 
the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.
6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
!
Only subjects enrolled in the study may receive study treatment.  Study 
medication is to be stored up to 30°C (86°F).  Maintenance of a temperature log 
(manual or automated) is required.
!
The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  
Study treatment must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the study treatment 
will be limited to the investigator and authorized site staff.
!
Further guidance and information for final disposition of unused study treatment 
are provided in the SRM.
!
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.
!
A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.6.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee.  The date and time of each dose administered in the clinic, as 
well as the bottle number will be recorded in the source documents.
When a subject self-administers study treatment at home, compliance with GSK1278863 
will be documented in a subject-completed paper diary and assessed through querying the 
subject during the site visit, documented in the source document and recorded into the 
eCRF.  A record of the number of GSK1278863/placebo tablets dispensed to and taken 
by each subject must be maintained and reconciled with study treatment and compliance 
records.  Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the eCRF.
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6.7.
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.  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, patients should be monitored 
closely for cardiovascular events, increased heart rate and hematologic abnormalities.
6.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.9.
Concomitant Medications and Non-Drug Therapies
Concomitant medications, including over-the-counter and supplements, taken during the 
study will be recorded in the eCRF.  Start and stop dates will be recorded for general 
concomitant medications, while additional details of dose, route, and frequency will be 
recorded for supplemental iron.  The potential for drug-drug interactions is described in 
Section 12.3 Appendix 3.
6.9.1.
Permitted Medications and Non-Drug Therapies
Unless specified as a prohibited medication in Section 6.9.2, all concomitant prescription 
medications should be considered permitted provided they are not contraindicated for the 
individual subject concerned.
Regular multivitamins (at recommended daily allowance including for iron) and other 
vitamin supplements such as calcium and vitamin D are permitted at the discretion of the 
principal investigator or his/her designee.
GSK1278863 is a substrate of breast cancer resistance protein (BCRP).  The potential for 
inhibitors of BCRP to increase the plasma exposure of GSK1278863 to any relevant 
extent is unknown.  BCRP inhibitors are not excluded from safety/efficacy studies; 
Hemoglobin stopping criteria mitigate risk of increased pharmacology if co-administered.  
Co-administration of GSK1278863 with strong BCRP inhibitors [i.e., cyclosporine, HIV 
antivirals (atazanavir, lopinavir, ritonavir, tipranavir), lapatanib and curcumin] should be 
performed with caution.
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6.9.2.
Prohibited Medications and Non-Drug Therapies
Any herbal or dietary supplements, unless, in the opinion of the investigator (who should 
consult the Sponsor), the therapy will not interfere with the study, are prohibited from 
Screening to the Follow-up Visit.
New androgen therapy within the 12 weeks prior to Screening, at any time during the 
study, or changes to pre-existing androgen regimen during the study is prohibited.
Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) with the exception of 
low dose (≤325 mg/day) aspirin/acetylsalicylic acid is prohibited.  Occasional NSAID 
use is permitted.
Use of any of the following prescription drugs from Day 1 until seven days after the last 
dose of study treatment is prohibited and will constitute a protocol violation:
!
Strong inhibitors of CYP2C8 (e.g., gemfibrozil)
!
Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)
7.
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 (Section 7.1), are essential and required for study 
conduct.
Time and Events Tables are provided in Section 7.1 for the overall study and for the 
specific Pharmacokinetic/Pharmacodynamic assessments (Table 2).
Study visit days are based on the schedule for hemodialysis as follows:
!
Three times weekly: Hgb levels may have the greatest variability around study 
visits at the beginning of the week; therefore, the Day 1, 15 and 29 study visit 
must not occur on the first dialysis session of the week (e.g., if Monday-
Wednesday-Friday dialysis schedule, then the study visit cannot be on Monday).
!
Four to five times weekly: Designated study visit can be on any hemodialysis 
session of the week.
To allow scheduling flexibility, study visits should occur within a window of ±2 days, 
except for subjects on a three times weekly dialysis schedule for whom study visits 
must not be scheduled on the first dialysis session of the week.  Post-randomization 
visits should be referenced back to the Randomization visit (Day 1).  In exceptional 
circumstances, minor changes to visit structure may be permitted after consultation with 
the GSK Medical Monitor.
The following points must be noted:
!
If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. Vital signs
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3. Blood draws
NOTE: The timing of the assessments should allow the blood draw to occur at 
the exact nominal time.
!
The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment.
!
The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form.
!
No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.
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7.1.
Time and Events Table
Protocol Activity 1, 2
Screening
Day 1
Treatment Period
Follow-up
Week 
-4
Week 
-2
Day 15
Day 29
Un-scheduled
Early 
Withdrawal
Day 43 ± 3 6
Informed Consent
X
Entry Criteria
X
X
Physical, Medical History, Demography
X
HemoCue Hgb
X
X
X
X
X
X
X
IVWRS Call
X
X
X
X
X
X
X
X
Females Only: Serum Pregnancy Test 3
X
X
X
Females Only: Estradiol and FSH (if required) 3
X
ECG
X
X
X
Vitals (Pre-dialysis and Post-dialysis) 4
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Folate and Vitamin B12
X
Ferritin, transferrin, total iron, UIBC
X
X
X
X
X
Pharmacokinetic/Pharmacodynamic Samples
X
X
X
X 5
Blood draw for PGx
X
Adverse Events Assessment 7
X
X
X
X
X
X
Review Concomitant Medications
X
X
X
X
X
X
X
1.
All assessments should be done pre-dialysis except as noted.
2.
Allowable time window of ± 2 days for all study visits, except the follow-up visit for which it is ± 3 days.
3.
As detailed in Exclusion Criteria in Section 5.3.
4.
Weight measured post-dialysis only & height measured at screening only.
5.
Obtain samples as per the Day 29 visit in Table 2.  If subject does not receive a dose of study medication at this early withdrawal visit, no post-dose PK/PD samples should 
be obtained.
6.
Subjects who withdraw early from treatment should attend a follow-up visit 14 days ± 3 days after the last dose of study treatment.
7.
Serious adverse events are assessed from the time of consent as stated in Section 7.4.1.1.
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Table 2
Pharmacokinetic/Pharmacodynamic Time and Events Table
PK/PD 
Sample
Day 1
(dose study 
med at clinic)
Day 15
(dose study med at home1)
Day 29
(dose study med at clinic)
Plasma 
PK2
Pre-dose
1st sample collected approx 6-10 hr post-
dose on arrival.
Additional sampling: 1, 2, and 3 h after 
this 1st sample
Pre-dose, 1, 2, and 3 h post 
dose
EPO & 
VEGF2
Pre-dose
1st sample collected approx 6-10 h post-
dose on arrival.
Additional sampling: 1, 2, and 3 h after 
this 1st sample
Pre-dose and 3 h post dose
Hepcidin3
Pre-dose
Single sample during visit
Single sample during visit
1.
Subject to take their dose of study medication at home and arrive for clinic visit approx 6-10 h post-dose.  
Subjects may take their Day15 dose the evening prior to the Week 2 study visit to accommodate the 6-10 h 
PK/PD sampling window.
2.
Sample to be collected within 30 minutes of planned collection time.
3.
Sample can be pre- or post-GSK1278863 administration.
7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history and risk factors (as detailed in the eCRF) will be assessed 
at screening.
Entry into the study requires a stable Hgb of 9.0 - 11.5 g/dL.  A stable Hgb value will be 
confirmed from three Hgb values taken during the screening period at Day -28, Day -14 
and Day 1 (randomization) as outlined in Section 5.1.
7.3.
Efficacy
Hgb values to be used in the determination of the primary endpoint (Hgb change from 
baseline at Day 29) will be measured by the central laboratory as part of the Clinical 
Safety Laboratory Assessments (Section 7.4.6).  Day 1 measurement will serve as the 
baseline value.
7.4.
Safety
Regular monitoring of hematology, blood chemistry and vital signs will occur throughout 
the study.  Serum pregnancy tests will be performed in women of child-bearing potential 
at Screening and Follow-up.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 12.5.
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The investigator or their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
7.4.1.1.
Time period and Frequency for collecting AE and SAE information
!
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.
!
AEs will be collected from the start of Study Treatment (Day 1) until the Follow-
up visit (see Section 7.4.1.4).
!
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 eCRF.
!
All SAEs will be recorded and reported to PPD within 24 hours, as indicated in 
Section 12.5.4.
!
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 PPD.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to PPD are provided in 
Section 12.5.6.
7.4.1.2.
Adverse Events of Special Interest
The following have been identified as adverse events of special interest (AESIs) for 
GSK1278863 based on nonclinical studies, the mechanism of action and pharmacological 
activity of GSK1278863, current information about hypoxia-associated pathophysiology, 
studies of genetically engineered animal models, and naturally occurring mutations in 
man:
!
Thrombosis and tissue ischemia secondary to excessive erythropoiesis
!
Death, MI, 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
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!
Exacerbation of rheumatoid arthritis
The results of any investigation should be recorded in the relevant sections of the 
subject’s eCRF
7.4.1.3.
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?”
7.4.1.4.
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 7.4.1.2) 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 5.6.3).  Further information on follow-up procedures is given in 
Section 12.5.4.
7.4.1.5.
Cardiovascular and Death Events
For any events that may represent the cardiovascular events detailed in Section 12.5.3
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.
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.
7.4.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK/PPD (or designee) of SAEs related to 
study treatment (even for non- interventional post-marketing studies) is essential so that 
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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.
Pregnancy
!
Details will be collected about all pregnancies reported after the start of dosing 
and until the Follow-up Visit.
!
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 12.6.2.
Subjects must permanently discontinue study medication if pregnancy occurs (see 
Section 5.6.1).
7.4.3.
Physical Exams
!
A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, including vascular access, Respiratory, Gastrointestinal and 
Neurological systems.  Height and weight will also be measured and recorded.
!
Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
7.4.4.
Vital Signs
Vital signs include systolic blood pressure (SBP), diastolic blood pressure (DBP), heart 
rate (HR), height and weight.  Three measurements of SBP, DBP and HR will be 
recorded at each study-specified visit.  Measurements will be taken from the subject 
while in a seated position or semi-supine in the dialysis chair.  Vital signs will be 
recorded pre-dialysis (except weight) and post-dialysis as outlined in Section 7.1.  Height 
will be measured during the Screening period (at Day -14) only.  Additional details are 
provided in the SRM.
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7.4.5.
Electrocardiogram (ECG)
Full 12-lead ECGs will be recorded in subjects while in a supine position at the times as 
outlined in Section 7.1, Time and Events Table.  The parameters to be measured include 
heart rate, PR interval, QRS duration, and QT (uncorrected) interval.  QTcB is to be 
calculated.
While it is preferred that ECGs are performed pre-dialysis, it is acceptable for this to 
occur at any time during the dialysis session.  However, it is requested that the timing of 
the ECGs be performed consistent with the Screening assessment.
At any study visit when ECGs are performed, two additional ECGs are required if initial 
ECG indicates prolonged QTcB using the manually-calculated QTcB value.  The average 
QTcB value of three ECGs will be used to determine eligibility as provided in Section 
5.3, Eligibility Criteria.  Additional details are provided in the SRM.
7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 3, 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 labelled 
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 laboratory and are 
detailed in the SRM.  Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.
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 (e.g., SAE or AE) the results must be 
recorded in the eCRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory, apart 
from the HemoCue Hgb, with the results of each test entered into the eCRF.
NOTE: Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed.  If a local sample is required it is important that the sample for central 
analysis is obtained at the same time.  Additionally, if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
eCRF.
Hematology, clinical chemistry and additional parameters to be tested are listed in Table 
3.
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Table 3
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
WBC Count with 
Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
WBC Count (absolute)
RDW
Eosinophils
Reticulocyte Count
CHr
Basophils
Clinical 
Chemistry
Potassium
AST (SGOT)
Total and direct/indirect 
bilirubin
Sodium
ALT (SGPT)
Total Protein
Glucose
Calcium (Albumin 
adjusted)
Alkaline Phosphatase
Albumin
Phosphate
Other laboratory 
Tests
Erythropoietin
Vascular Endothelial 
Growth Factor
Hepcidin
Serum ferritin
Serum iron
Serum transferrin
Transferrin saturation (% 
saturation)
Unbound iron binding 
capacity
Folate
Vitamin B12
Other Screening 
Tests1
FSH
Estradiol
Serum hCG Pregnancy 
test
NOTE: Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver 
stopping or monitoring event are given in Section 12.2 Appendix 2
1As required per Appendix 6
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 5 days after the last dose of study treatment 
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, the etiology
should be identified and the sponsor notified.
7.5.
Pharmacokinetics/Pharmacodynamics
Blood samples for PK (GSK1278863 and metabolites) and PD (EPO, VEGF, hepcidin) 
will be collected from all subjects as outlined in Table 2.
7.5.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of parent GSK1278863 and 
metabolites (GSK2391220 [M2], GSK2531403 [M3], GSK2487818 [M4], GSK2506102 
[M5], GSK2531398 [M6], and GSK2531401 [M13]) will be collected at the time points 
indicated in Section 7.1, Time and Events Table.  The actual date and time of each blood 
sample collection will be recorded.  The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring.
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For the PK/PD visits outlined in Table 2, sample times are approximate; however, it is 
imperative that the actual date and time of sampling is recorded in the eCRF.
!
At the Day 1 Visit, pre-dose PK/PD samples will be obtained from all subjects.  
Record the date and time of the last ESA dose administered prior to PD sampling and 
the date and time of the GSK1278863 dose administered at this visit.
!
At Day 15 Visit, post-dose PK/PD samples will be obtained.  Initial PK/PD samples 
will be obtained from all subjects soon after arrival.
o Record the date and time of the last two GSK1278863 doses taken prior to the 
Day 15 Visit (the last dose of GSK1278863 may be taken early on the day of the 
Day 15 Visit, or in the evening of the day before).
o At Day 29 Visit, pre- and post-dose PK/PD samples will be obtained.  Record the 
date and time of the last GSK1278863 dose taken prior to the Day 29 Visit, and 
the date and time of the dose taken at the Day 29 Visit.
Based on the time of dosing, samples may be obtained before, during, and after the 
hemodialysis procedure.  The start date/time and stop date/time of the hemodialysis 
procedure at the Day 15 and 29 Visits will be recorded.
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the Study Reference Manual (SRM).
7.5.2.
Sample Analysis
Plasma PK analysis will be performed under the management of Bioanalytical Science 
and Toxicokinetics, PTS DMPK, GlaxoSmithKline, the details of which will be included 
in the SRM.  Concentrations of parent GSK1278863 and metabolites (GSK2391220 
[M2], GSK2531403 [M3], GSK2487818 [M4], GSK2506102 [M5], GSK2531398 [M6], 
and GSK2531401 [M13]) will be determined in plasma samples using the currently 
approved bioanalytical methodology.  Raw data will be archived at the bioanalytical site 
(detailed in the SRM).
Analysis of plasma EPO, VEGF and hepcidin are described in the SRM.
7.6.
Genetics
A blood sample will be collected for Genetic research from consenting subjects.  This 
sample should be collected on Day 1 (randomization) once written informed consent has 
been obtained.
Information regarding genetic research is included in Section 12.4 Appendix 4.
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8.
DATA MANAGEMENT
!
For this study subject data will be entered into GSK defined eCRFs, 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
9.1.
Estimation
The primary objective of the study is to estimate the relationship between three-times 
weekly doses of GSK1278863 and Hgb response after 29 days of treatment.  To achieve 
this, a model-based dose-response analysis is planned with the primary endpoint of 
change in Hgb from baseline at Day 29.  It is anticipated that the data and the estimated 
parameters generated from this model will enable conversion of QD starting and 
maintenance dose regimens to three-times weekly doses/regimens.
Three-times weekly data from this study will be compared to the QD data from study 
PHI113633, which was a phase 2B dose-ranging study to evaluate the dose-response 
relationship of GSK1278863 over the first 4 weeks of treatment and evaluate the safety 
and efficacy of GSK1278863 over 24 weeks in hemodialysis-dependent subjects with 
anemia associated with CKD.
Although the primary analysis of dose-response relationship was estimated by a four 
parameter Emax model for study PHI113633, the estimated slope of 1.17 suggests that a 
simple, three parameter Emax model, which is a special case of the four parameter Emax 
model when the slope parameter has a value of one, is an appropriate option.  For this 
study it is proposed to fit a three parameter Emax model to account for dose using 
Bayesian statistical methods (i.e. posterior Emax model), and the results will be 
compared back to QD dose-response data from study PHI113633 based on a similar three 
parameter Emax model.  For this study, the prior distributions for each model parameter 
are informed by the QD dose-response from study PHI113633.  For the purpose of 
estimating dose-ratio (three-times weekly:QD), a linear model will also be fitted if the 
dose-response data shows a linear trend within the three-times weekly dose range (see 
Section 9.4.1.1).
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A posterior dose-response model, once fitted, will be used to make the following 
inferences to describe the dose response relationship:
!
Estimation of the three-times weekly minimally effective dose (MED), defined as the 
smallest dose achieving a change of -0.5 g/dL over 29 days after being switched 
from ESA.
!
Estimation of three-times weekly dose levels from the MED in +0.25 g/dL mean 
Hgb increments, including estimation of the target dose (TD), defined as the three-
times weekly dose of GSK1278863 that achieves a 0 g/dL change over 4 weeks after 
being switched from ESA.
!
Estimation of dose ratio between three-times weekly and QD doses that produce the 
same Hgb response.
9.2.
Sample Size Considerations
No formal sample size and power calculations were performed because the focus of this 
study is on characterizing the Hgb-three-times weekly dose-response relationship and 
using the results to estimate the dose ratio between three-times weekly and QD doses that 
produce the same Hgb response, not on formal testing of hypotheses.  A sample size of 
approximately 90 randomized subjects has been determined based on feasibility (18 per 
arm).
Assuming a maximum dropout rate of 15% between randomization and Day 29, it is 
anticipated that approximately 75 subjects will complete 29 days treatment.
Subjects will be stratified by prior ESA dose (low, high), and then randomized in equal 
proportions to receive placebo three-times weekly, or GSK1278863 dose of 10 mg three-
times weekly, 15 mg three-times weekly, 25 mg three-times weekly, or 30 mg three-times 
weekly.
9.2.1.
Sample Size Assumptions
For the three parameter Emax model, assuming that the sample size is 75, E0 = -0.666 
and Emax = 5.258 (estimates based on PHI113633 Emax model), and SD for Hgb change 
= 1 g/dL (as assumed for study PHI113633 sample size calculation), the following table 
describes the precision for estimation of target dose (TD) and minimally effective dose 
(MED) based on different assumptions for the unknown parameter ED50.  The relatively 
low precisions are at least partly due to the fact that the assumed ED50s lie outside the 
three-times weekly dose range for this study.
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Table 4
Precision for Target Dose (TD) and Minimally Effective Dose (MED)
Sample Size
ED50
Precision (Half-width of 95% CI) for target dose/MED
TD
75
37.281
2.86
75
782
5.94
MED
75
37.281
2.85
75
782
5.34
1.
ED50 = 16 mg (assumed ED50 for PHI113633) x 2.33 (theoretical dose ratio).
2.
ED50 = 33.41 mg (estimated ED50 from PHI113633) x 2.33 (theoretical dose ratio).
For the linear model described in Section 9.4.1.2, assuming the sample size is 75, the 
following table describes the precision for a range of estimated slopes from 0.03 to 0.07 
and different standard deviations for three-times weekly dose (SDx) and Hgb change 
(SDy).  Based on the dose-response curve of GSK study PHI113633 and the assumed 
theoretical dose ratio of 2.33 between three-times weekly and QD doses, it is estimated 
that the slope for the linear model with three-times weekly dose as the independent 
variable is about 0.05.  The slopes of 0.03 and 0.07 are also explored as part of the 
sensitivity analysis.
Table 5
Precision for Linear Regression Slop (Actual distance from slope to 
limits)
Slope
SDx
SDy
Precision
0.03
9.0
1.0
0.025
0.03
9.0
1.5
0.038
0.03
10.0
1.0
0.022
0.03
10.0
1.5
0.034
0.03
11.0
1.0
0.020
0.03
11.0
1.5
0.031
0.05
9.0
1.0
0.023
0.05
9.0
1.5
0.037
0.05
10.0
1.0
0.020
0.05
10.0
1.5
0.033
0.05
11.0
1.0
0.018
0.05
11.0
1.5
0.030
0.07
9.0
1.0
0.020
0.07
9.0
1.5
0.035
0.07
10.0
1.0
0.017
0.07
10.0
1.5
0.031
0.07
11.0
1.0
0.014
0.07
11.0
1.5
0.027
9.2.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned for this study.
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9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The analysis populations are:
!
All Randomized: The All randomized population consists of all randomized 
subjects regardless of whether they took study drug.  This population will be used for 
listings and to describe the breakdown of populations used for the trial.  Subjects will
be analyzed according to the treatment group they were randomized.
!
Intent-to-Treat (ITT): The ITT population consists of all randomized subjects who 
received at least one dose of study drug, have a baseline and at least one 
corresponding on treatment assessment.  This population will be used to summarize 
subject disposition, baseline and demographic data and will be the primary 
population used in the efficacy analyses.  Subjects will be classified according to the 
treatment group to which they were randomized.
!
Per-Protocol (PP): The PP population consists of all ITT subjects who are not major 
protocol violators with regards to inclusion/exclusion criteria, investigational product 
compliance and concomitant medication instructions.  The PP population will not be 
analyzed if this population comprises more than 80% of the ITT population.  
Protocol violations that would exclude subjects from the PP population will be 
defined and documented in the RAP prior to unblinding.
!
Completers: The Completers population consists of all ITT subjects who fully 
complete the Day 29 study assessments without prematurely discontinuing study 
drug.
!
Safety: The Safety population consists of all subjects who received at least one dose 
of study drug.  This population will be used for all assessments of safety and 
tolerability.  Subjects will be analyzed according to actual dose of study drug taken.
!
Pharmacokinetic (PK): The PK population consists of all subjects from whom a PK 
sample has been obtained and analyzed.
9.3.2.
Analysis Datasets
Efficacy inference will be based on the ITT population using an observed case dataset, 
comprising of all non-missing data collected up to discontinuation of study drug and 
withdrawal from the trial.
The dose response dataset will be based on the ITT population using an observed case 
dataset, comprising of all non-missing data collected up to Day 29.  In addition, for 
subjects who have a Day 15 Hgb measurement but a missing Day 29 Hgb measurement, a 
Day 29 value will be imputed based on the subject’s Day 1 and Day 15 data.  However, 
subjects with missing Hgb measurements at Day 15 and Day 29 will be excluded from 
the dose-response analysis.
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9.3.3.
Interim Analysis
No interim analysis is planned.
9.4.
Key Elements of Analysis Plan
The analyses planned in this protocol will be expanded upon in the RAP, any subsequent 
deviations will be explained either in the RAP or the final study report as appropriate.
Demographics, all baseline characteristics and subject withdrawals (from IP and study) 
will be summarized.
The impact of key (pre-defined) baseline subject characteristics and covariates of specific 
clinical interest on the primary Hgb endpoint (and potentially other key PD endpoints) 
will be explored.
Baseline characteristics and clinical covariates include:
!
Baseline Hgb
!
Prior ESA dose (high, low)
!
Weight
!
Gender
9.4.1.
Primary Analyses
9.4.1.1.
Dose Response Model
The primary endpoint is change in Hgb from baseline at Day 29.  To model the dose-
response relationship a three-parameter Emax model is planned, where Emax is assumed 
an appropriate model based on the biology and QD-dose-response modeling completed to 
date for GSK1278863.
This model assumes the following form:
Where:
!
ΔHgb is the change in Hgb from baseline at Day 29
!
E0 is the placebo response
!
Emax is the maximum response
!
ED50 is the dose that attains the intermediate response, i.e. where (E0+Emax) / 2, is 
attained
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!
ε is a random error assumed to be normally distributed with mean zero and constant 
variance (σ2 )
The observed change in Hgb from baseline at Day 29 will be used as the response 
variable in the Emax model.  Subjects who have a Day 15 Hgb measurement but a 
missing Day 29 Hgb measurement will be included with a Day 29 value imputed (see 
Section 9.3.2).  Any subject who prematurely discontinues dosing prior to Day 15 will be 
non-evaluable for the dose-response analysis.
The Emax model will be fitted using Bayesian statistical methods (i.e. a posterior Emax 
model).  Prior distributions for the model parameters have been based on the estimates 
obtained from GSK study PHI113633.  This modeling provides confidence in setting 
prior distributions for E0, however, there is greater uncertainty in the estimation of Emax 
and ED50 and this will be explored in sensitivity analyses that will apply alternative 
(weaker) prior distributions.
Table 6
Prior Distributions for the Primary Model
Emax Model Parameters
Bayesian Priors
E0
~Normal (-0.67, (0.146)2)
Emax
~Normal (5.26, (1.337)2)
ED50
~Uniform (10, 120)
Tau (1/σ2)
~Gamma (1,1)
Once the dose response model has been fitted satisfactorily, the posterior distribution of 
the model parameters (E0, Emax, ED50, and variance) will be summarized through 
means, standard deviation, median, MCSE, MCSE/SD and equal-sided 95% credibility 
intervals. The predicted value at a series of doses (range of possible doses from 0 to 30 
will be sectioned off into a sequence of 1 increments; i.e. dose levels of 0, 1.0, 2.0, …, 
30.0.) will also be monitored and the median and 95% credibility values obtained at each 
dose. The Hgb dose response curve will be plotted as a line through these medians and 
95% credibility bands, and overlaid on a scatter plot of the observed data. This estimated 
dose response curve is a composite best fit at each dose and is not in itself an Emax 
curve.
The dose response model will be used to make the primary efficacy inferences as 
described in Section 9.1.
To assess the robustness of the primary efficacy conclusions the dose-response analysis 
will be repeated using the following sensitivity approaches:
!
excluding subjects who fail to complete 29 days of treatment (completers population)
!
using alternative (weaker) prior distributions for the Emax model parameters (pre-
specified in the RAP)
!
fitting a Frequentist Emax model to the dose-response data (if possible to fit the 
model) 
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!
fitting a linear model to the dose-response data, if a linear relationship looks 
plausible across the three-times weekly dose range
If problems are encountered fitting a three parameter Emax model or if the Emax shape is 
a poor fit for the data, alternative models will be investigated until an appropriate model 
can be chosen (i.e. power model, linear model, quadratic model, log-transformed dose et 
al.).  Full details for model selection will be provided in the RAP.
9.4.1.2.
Estimation of Dose Ratio
Both Emax model (if fitted well) and linear model (if the dose-response relationship is 
approximately linear over the three-times weekly dose range) will be explored to estimate 
the dose ratio between three-time weekly and QD doses.  If the dose ratio is not dose-
dependent, the ratio between two estimated ED50s from the QD Emax model (GSK study 
PHI113633) and three-times weekly Emax model (this study) and the ratio between two 
estimated slopes from the QD linear model (GSK study PHI113633) and three-times 
weekly linear model (this study) would be equivalent to the dose ratio.
If the linear model is appropriate across the three-times weekly dose range then it is 
anticipated that the dose ratio estimated using the slopes from the linear models will be 
more reliable than that estimated using the ED50s from the Emax models, since the 
ED50s lie outside the QD and three-times weekly dose ranges, and therefore are poorly 
estimated.
One way to investigate whether the dose ratio is dose-dependent is to calculate “point 
estimates” of the dose ratio at two or more three-times weekly dose levels.  Specifically, 
for each of the selected three-times weekly doses, the observed Hgb response could be 
used to “read off” the equivalent QD dose with the same Hgb response, using the fitted 
dose-response curve from GSK study PHI113633, and then derive the point estimates of 
the dose ratio.  If these dose ratios are not consistent with each other, it would suggest the 
dose ratio may be dose-dependent.
Further exploratory analysis, to investigate whether the dose ratio is consistent with the 
theoretical dose ratio of 2.33 will be performed.  Details will be provided in the RAP.
Full details for estimating the dose ratio between three-times weekly and QD doses that 
produce the same Hgb response will be provided in the RAP.
9.4.2.
Secondary Analyses
In general, all planned secondary analyses are descriptive and estimation based.
Summaries over time and change from baseline will be produced by treatment group for 
hematocrit, RBC count, reticulocyte count and reticulocyte Hgb (CHr).
EPO and change from baseline in EPO will be summarized at each time point within visit 
by treatment group.  In addition, maximum observed change from baseline across all 
assessments will be summarized by treatment group.
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VEGF and percent change from baseline in VEGF will be summarized at each time point 
within visit by treatment group (based on log-transformed data).  In addition, maximum 
observed percent change from baseline across all assessments will be summarized by 
treatment group.
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modelling & Simulation department within GlaxoSmithKline. Plasma GSK1278863 and 
its major metabolite concentration-time pharmacokinetic data will be presented in 
graphical and/or tabular form and will be summarized descriptively.  Data will be 
graphically compared with concentration-time simulations of the current population PK 
model to ensure that TIW PK from this population is within the model predictions.
Full details of planned analyses of secondary endpoints will be provided in the RAP.
9.4.3.
Safety Analyses
Overall safety evaluations will be descriptive using the Safety Population (as described in 
Section 9.3.1).  Graphical and tabular displays will be presented to facilitate safety data 
review.
9.4.3.1.
Exposure
The complete dosing experience will be listed for all subjects.  The total duration of 
exposure (number of days), final dose and cumulative dose will be summarized by 
treatment group.
9.4.3.2.
Adverse Events
All AE data will be summarized, sorted by the system organ class and preferred term 
assigned by MedDRA, and presented by treatment group.  The following summaries will 
be provided:
!
All AEs (details for all AEs will be listed)
!
Serious AEs
!
AEs leading to discontinuation of study drug / withdrawal from study
!
Treatment-related AEs
!
AEs of special interest as defined in Section 7.4.1.2
Graphical displays will include incidence of most frequent AEs and AEs of special 
interest.
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9.4.3.3.
Other Safety Measures
Laboratory Evaluations
Laboratory values and change from baseline (or percentage change from baseline, where 
appropriate) will be summarized by visit and treatment group.  In addition, the number 
and percentage of patients with values outside the potential clinical importance range at 
each visit, and separately for those who report at least one occurrence of laboratory 
values of potential clinical importance will be summarized.  Criteria for potential clinical 
importance will be specified in the RAP.  The number and percentage of subjects meeting 
Lab withdrawal criteria will be presented.
Laboratory data will be summarized graphically, as appropriate.  Graphical displays of 
liver function tests (LFT) will include scatter plots of shifts from baseline to maximum 
values and scatter plots of maximum shifts comparing across LFTs.
Vital Signs
All vital sign data and change from baseline will be summarized by visit and treatment 
group.  For systolic and diastolic blood pressure and heart rate, the number and 
percentage of subjects with values of potential clinical importance will be summarized by 
treatment group.  Criteria for potential clinical importance will be specified in the RAP.
Graphical displays of vital signs data will include box plots and mean changes over time.
Pregnancy
A listing of subjects who become pregnant will be reported by treatment group.
Electrocardiographs
All ECG measures will be included in a subject listing.  Data will not be summarized by 
treatment group, since the ECG will be read locally as opposed to being read by a central 
reader.
9.4.3.4.
Pharmacokinetic/Pharmacodynamic Analyses
PK data (GSK1278863 and metabolites) and PD data (e.g., EPO, VEGF, hepcidin) will 
be listed and summarized by planned collection time, visit, and GSK1278863 dose level.
Exploratory modeling of the plasma EPO, VEGF and/or hepcidin concentrations also 
may be conducted, as a function of GSK1278863 dose or PK, and may be used to further 
characterize the effect of GSK1278863 on the Hgb profile.  Other PD data such as iron 
parameters and RBC indices may also be included if relevant to characterize the PD 
response.  Additional details will be provided in separate PK/PD RAP(s) and the results 
of these analyses will be reported in separate PK/PD report(s).
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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
Prior to initiation of a site, GSK/PPD will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK/PPD policies.
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
!
Obtaining signed informed consent
!
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)
!
GSK/PPD will provide full details of the above procedures, either verbally, in 
writing, or both.
!
Signed informed consent must be obtained for each subject prior to participation 
in the study (i.e., prior to performing any screening procedures).
!
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.
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10.3.
Quality Control (Study Monitoring)
!
In accordance with applicable regulations including GCP, and PPD procedures, 
PPD 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 PPD requirements.  
!
When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF
will serve as the source document.
PPD 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, PPD 
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 PPD monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and PPD 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/PPD 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 
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investigator or the head of the medical institution, where applicable, of the 
impending action.
!
If the study is suspended or prematurely discontinued for safety reasons, 
GSK/PPD will promptly inform all investigators, heads of the medical institutions 
(where applicable) and/or institution(s) conducting the study. GSK/PPD 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 PPD 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.
!
PPD 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, PPD 
standards/procedures, and/or institutional requirements.
!
The investigator must notify PPD 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.
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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The 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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11.
REFERENCES
Agarwal R, Kusek JW, Pappas MK. A randomized trial of intravenous and oral iron in 
chronic kidney disease. Kidney Int 2015; 88: 905-914.
FDA Drug Safety Communication: Modified dosing recommendations to improve the 
safe use of erythropoiesis-stimulating agents (ESAs) in chronic kidney disease. Safety 
Announcement issued June 24, 2011.  Link: 
http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm#sa
GlaxoSmithKline Document Number 2015N266524_00 Investigator’s Brochure
Supplement, 17-DEC-2015.
GlaxoSmithKline Document Number 2015N266524_01 Investigator’s Brochure
Supplement, 08-APR-2016. 
GlaxoSmithKline Document Number RM2008/00267/07 Investigator’s Brochure, 14-
OCT-2015.
Haase VH. Mechanisms of Hypoxia Responses in Renal Tissue. JASN 2013 24: 537-541.
McGowan T, Vaccaro NM, Beaver JS, Massarella J, Wolfson M. Pharmacokinetic and 
pharmacodynamics profiles of extended dosing of epoetin alfa in anemic patients who 
have chronic kidney disease and are not on dialysis. Clin J Am Soc Nephrol 2008; 3: 
1006-1014.
Pfeffer MA, Burdmann EA, Chen C et al. for the TREAT Investigators. A Trial of 
Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. N Engl J Med 2009; 
361: 2019-2032.
Provenzano R, Tumlin J, Zabaneh R, et al. Pharmacokinetics of oral FG-4592 to treat 
anemia in hemodialysis patients. National Kidney Foundation Conference, 2011 
(Abstract #189).
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALT
Alanine Transaminase
AST
Aspartate Transaminase
AUC
Area Under the Curve
BP
Blood Pressure 
CKD
Chronic Kidney Disease
CONSORT
Consolidated Standards of Reporting Trials
CV
Cardiovascular
DBP
Diastolic Blood Pressure
dL
Deciliter
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EPO
Erythropoietin
ESA
Erythropoiesis-Stimulating Agent
FDA
Food and Drug Administration 
FSH
Follicle Stimulating Hormone 
g
grams
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance 
GI
Gastrointestinal
GSK
GlaxoSmithKline
HBsAg
Hepatitis B Surface Antigen
hCG
Human Chorionic Gonadotropin 
HD
Hemodialysis
HDF
Hemodiafiltration 
HF
Hemofiltration 
Hgb
Hemoglobin
HIF
Hypoxia-Inducible Factor
HR
Heart Rate 
HRT
Hormone Replacement Therapy
IB
Investigator Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee 
INR
International Normalized Ratio 
IRB
Institutional Review Board
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities 
MI
Myocardial Infarction 
MSDS
Material Safety Data Sheet 
NSAID
Non-Steroidal Anti-Inflammatory Drug
NYHA
New York Heart Association
PD
Pharmacodynamic
pg
Picograms
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PHD
Prolyl Hydroxylase Domain enzymes
PHI
Prolyl Hydroxylase Inhibitor
PK
Pharmacokinetics
pmol
Picomoles
QD
Once Daily
QT
Q-T Interval 
QTcB
Bazett’s Correction of Q-T Interval 
rhEPO
Recombinant Human Erythropoietin 
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SC
Subcutaneous
SD
Standard Deviation
SRM
Study Reference Manual 
TIW
Three Times Weekly
TSAT
Transferrin Saturation
UF
Ultrafiltration
UIBC
Unsaturated Iron Binding Capacity
ULN
Upper Limit Normal
URR
Urea Reduction Ratio 
VEGF
Vascular Endothelial Growth Factor
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Aranesp
Epoetin
HemoCue
Mircera
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
The procedures listed below are to be followed if a subject meets the liver chemistry 
stopping criteria defined in Section 5.6.4:
!
Immediately withdraw the subject from study treatment
!
Notify the Medical Monitor within 24 hr of learning of the abnormality to confirm 
the subject’s study treatment cessation and follow-up.
!
Complete the “Safety Follow-Up Procedures” listed below.
!
Complete the liver event case report forms.  If the event also meets the criteria of an 
SAE (see Section 12.5.2), the SAE data collection tool will be completed separately 
with the relevant details.
!
Upon completion of the safety follow-up withdraw the subject from the study unless 
further safety follow up is required
!
Do not restart study treatment
!
Refer to the Flow chart for a visual presentation of the procedures listed below.
Safety Follow-Up Procedures for subjects with ALT ∀3xULN:
!
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values.
Safety Follow-Up Procedures for subjects with ALT ∀3xULN and total bilirubin 
∀2xULN (>35% direct bilirubin); or ALT ∀3xULN and INR1 > 1.5:
!
This event is considered an SAE (see Section 7.4.1.)  Serum bilirubin fractionation 
should be performed if testing is available.  If fractionation is unavailable, urinary 
bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury).
!
Make every reasonable attempt to have subjects return to the clinic within 24 hr for 
repeat liver chemistries, additional testing, and close monitoring (with specialist or 
hepatology consultation recommended).
!
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
1 INR testing not required per protocol and the threshold value does not apply to subjects receiving anticoagulants.
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In addition, for all subjects with ALT ∀3xULN, every attempt must be made to also 
obtain the following:
!
Viral hepatitis serology including:
o Hepatitis A IgM antibody.
o Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM). 
o Hepatitis C RNA.
o Cytomegalovirus IgM antibody.
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing).
o Hepatitis E IgM antibody.
!
Blood sample for pharmacokinetic (PK) analysis, obtained within 24 h of last dose. 
Record the date/time of the PK blood sample draw and the date/time of the last dose 
of study treatment prior to blood sample draw on the CRF.  If the date or time of the 
last dose is unclear, provide the subject’s best approximation.  If the date/time of the 
last dose cannot be approximated OR a PK sample cannot be collected in the time 
period indicated above, do not obtain a PK sample.  Instructions for sample 
handling and shipping are included in the SRM.
!
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).
!
Fractionate bilirubin, if total bilirubin ∀2xULN.
!
Assess eosinophilia
!
Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) 
on the AE CRF.
!
Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins on the Concomitant Medications 
CRF.
!
Record alcohol use on the Liver Events CRF.
The following are required for subjects with ALT ∀3xULN and bilirubin ∀2xULN 
(>35% direct) but are optional for other abnormal liver chemistries:
!
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.
Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in the 
preceding week [James, 2009].
!
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.
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!
The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these tests 
are performed.
Refer to the diagram below for a visual presentation of the procedures listed above.
ALT≥3xULN ?
Bilirubin ≥ 2xULN
(or INR > 1.5 if 
measured)* ?
No
No
Yes
Yes
Continue investigational product (IP)
 Instruct subject to stop IP
 Notify GSK within 24 hrs 
 Obtain weekly liver chemistries until resolved, stabilized or returned 
to baseline values
 Perform liver event follow up assessments (serology, PK sample, etc 
as in protocol) 
 Complete liver event CRF
 Withdraw subject from study after liver chemistry monitoring 
complete + do not re-challenge with IP
 Instruct subject to stop IP
 Notify GSK and arrange clinical followup within 24 hrs
 Perform liver event follow up assessments (serology, PK sample etc 
as in protocol) 
 Report as SAE (excl. hepatic impairment or cirrhosis studies); 
complete SAE & liver event CRF + liver imaging  
and biopsy CRFs (if these tests are performed)
 Obtain twice weekly liver chemistries until resolved, stabilized or 
returned to baseline values 
 Consultation with hepatologist/specialist recommended
 Withdraw subject from study after liver chemistry monitoring 
complete + do not re-challenge with IP
*INR threshold does not apply to 
subjects receiving anticoagulants.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA Davern TJ Lee 
WM. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen 
overdose and acute liver failure. Drug Metab Dispos 2009; 37: 1779-1784.
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12.3.
Appendix 3: GSK1278863 Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Excessive erythropoiesis (polycythemia) leading 
to thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis attributed to 
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
!
Hgb will be closely monitored throughout 
the dosing period as outlined in the Time 
and Events Table (Section 7.1)
!
Specific guidance for discontinuation of 
GSK1278863 based on achieved Hgb is 
provided in Section 5.6.2
!
Blinded monitoring of emerging safety 
data by an internal GSK Safety Review 
Team
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 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 
!
Follow-up should be conducted (i.e., 
endoscopic examination) in subjects 
exhibiting symptoms of significant 
gastrointestinal distress as clinically 
appropriate
!
Blinded monitoring of emerging safety 
data by an internal GSK Safety Review 
Team
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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.
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 5.3
!
Hgb will be closely monitored throughout 
the dosing period as outlined in the Time 
and Events Table (Section 7.1)
!
Blinded monitoring of emerging safety 
data by an internal GSK Safety Review 
Team
Cancer-related mortality and 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 60mg/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 
!
Specific eligibility criteria related to cancer 
risk are outlined in Section 5.3
!
Stopping criteria for subjects with 
treatment emergent malignancy are 
outlined in Section 5.6.1
!
Blinded monitoring of emerging safety 
data by an internal GSK Safety Review 
Team
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
been identified as a safety concern for GSK1278863.
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.
Results from a clinical study of acute hypoxic challenge in 
healthy volunteers demonstrated that short-term (5 days) 
therapy with GSK1278863 5mg or 100mg 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 
!
Blinded monitoring of emerging safety 
data by an internal GSK Safety Review 
Team
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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.
!
Blinded monitoring of emerging safety 
data by an internal GSK Safety Review 
Team
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 
[Nguyen, 2006].
Administration of 60 mg/kg GSK1278863 to mice caused 
minimal increases in circulating VEGF while significant EPO 
!
Suspected proliferative retinopathy, 
macular edema, choroidal 
neovascularization or symptoms 
consistent with these events should be 
investigated by ophthalmologic 
consultation as clinically warranted
!
Blinded monitoring of emerging safety 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 25mg, 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.
data by an internal GSK Safety Review 
Team
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.
!
Blinded monitoring of emerging safety 
data by an internal GSK Safety Review 
Team
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Drug-drug interactions
Co-administration of 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 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.
!
Co-administration of GSK1278863 with 
strong CYP2C8 inhibitors (e.g., 
gemfibrozil) and inducers (e.g., 
rifampin/rifampicin) is not permitted as 
outlined in Section 6.9.2
!
Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in 
Section 6.9.
!
Hgb will be closely monitored throughout 
the dosing period as outlined in the Time 
and Events Table (Section 7.1)
!
Specific guidance for discontinuation of 
GSK1278863 based on achieved Hgb is 
provided in Section 5.6.2
!
Blinded monitoring of emerging safety 
data by an internal GSK Safety Review 
Team
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References
Formenti F, Beer PA, Croft QPP, Dorrington KL, Gale DP, Lappin TRJ, Lucas GS, 
Maher ER, Maxwell PH, McMullin MF, O’Connor DF, Percy MJ, Pugh CW, Ratcliffe 
PJ, Smith TG, Talbot NP, Robbins PA. Cardiopulmonary function in two human 
disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and 
HIF-2α gain-of-function mutation. FASEB J. 2011; 25:2001-2011.
Muz B, Khan MN, Kiriakidis S, Paleolog EM. The role of hypoxia and HIF-dependent 
signalling events in rheumatoid arthritis. Arthritis Research & Therapy 2009; 11:201-209.
Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, Zimmer-Galler I, Do 
DV, Campochiaro PA. Vascular endothelial growth factor is a critical stimulus for 
diabetic macular edema. Amer J Ophthalmol 2006; 142:961-969.
Smith TG, Brooks JT, Balanos GM, Lappin TR, Layton DM, Leedham DL, Liu C, 
Maxwell PH, McMullin MF, McNamara CJ, Percy MJ, Pugh CW, Ratcliffe PJ, Talbot 
NP, Treacy M, Robbins PA. Mutation of von Hippel-Lindau tumour suppressor and 
human cardiopulmonary physiology. PLoS Med 2006;3:e290
Westra J, Molema G, Kallenberg CG. Hypoxia-inducible factor-1 as regulator of 
angiogenesis in rheumatoid arthritis - therapeutic implications. Curr Med Chem 2010; 
17:254-63.
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12.4.
Appendix 4: Genetic Research
Genetics – 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 objectives of the genetic research are to investigate the relationship between genetic 
variants and:
!
Response to medicine, including GSK1278863 or any concomitant medicines;
!
Susceptibility to anemia associated with chronic kidney disease; severity, and 
progression of disease(s) under study and related conditions
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 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 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 genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
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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 to help understand 
variability in disease and medicine response.  
!
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 
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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.  
!
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
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol Asp Med 2012; 33:467-486.
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
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12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.5.1.
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 
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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.
12.5.2.
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, 
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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; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT ∀3xULN 
and total bilirubin ∀2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
!
Refer to Section 12.2 Appendix 2 for the required liver chemistry follow-up 
instructions
12.5.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the eCRF for 
events that represent the following AEs and SAEs:
!
Myocardial infarction/unstable angina
!
Congestive heart failure
!
Arrhythmias
!
Valvulopathy
!
Pulmonary hypertension
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!
Cerebrovascular events/stroke and transient ischemic attack
!
Peripheral arterial thromboembolism
!
Deep venous thrombosis/pulmonary embolism
!
Revascularization
12.5.4.
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 eCRF
!
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 eCRF 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.
12.5.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:
!
Mild: An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.
!
Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities.
!
Severe: An event that prevents normal everyday activities - an AE that is assessed as 
severe will not be confused with an SAE.  Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.
!
An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
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Assessment of Causality
!
The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.
!
A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.
!
The investigator will use clinical judgment to determine the relationship.
!
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.
!
The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.
!
For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
!
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.
!
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.
!
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs
!
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.
!
The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.
!
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.
!
New or updated information will be recorded in the originally completed eCRF.
!
The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
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12.5.6.
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 PPD Safety Hotline.
!
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 and fax it to the 
PPD Safety Hotline or to the Medical Monitor by telephone.
!
Contacts for SAE receipt can be found at the beginning of this protocol on the 
Medical Monitor/Sponsor Information Page.
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12.6.
Appendix 6: Female Eligibility Criteria
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum hCG test for females of reproductive potential only), not breastfeeding, or 
at least one of the following conditions applies:
!
Reproductive potential and agrees to follow one of the options listed in the GSK 
Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP (see 
below) from 30 days prior to the first dose of study treatment and until seven days 
after the last dose of study treatment and completion of the follow-up visit.
!
Non-reproductive potential defined as either:
o
Pre-menopausal with one of the following: (i) documented tubal ligation; (ii) 
documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion; (iii) hysterectomy; or (iv) 
documented bilateral oophorectomy, or;
o
Postmenopausal defined as 12 months of spontaneous amenorrhea and age 
appropriate (i.e. >50 years).  In questionable cases, a blood sample with 
simultaneous FSH and estradiol consistent with menopause is confirmatory 
(FSH 23.0-116.3 mIU/mL and estradiol ≤10 pg/mL (or ≤37 pmol/L) is 
confirmatory).  Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to use one of the highly 
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.
12.6.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
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.
!
Contraceptive subdermal implant that meets effectiveness criteria including a 
<1% rate of failure per year, as stated in the product label.
!
Intrauterine device or intrauterine system that meets effectiveness criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 
2011]
!
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
!
Injectable progestogen [Hatcher, 2011]
!
Contraceptive vaginal ring [Hatcher, 2011]
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!
Percutaneous contraceptive patches [Hatcher, 2011]
!
Male partner sterilization prior to the female subject's entry into the study, and 
this male is the sole partner for that subject [Hatcher, 2011].  The documentation 
on the male sterility can come from the site personnel’s review of subject’s 
medical records, medical examination and/or semen analysis, or medical history 
interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
12.6.2.
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 12.5 Appendix 5.  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 and be withdrawn from the study
Reference
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, editors. 
Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50. 
Table 3-2.
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12.7.
Appendix 7: Country Specific Requirements
No country-specific requirements exist.
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12.8.
Appendix 8: Protocol Changes
Protocol Amendment 01
Amendment 01 is applicable to all sites.
Brief Summary of Protocol Changes and Rationale for Revisions:
Inclusion criterion #5 was modified to include the complete timeframe in which this 
criterion is applicable.  Other eligibility criteria have been clarified or updated for 
consistency with project level requirements.  Minor clarifications were made throughout 
the protocol, including clarifications related to hemoglobin stopping criteria, wording of 
the AEs of special interest, visit windows and the Time and Events Table. References to 
IB Supplements 1 and 2 were added, and corresponding updates to the Risk Assessement 
Table were made. Flexible language was added to allow for subjects to be dosed outside 
of the study clinic in exceptional circumstances. The definition of the PK analysis 
population was added.
List of Specific Changes and Rationale:
1. Clarification of allowable window for study visits
Rationale: To clarify that the allowable window of ±2 days which was allowed for post-
randomization visits is also applicable to the screening visits.  
Section 1 Protocol Synopsis, Treatment Arms and Duration, and Section 4.2 
Treatment Arms and Duration
Added Text: A window of ±2 days will be allowed for visits during the Screening period.
Added Text: A window of ±2 days will be allowed for visits during the Treatment period.
Section 7 Study Assessments and Procedures
Amended Text using revision marks: To allow scheduling flexibility, post-randomization
study visits should occur within a window of ±2 days, excepting that for subjects on a 
three times weekly dialysis schedule Day 15 or 19 is not for whom study visits must 
not be scheduled on the first dialysis session of the week.
2. Clarification that ESA therapy can restart after the follow-up visit
Rationale: To clarify the expectation that treatment with ESA, which was to be 
discontinued prior to Day 1, should be held through the follow-up period, and therapy 
with ESAs can resume after the follow-up visit.  Flexibility is included in cases where 
there is clinical rationale to restart ESA after the last dose of study treatment.
Section 1 Protocol Synopsis, Treatment Arms and Duration, and Section 4.2 
Treatment Arms and Duration
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Added Text: At Day 29, all subjects will receive their last dose of study treatment and 
should not re-start ESA therapy until after the follow-up visit (Day 43).  However, if the 
Investigator has a compelling clinical reason why a subject should restart ESA between 
Day 29 and Day 43, then ESA may be restarted prior to Day 43.
3. Correction of the timeframe in which ESA dosing must remain stable
Rationale: The timeframe in which the ESA dosing must remain stable was corrected to 
include the 28 day screening period. ESA dosing is required to remain stable from 4 
weeks prior to the start of the screening period through to Day 1.
Section 1 Protocol Synopsis, Type and Number of Subjects, and Section 4.3 Type 
and Number of Subjects
Amended Text with revision marks: The range of Hgb values for study eligibility is 9.0 -
11.5 g/dL and the subjects must have received the same ESA product with total weekly 
doses that varied by no more than 50% during the 4 weeks prior to the Screening visit 
from 4 weeks prior to the Day -28 Screening visit through to Day 1.
Section 5.2 Inclusion Criteria
Amended Text with revision marks: 5. Stable ESA dose: Treated with the same ESA 
(epoetins or their biosimilars, or darbepoetin or methoxy PEG-epoetin beta) with total 
weekly dose varying by no more than 50% during the 4 weeks prior to Day -28from 4 
weeks prior to Day -28 through Day 1 (randomization).
4. Clarification of the number of evaluable subjects expected in each 
treatment group
Section 1 Protocol Synopsis, Type and Number of Subjects, and Section 4.3 Type 
and Number of Subjects
Amended Text: Approximately 200 subjects will be screened to achieve approximately 
90 randomized and 75 evaluable subjects for a total of, with approximately 15 evaluable 
subjects per treatment group. 
5. Update to references for the Investigator Brochure Supplements
Rationale: Added references for IB Supplement 1 and 2, which were published after the 
original protocol was published.
Section 2.1 Brief Background, Section 4.6 Benefit:Risk Assessment, Section 5 
Selection of Study Population and Withdrawal Criteria, Section 5.3 Exclusion 
Criteria, Section 11 References
Added to applicable sections: IB Supplements [GlaxoSmithKline Document Number 
2015N266524_00, GlaxoSmithKline Document Number 2015N266524_01]  
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Section 5.3 Exclusion Criteria
Rationale: For Exclusion Criterion #17, the reference to the IB was removed, rather than 
being updated, since the reference is not required to be included in the eligibility criterion 
text and it is understood that the list of excipients of the investigational product can be 
found in the IB and IB supplements.
Amended Text with revision marks:
17.
Severe allergic reactions: History of severe allergic or anaphylactic reactions or 
hypersensitivity to excipients in the investigational product (see GSK1278863 IB for list 
of excipients [GlaxoSmithKline Document Number RM2008/00267/07]).
6. Clarification of the Hemoglobin Stability Criteria
Rationale: Text was revised to remove any ambiguity to the hemoglobin stability criteria 
and the calculations that are to be made at the Day 1 visit. Text was also revised to clarify 
the timeframe in which subjects could be rescreened.
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Section 5.1, Figure 2
Original Figure:
Obtain Hgb sample (HemoCue). Is Hgb within 
9.0 – 11.5 g/dL? 
Not eligible for study; 
can be rescreened in 
2 weeks
No
Obtain Hgb sample (HemoCue). Is the absolute 
difference (max-min) <1.3 g/dL from 1st Hgb
(with no clinical evidence of overt bleeding)?
Yes
Not eligible for study; 
can be rescreened in 
2 weeks
No
Subject eligible for full 
screening
Yes
Screening Criteria Met?
Not eligible for study; 
can be rescreened in 
1 mo unless otherwise 
stated in protocol
No
Subject eligible for 
randomization visit
Yes
Obtain Hgb sample (HemoCue). Are the following met:
•Average across the 3 Hgb values in range of 9.0 – 11.5 g/dL 
AND
•Absolute difference (max-min) <1.3 g/dL with no clinical 
evidence of overt bleeding
Randomize Subject
Yes
Not eligible for study; 
can be rescreened in 
2 weeks
No
Hgb #1 – Day -28
Hgb #2 – Day -14
Hgb #3 – Day 1
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Amended Figure:
Obtain Hgb sample (HemoCue). 
Is Hgb within 9.0 – 11.5 g/dL? 
Not eligible for study; 
can be rescreened in 
2 weeks
No
Obtain Hgb sample (HemoCue). Is the absolute 
difference (max-min) <1.3 g/dL from 1st Hgb
(with no clinical evidence of overt bleeding)?
Yes
Not eligible for study; 
can be rescreened in 
2 weeks
No
Subject eligible for full 
screening
Yes
Screening Criteria Met?
Not eligible for study; 
can be rescreened as 
stated in Section 5.5
No
Subject eligible for 
randomization visit
Yes
Obtain Hgb sample (HemoCue). Are the following met for the 
3 Hgb values (Day -28, Day -14, Day 1)?
• Average in range of 9.0 – 11.5 g/dL AND
• Absolute difference (max-min) <1.3 g/dL with no clinical 
evidence of overt bleeding
Randomize Subject
Yes
Not eligible for study; 
can be rescreened in 
2 weeks
No
Hgb #1: Day -28
Hgb #2: Day -14
Hgb #3: Day 1
7. Clarification of the inclusion criterion for stable iron replacement 
therapy
Rationale: To clarify that the ≤100 mg/week limit relates to IV iron supplementation, and 
to clarify criterion by changing the term stable to state that the dose must not be changed.
Section 5.2 Inclusion Criteria
Amended Text with revision marks: 6. Iron replacement therapy: Subjects may be on 
stable maintenance oral or IV (≤100 mg/week) iron supplementation.  If subjects are on 
oral or IV iron, then the type of iron and doses must be stable not be changed for the 4 
weeks prior to Day -28, during the screening phase, and through the 29 days of treatment.  
If subjects are on IV iron, then doses must be ≤100 mg/week, and doses must not be 
changed for the 4 weeks prior to Day -28, during the screening phase, and through the 29 
days of treatment.
8. Clarification of the exclusion criterion for planned kidney transplant
Rationale: To clarify that any planned kidney transplant from a living donor is excluded, 
including a planned living-unrelated kidney transplant.
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Section 5.3 Exclusion Criteria
Amended Text with revision marks: 2. Renal transplant: Planned for living-related or 
living-unrelated kidney transplant
9. Clarification of the exclusion criterion for administration of Mircera
Rationale: To clarify that the timeframe for restriction of Mircera administration is 
dependent upon the dosing schedule of Mircera.
Section 5.3 Exclusion Criteria
Amended Text with revision marks: 4. Mircera: Administration of Mircera (methoxy 
PEG-epoetin beta) within the prior 4 weeks through Day 1 (randomization) 2 weeks prior 
to Day 1 if subject is on a once-every-2-weeks schedule or within 4 weeks prior to Day 1 
if subject is on a once-every-4-weeks schedule.  
10.Update to the exclusion criterion for malignancy 
Rationale: The exclusion criterion for malignancy was updated to be in alignment with 
the current requirements for the GSK1278863 program.
Section 5.3 Exclusion Criteria
Amended Text: 16. Malignancy: History of malignancy within the two years prior to 
Day -28 through to Day 1 (randomization) or currently receiving treatment for cancer, or 
has a known ≥ 4 cm complex kidney cyst (i.e. Bosniak Category II F, III of IV) > 3cm.  
NOTE: The ONLY exception is squamous cell or basal cell carcinoma of the skin that 
has been definitively treated ∀8 weeks prior to Screening.
11.Clarification of the screening visit at which the diagnostic assessments 
should be verified for eligibility
Rationale: To clarify the screening visit during which the diagnostic assessments are 
required to be verified.
Section 5.3 Exclusion Criteria
Added Text under the heading “DIAGNOSTIC ASSESSMENTS AND OTHER 
CRITERIA”: (To be verified on Day -28 only)
12.Clarification of screen failures
Rationale: To clarify that after consent, a subject must attend at least the first screening 
visit before he/she can be considered a screen failure.
Section 5.5 Screening/Baseline/Run-in Failures
Added Text: In this study, a subject can become a screen failure at any time from the 
Day -28 visit to the Day 1 visit, prior to randomization.
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13.Clarification of actions to be taken for subjects who are permanently 
discontinued from study medication
Rationale: To clarify that a subject who is permanently discontinued from study 
medication should return for an Early Withdrawal visit and a Follow-up Visit.
Section 5.6.1 Criteria for Permanent Discontinuation from Study Medication and 
Early Withdrawal
Amended Text with revision marks: Subjects must permanently discontinue study 
medication and be withdrawn from the study for the following reasons:
Added Text: 
The subject should attend the clinic as soon as possible to complete the Early Withdrawal 
assessments and return for a Follow-up visit as described in Section 7.1, Time and 
Events.
The reason for discontinuation of study medication and date of last dose will be recorded 
in the eCRF.
14.Clarification of Hemoglobin Stopping Criteria
Rationale: Clarification of the hemoglobin stopping criteria by eliminating the 
discrepancy between the text and the figure.
Section 5.6.2 Hemoglobin Stopping Criteria
Amended Text with revision marks:
!
Confirmed Hgb (2 measurements by HemoCue pre-dialysis) # < 7.5 g/dL
Original Text within the figure:
Hgb (g/dL) 
at visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, permanently discontinue study drug and withdraw 
subject from the study.
∀7.5-<13.0
∀2.0 decrease in Hgb over 2 
weeks
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  
If confirmed, permanently discontinue study drug and 
withdraw subject from the study.
<1.absolute change in Hgb over 
2 weeks
Continue study drug
∀1.0 increase in Hgb over 2 
weeks
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  
If confirmed, permanently discontinue study drug and 
withdraw subject from the study.
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∀13.0
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, consider permanently discontinuing study drug and 
withdrawing subject from the study in consultation with GSK Medical Monitor.
Amended Text within the figure:
Hgb (g/dL) 
at visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, permanently discontinue study drug.
∀7.5-<13.0
∀2.0 decrease in Hgb over 2 
weeks
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  
If confirmed, permanently discontinue study drug.
<1.0 increase or <2.0 decrease 
in Hgb over 2 weeks
Continue study drug
∀1.0 increase in Hgb over 2 
weeks
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  
If confirmed, permanently discontinue study drug.
∀13.0
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, consider permanently discontinuing study drug in 
consultation with GSK Medical Monitor.
Rationale: While the HemoCue values will be the primary values used to monitor 
hemoglobin for safety purposes, text was added to clarify how discrepancies in 
hemoglobin values between central laboratory and HemoCue device should be managed.
Added Text: In cases where the Hgb values from the central laboratory meet any of the 
Hgb stopping criteria in the above table, but the Hgb values from the HemoCue device do 
not, then the Investigator and the GSK Medical Monitor should discuss this situation 
before potentially discontinuing study medication.
Amended Text with revision marks: If a subject is permanently discontinued from study 
medication, then the subject should attend the clinic as soon as possible to complete the 
Early Withdrawal assessments and Follow-up visit (see Section 7.1, Time and Events) as 
described in Section 5.6 5.7.
In all cases, The reason for discontinuation of study medication and date of last dose will 
be recorded in the eCRF.
15.Revision to allow flexibility for subjects to self-administer study 
medication on additional days
Rationale: Currently the protocol only allows subjects to take the study medication home 
prior to the PK visit.  This change will allow some flexibility for subjects to take 
medication home on additional occasions.
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Section 6.1 Investigational Product and Other Study Treatment
Amended Text with revision marks: All study medication will be taken should be taken
in the clinic EXCEPT prior to the PK day (Day 15 study visit), or on other days only if 
the Investigator and GSK Medical Monitor agree that it will not interfere with the study 
procedures or affect the subject’s compliance with the protocol.  
Added Text: The study site must ensure that the date and time the subject took each dose 
of study treatment is documented.  
16.Clarification of Text
Rationale: GSK1278863 dose titrations were not allowed in this study.  Non-applicable 
text was deleted.
Section 6.9.1 Permitted Medications and Non-Drug Therapies
Amended Text with revision marks: GSK1278863 dose titrations and Hemoglobin 
stopping criteria mitigate risk of increased pharmacology if co-administered.
17.Clarification of Time and Events Table
Rationale: Clarifications were made to the Time and Events table for consistency with 
changes made to other sections as well as to remove ambiguities in original table.
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Original Table:
7.1
Time and Events Table
Protocol Activity1
Screening
Day 1
Treatment Period
Follow-up
Week 
-4
Week 
-2
Day 152
Day 292
Un-scheduled
Early 
Withdrawal
Day 43 ∃3
Informed Consent
X
Entry Criteria
X
X
Physical, Medical History, Demography
X
HemoCue Hgb
X
X
X
X
X
X
X
IVWRS Call
X
X
X
X
X
X
X
X
Females Only: Serum Pregnancy Test
X
X
X
Females Only: Estradiol and FSH (if required)3
X
ECG
X
X
X
Vitals (Pre-dialysis and Post-dialysis)4
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Folate
X
Ferritin, transferrin, total iron, UIBC
X
X
X
X
X
Pharmacokinetic/Pharmacodynamic Samples
X
X
X
X5
Blood draw for PGx
X
Adverse Events Assessment
X
X
X
X
X
X
Review Concomitant Medications
X
X
X
X
X
X
X
1.
All assessments should be done pre-dialysis except as noted.
2.
Allowable time window ∃2 days.
3.
As detailed in Inclusion Criteria in Section 5.2.
4.
Weight measured post-dialysis only & height measured at screening only.
5.
Obtain samples as per the Day 29 visit in Table 2.  If subject does not receive a dose of study medication at this early withdrawal visit, no post-dose PK/PD samples should be 
obtained.
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Amended Table:
7.1
Time and Events Table
Protocol Activity 1, 2
Screening
Day 1
Treatment Period
Follow-up
Week 
-4 
Week 
-2 
Day 15 
Day 29 
Un-scheduled
Early 
Withdrawal
Day 43 ± 3 6
Informed Consent
X
Entry Criteria
X
X
Physical, Medical History, Demography
X
HemoCue Hgb
X
X
X
X
X
X
X
IVWRS Call
X
X
X
X
X
X
X
X
Females Only: Serum Pregnancy Test 3
X
X
X
Females Only: Estradiol and FSH (if required) 3
X
ECG
X
X
X
Vitals (Pre-dialysis and Post-dialysis) 4
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Folate and Vitamin B12
X
Ferritin, transferrin, total iron, UIBC
X
X
X
X
X
Pharmacokinetic/Pharmacodynamic Samples
X
X
X
X 5
Blood draw for PGx
X
Adverse Events Assessment 7
X
X
X
X
X
X
Review Concomitant Medications
X
X
X
X
X
X
X
1.
All assessments should be done pre-dialysis except as noted.
2.
Allowable time window of ± 2 days for all study visits, except the follow-up visit for which it is ± 3 days.
3.
As detailed in Exclusion Criteria in Section 5.3.
4.
Weight measured post-dialysis only & height measured at screening only.
5.
Obtain samples as per the Day 29 visit in Table 2.  If subject does not receive a dose of study medication at this early withdrawal visit, no post-dose PK/PD samples should 
be obtained.
6.
Subjects who withdraw early from treatment should attend a follow-up visit 14 days ± 3 days after the last dose of study treatment.
7.
Serious adverse events are assessed from the time of consent as stated in Section 7.4.1.1.
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18.
Update of Terms for Adverse Events of Special Interest
Rationale: Adverse events of special interest terms were updated to be consistent with 
current list of terms for the GSK1278863 project.  
Section 7.4.1.2 Adverse Events of Special Interest
Amended Text:
!
Risk of Death, MI, stroke, venous thromboembolism, thrombosis of vascular 
access
Amended Text:
!
Increased Cancer-related mortality and tumor progression and recurrence
19.
Clarification of Laboratory Assessments
Rationale: To clarify which subjects require the screening tests.
Section 7.4.6 Clinical Safety Laboratory Assessments, Table 3
Amended Footnote to table with revision marks: 1 As needed in women of non-child bearing 
potential only. As required per Appendix 6.
20.
Inclusion of the PK Analysis Population
Rationale: The definition of the PK Analysis Population was added.
9.3.1 Analysis Populations
Added Text: 
!
Pharmacokinetic (PK): The PK population consists of all subjects from whom a PK 
sample has been obtained and analyzed.
21.
Update to Risk Assessment Table
Rationale: The GSK1278863 Risk Assessment Table was updated to be consistent with 
the current risk assessment for the GSK1278863 project.
Section 12.3 Appendix 3
Amended Text with revision marks in “Potential Risk of Clinical Significance” Column:
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)
Increased Cancer-related mortality and tumor progression and recurrence
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Added text in “Mitigation Strategy” Column for the potential risk of “Proliferative 
retinopathy, macular edema, choroidal neovascularisation”:
Suspected proliferative retinopathy, macular edema, choroidal neovascularization or 
symptoms consistent with these events should be investigated by ophthalmologic 
consultation as clinically warranted
22.
Correction of Minor Typographical Errors
Rationale: Minor typographical errors were corrected.
Section 2.1 Brief Background
The original text “rick” was corrected to “risk”
Section 5.3 Exclusion Criteria
The original text in exclusion criteria #6 and #10 “though” was corrected to “through”
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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
204836
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 204836: A 29-day, 
randomized, double-blinded, placebo-controlled,
parallel-group, multi-center study to evaluate the efficacy, 
safety and pharmacokinetics of three-times weekly dosing of 
GSK1278863 in hemodialysis-dependent subjects with 
anemia associated with chronic kidney disease who are 
switched from a stable dose of an erythropoiesis-stimulating 
agent
Compound Number 
:
GSK1278863
Effective Date 
:
14-FEB-2017
Description :

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204836.

This RAP is intended to describe the analyses of efficacy, safety and 
pharmacokinetics required for the study. 

This RAP will be provided to the study team members and CRO (PPD) to convey the 
content of the Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
14-FEB-2017
Manager, Statistics (Clinical Statistics)
14-FEB-2017
Principal Statistician (Clinical Statistics)
Approved via Email by: 
14-FEB-2017
Director, Statistics & Programming (Clinical Statistics)
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNOPSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objective(s) and Endpoint(s)...............................................................8
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Interim Analyses .........................................................................................10
3.2.
Final Analyses ............................................................................................10
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Analyses ...................................................................15
6.2.
Display Details............................................................................................16
6.2.1.
Subject Disposition ......................................................................16
6.2.2.
Protocol Deviations......................................................................17
6.2.3.
Populations Analyzed ..................................................................17
6.2.4.
Demography................................................................................17
6.2.5.
Medical Conditions and Concomitant Medications.......................18
6.2.6.
Exposure and Treatment Compliance..........................................19
7.
PRIMARY STATISTICAL ANALYSES....................................................................21
7.1.
Efficacy Analyses........................................................................................21
7.1.1.
Overview of Planned Efficacy Analyses .......................................21
7.1.2.
Planned Hgb Efficacy Statistical Analyses ...................................23
8.
SECONDARY STATISTICAL ANALYSES .............................................................32
8.1.
Efficacy Analyses........................................................................................32
8.1.1.
Overview of Planned Efficacy Analyses .......................................32
8.1.2.
Planned Efficacy Statistical Analyses...........................................34
8.2.
Safety Analyses..........................................................................................36
8.2.1.
Overview of Planned Analyses ....................................................36
8.2.2.
Display Details.............................................................................40
8.2.2.1.
Adverse Event Safety Analyses..................................40
8.2.2.2.
Clinical Laboratory Safety Analyses ...........................43
8.2.2.3.
Other Safety Analyses................................................44
8.2.2.3.1.
Electrocardiograms.................................44
8.2.2.3.2.
Vital Signs ..............................................44
8.2.2.3.3.
Hepatobiliary (Liver)................................44
8.3.
Pharmacokinetic Analyses..........................................................................46
8.3.1.
Overview of Planned Pharmacokinetic Analyses .........................46
8.3.2.
Drug Concentration Measures .....................................................46
 
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8.3.3.
Pharmacokinetic Parameters.......................................................47
8.4.
Pharmacokinetic / Pharmacodynamic Analyses..........................................48
9.
OTHER STATISTICAL ANALYSES .......................................................................49
10. REFERENCES.......................................................................................................50
11. APPENDICES........................................................................................................51
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................52
11.1.1.
Important Protocol Deviation........................................................52
11.1.2.
Exclusions from Per Protocol Population .....................................52
11.2.
Appendix 2: Time & Events.........................................................................55
11.2.1.
Protocol Defined Time & Events ..................................................55
11.3.
Appendix 3: Assessment Windows .............................................................57
11.3.1.
Assessment Windows Assignment ..............................................57
11.3.2.
Multiple Assessments ..................................................................58
11.4.
Appendix 4: Treatment States and Study Phases.......................................59
11.4.1.
Study Phases ..............................................................................59
11.4.2.
Treatment States .........................................................................59
11.4.2.1.
Treatment States for Laboratory Data, Vital 
Signs, ECG Data........................................................59
11.4.2.2.
Treatment States for AE Data.....................................59
11.4.2.3.
Classification of Prior, concomitant, an Post-
Therapy Medications ..................................................60
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................62
11.5.1.
Study Treatment & Sub-group Display Descriptors......................62
11.5.2.
Baseline Definition & Derivations .................................................62
11.5.2.1.
Baseline Definitions....................................................62
11.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................63
11.5.3.
Reporting Process & Standards...................................................65
11.6.
Appendix 6: Derived and Transformed Data ...............................................67
11.6.1.
General........................................................................................67
11.6.2.
Study Population..........................................................................68
11.6.3.
Safety ..........................................................................................72
11.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............73
11.7.1.
Premature Withdrawals................................................................73
11.7.2.
Handling of Missing Data.............................................................73
11.7.2.1.
Handling of Missing Hgb and Other Data....................73
11.7.2.2.
Handling of Missing/Partial Dates...............................75
11.8.
Appendix 8: Values of Potential Clinical Importance ...................................76
11.8.1.
Laboratory Values........................................................................76
11.8.2.
Vital Signs....................................................................................77
11.8.3.
ECG.............................................................................................77
11.9.
Appendix 9: Multicenter Studies..................................................................78
11.9.1.
Methods for Handling Centres .....................................................78
11.10. Appendix 10: Examination of Covariates and Subgroups............................79
11.10.1. Handling of Covariates and Subgroups........................................79
11.11. Appendix 11: Multiple Comparisons & Multiplicity .......................................80
11.11.1. Handling of Multiple Comparisons & Multiplicity...........................80
 
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11.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................81
11.13. Appendix 13 – Abbreviations & Trade Marks ..............................................82
11.13.1. Abbreviations...............................................................................82
11.13.2. Trademarks .................................................................................83
11.14. Appendix 14: List of Data Displays..............................................................84
11.14.1. Data Display Numbering..............................................................84
11.14.2. Mock Example Shell Referencing ................................................84
11.14.3. Data Display Convention .............................................................85
11.14.4. Study Population Tables..............................................................86
11.14.5. Study Population Figures.............................................................95
11.14.6. Efficacy Tables ............................................................................96
11.14.7. Efficacy Figures .........................................................................107
11.14.8. Safety Tables.............................................................................114
11.14.9. Safety Figures ...........................................................................120
11.14.10.Pharmacokinetic Tables.............................................................121
11.14.11.Pharmacokinetic Figures ...........................................................121
11.14.12.ICH Listings ...............................................................................122
11.14.13.Non-ICH Listings........................................................................129
11.15. Appendix 15: Example Mock Shells for Data Displays ..............................132
11.15.1. Study Population........................................................................132
11.15.1.1. Study Population Tables...........................................132
11.15.1.2. Study Population Figures..........................................178
11.15.2. Efficacy......................................................................................180
11.15.2.1. Efficacy Tables.........................................................180
11.15.2.2. Efficacy Figures........................................................257
11.15.3. Safety ........................................................................................309
11.15.3.1. Safety Tables ...........................................................309
11.15.3.2. Safety Figures ..........................................................363
11.15.4. ICH Listing.................................................................................368
11.15.5. Non-ICH Listings........................................................................441
11.15.6. PK..............................................................................................468
11.15.6.1. PK Tables.................................................................468
11.15.6.2. PK Figures ...............................................................471
11.15.6.3. PK Listings ...............................................................474
 
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1.
REPORTING & ANALYSIS PLAN SYNOPSIS
Overview
Key Elements of the RAP
Purpose
The purpose of this reporting and analysis plan (RAP) is to describe:

The planned analyses of haemoglobin (Hgb) dose-response relationship for 
three times weekly dosing of GSK1278863 at 29 days in order to describe the 
efficacy relationship between once-daily (QD) and three-times weekly (TIW) 
administration.

Other planned analyses and outputs required for the final Clinical Study Report 
(CSR) for study 204836.
Protocol

This RAP is based on the protocol amendment number 01 (Dated: 11-MAY-
2016) of study 204836 (GlaxoSmithKline Document Number 2015N241222_01)
and eCRF Version 4.00
Primary 
Objective

Characterize the dose-response relationship between GSK1278863 
administered three-times weekly and Hgb at Day 29
Primary 
Endpoint

Hgb change from baseline at Day 29
Study 
Design

A randomized, double-blinded, dose-ranging, placebo-controlled, parallel group 
study. 

There is a 28-day Screening period, a 29-day Treatment period, and a Follow-up 
visit 14 ± 3 days after completing treatment.

Subjects will be randomized 1:1:1:1:1 to receive one of four three-times weekly 
doses (10 mg, 15 mg, 25 mg, 30 mg), or placebo on a dialysis day.

Subjects will be stratified by prior ESA dose based on the average weekly (for 
epoetins or darbepoetin) or monthly (for methoxy PEG-epoetin beta) dosing 
during the 12 weeks prior to randomization (Day 1)

Approximately 200 subjects will be screened to achieve approximately 90 
randomized and 75 evaluable subjects, with approximately 15 evaluable 
subjects per treatment group.
Planned 
Analyses

No interim analysis is planned. 

Planned final analyses will be performed after all subjects have completed the 
study, database freeze has been declared, and study treatment has been 
unblinded.
Analysis 
Populations

All Screened population comprises all subjects who consented to participate in 
the clinical trial and were screened. 

All Randomized population comprises all randomized subjects regardless of 
whether they took study drug. This population will be based on the treatment to 
which the subject was randomized. 

The Intent-to-Treat (ITT) population comprises all randomized subjects who 
received at least one dose of study treatment, had a baseline and at least one 
corresponding on treatment assessment, including Hgb (Quest or HemoCue). 
This population will be used to summarize subject disposition, baseline and 
demographic data and will be the primary population used in the efficacy 
analyses. Subjects will be classified according to the treatment group to which 
they were randomized.
 
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Overview
Key Elements of the RAP

The Safety population comprises all subjects who received at least one dose of 
study treatment. This population will be based on the treatment and the actual 
dose the subject received, and will be used for all assessments of safety and
tolerability. 

The Per Protocol (PP) population comprises all ITT subjects who were not major 
protocol violators with regards to inclusion/exclusion criteria, investigational 
product compliance and concomitant medication instructions. The Per-Protocol 
population will be used for sensitivity analyses. The PP population will not be 
analyzed if this population comprises more than 80% of the ITT population.

The Completers population comprises all ITT subjects who fully completed the 
Day 29 study assessments without prematurely discontinuing study drug. The 
Completers Population will be used for sensitivity analyses

Pharmacokinetic population comprises all subjects from whom a 
pharmacokinetic sample has been obtained and analyzed.
Hypothesis

No formal hypothesis will be tested. 
Primary 
Analyses

A three-parameter Emax model is planned to model the dose-response 
relationship. The Emax model will be fitted using Bayesian statistical methods. 

If problems are encountered fitting a three parameter Emax model or if the 
Emax shape is a poor fit for the data and a linear relationship looks plausible 
across the three-times weekly dose range, then a linear model will be 
considered. Alternative models will also be investigated until an appropriate 
model can be chosen (e.g., quadratic model, log-transformed dose et al.).
Secondary 
Analyses

Efficacy: In general, all planned secondary analyses of efficacy endpoints (i.e.
hepcidin, hematocrit, RBC count, reticulocyte count, reticuloctye Hgb, EPO, and 
VEGF) are descriptive and estimation based. 

Safety: Overall safety evaluations will be descriptive using the Safety 
Population. Graphical and tabular displays will be presented to facilitate safety 
data review. 
PK/PD 
Analyses

Daprodustat (GSK1278863) and its six metabolites (GSK2391220 (M2), 
GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), GSK2531398 (M6), 
GSK2531401 (M13)) plasma pharmacokinetic concentration will be summarized 
by visit and planned collection time point for each dose level of daprodustat, will 
be plotted appropriately, and will be listed. Plasma concentration-time data for 
daprodustat and its six metabolites will be analyzed by non-compartmental 
methods. Pharmacokinetic parameters (AUC(0-t), AUC(0-∞), Cmax, tmax, t1/2) will 
be determined from the plasma concentration-time data for daprodustat and its 
six predominant metabolites, as data permits. Pharmacokinetic parameters will 
be summarized by treatment group using descriptive statistics, and will be 
listed.

The relationship between plasma concentrations of daprodustat and selected 
endpoints may be explored using appropriate pharmacokinetic/ 
pharmacodynamic models.  Exploratory modeling of the plasma EPO, VEGF 
and/or hepcidin concentrations also may be conducted, as a function of 
 
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Overview
Key Elements of the RAP
daprodustat dose or PK, and may be used to further characterize the effect of 
daprodustat.  Other PD data such as iron parameters and RBC indices may 
also be included if relevant to characterize the PD response.  Relevant 
measures of the secondary and exploratory endpoints (if meaningful) will be 
initially explored graphically and where appropriate modeling approaches will be 
used. Pharmacokinetic/Pharmacodynamic exploratory analysis will be the 
responsibility of CPMS. If additional details are needed, they will be included in
a separate PK/PD RAP. The results of the PK/PD analyses may be reported in 
separate PK/PD report(s).
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Any changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

For Hgb Day 1 measurement
using central lab Quest will serve 
as the baseline value. (Section 
7.3)

For Hgb the average of Hgb 
measured by the central 
lab, Quest, at Week -2 and 
Day 1 visits will serve as the 
baseline value.

Average of Hgb measured 
by the central lab, Quest, at 
Week -2 and Day 1 visits
will reflect the overall pre-
treatment stable Hgb level.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

Characterize the dose-response 
relationship between GSK1278863 
administered three-times weekly and 
Hgb at Day 29

Hgb change from baseline at Day 29
Secondary Objectives
Secondary Endpoints

Characterize the pharmacodynamic 
(PD) effect of GSK1278863 dose 
regimens on EPO, vascular 
endothelial growth factor (VEGF), 
hepcidin and red blood cells

Maximum observed change from baseline in EPO

Maximum observed % change from baseline in VEGF

Change from baseline in hepcidin at Day 29

Change from baseline in hematocrit, red blood cell (RBC) 
count, reticulocyte count and reticulocyte Hgb (CHr) at 
Day 29

Characterize the steady-state PK of 
GSK1278863 and major metabolites

Descriptive PK summaries of GSK1278863 and major 
metabolites

Assess the safety and tolerability of 
GSK1278863 with three-times weekly 
administration for 29 days

Incidence and severity of AEs and SAEs

Reasons for discontinuation of investigational product

Discontinuation for safety-related reasons, e.g., pre-
specified stopping criteria or AE

Absolute values and changes from baseline over time in 
laboratory parameters, ECGs and vital signs.
Exploratory Objectives
Exploratory Endpoints

Evaluate exposure-response 
relationships between GSK1278863 
and PD endpoints

Further models (as appropriate) to describe the 
GSK1278863 exposure (PK or dose)-response 
relationship with PD endpoints
 
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2.3.
Study Design
Overview of Study Design and Key Features
10 mg
Three-times weekly
15 mg 
Three-times weekly
25 mg
Three-times weekly
30 mg
Three-times weekly
Treatment Period Day 1 - 29
Randomization
(1:1:1:1:1)
Follow-Up
Day 43 (+ 3 Days)
Screening
Day -28 to Day -1
Placebo
Design Features

A randomized, double-blinded, dose-ranging, placebo-
controlled, parallel group study. 

There is a 28-day Screening period, a 29-day Treatment 
period, and a Follow-up visit 14 ±3 days after completing 
treatment.
Dosing

Subjects who meet eligibility criteria will be randomized and 
begin dosing on Day 1.  Subjects will discontinue their current 
ESA therapy and will be randomized to receive one of four 
three-times weekly doses (10 mg,15 mg, 25 mg, or 30 mg of 
GSK1278863), or placebo on a dialysis day.

This should be timed such that randomization (Day 1) 
occurs on the date that would have been the next 
scheduled dose of ESA (or as close as practicable).

For subjects with a three-times weekly dialysis schedule, 
Day 1 must not occur on the first dialysis session of the 
week (e.g., if Monday-Wednesday-Friday schedule, the 
study visit cannot be on Monday).

For subjects with a four- to five-times weekly dialysis 
schedule, Day 1 can be on any hemodialysis session of the 
week.

The treatment period will be for a total of 29 days.
Treatment Assignment

Approximately 200 subjects will be screened to achieve 
approximately 90 randomized and 75 evaluable subjects, with 
approximately 15 evaluable subjects per treatment group.

Subjects will be randomized 1:1:1:1:1 to receive one of four 
three-times weekly doses (10 mg, 15 mg, 25 mg, 30 mg), or 
placebo on a dialysis day
 
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Overview of Study Design and Key Features

Randomization schedule will be computer generated by PPD 
using the randomization system Prism.

Subjects will be stratified by prior ESA dose based on the 
average weekly (for epoetins or darbepoetin) or monthly (for 
methoxy PEG-epoetin beta) dosing during the 12 weeks prior 
to randomization (Day 1). 

Central randomization and PPD’s Interactive Voice/Web 
Response System (IVWRS) will be used for treatment 
allocation. 
Interim Analysis

No interim analysis is planned.
2.4.
Statistical Hypotheses
No formal hypothesis will be tested. This study is designed to estimate the relationship 
between three-times weekly doses of GSK1278863 and Hgb response after 29 days of 
treatment in hemodialysis-dependent subjects with anemia associated with chronic 
kidney disease who are switched from a stable dose of an erythropoiesis-stimulating 
agent. To achieve this, a model-based dose-response analysis is planned with the primary 
endpoint of change in Hgb from baseline at Day 29. It is anticipated that the data and the 
estimated parameters generated from this model will enable conversion of QD starting 
and maintenance dose regimens to three-times weekly doses/regimens.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis is planned
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed or withdrawn from the study as defined in the protocol 
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by both PPD and GSK Data 
Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to GSK and PPD procedures.
The final analyses with the exception of the dose-response analysis will be performed by 
PPD. All dose-response analyses as described in Section 7.1.2 will be carried out by 
GSK.
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Screened

Comprise all subjects who consented to 
participate in the clinical trial and were 
screened.

Summarize the 
screen failure 
subjects
All Randomized

Comprise all randomized subjects regardless 
of whether they took study drug. 

This population will be based on the treatment 
to which the subject was randomized.

Any subject who received a treatment 
randomization number will be considered to 
have been randomized.

Describe the 
breakdown of Study 
Populations

Study Population

Selected listings  
Safety

Comprise all subjects who received at least 
one dose of study treatment.

This population will be based on the treatment
and the actual dose the subject received.
Note: (1) If a subject randomized to the placebo 
arm, temporarily received daprodustat by mistake 
during the study, then the subject would be 
included in the corresponding daprodustat arm in 
the Safety population. (2) If a subject randomized 
to one of the daprodustat arms, temporarily 
received placebo by mistake during study, then the 
subject would remain in the randomized 
daprodustat arm in the Safety population.(3) If a 
subject randomized to one of the daprodustat 
arms, received a wrong dose of daprodustat by 
mistake throughout the study, then the subject will 
be included in the daprodustat arm in the Safety 
population based on the actual daprodustat dose 
received.(4) If a subject randomized to one of the 
daprodustat arms, temporarily received wrong 
dose of daprodustat by mistake during study, then 
the subject would be included in the daprodustat 
arm from which the subject received >50% of the
study medication.

Study Population

Safety and 
tolerability
Intent-To-Treat

Comprise all randomized subjects who 
received at least one dose of study treatment, 
had a baseline and at least one corresponding 
on treatment assessment, including Hgb 
(Quest or HemoCue)

This population will be based on the treatment 
to which the subject was randomized.

Efficacy
Per-Protocol

Comprise all Intent-To-Treat subjects who 

Efficacy
 
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Population
Definition / Criteria
Analyses Evaluated
were not major protocol violators with regards 
to inclusion/exclusion criteria, investigational 
product compliance and concomitant 
medication instructions.

Protocol deviations that would exclude 
subjects from the PP population are defined in 
Section 4.1 (Protocol Deviations) and 
Appendix 1 (Protocol Deviation Management 
and Definition for Per-Protocol Population).

The Per-Protocol population will be used for 
sensitivity analyses. The Per-Protocol 
population will not be analyzed if this 
population comprises more than 80% of the 
Intent-To-Treat population.
Completer

Comprise all Intent-To-Treat subjects who fully 
completed the Day 29 study assessments 
without prematurely discontinuing study drug.

The Completer Population will be used for 
sensitivity analyses.

Efficacy
Pharmacokinetic
Population

Comprises all subjects from whom a 
pharmacokinetic sample has been obtained 
and analyzed.

PK
NOTES : 

Please refer to Appendix 14: List of Data Displays which details the population to be used for each displays being 
generated.
4.1.
Protocol Deviations

Important/significant protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Important/significant deviations which result in exclusion from the analysis 
population will also be summarised and listed. (Please refer to Appendix 1: Protocol 
Deviation Management and Definitions for Per Protocol Population).
All protocol deviations, including significant protocol deviation, will be tracked in
PPD CTMS (Clinical Trial Management System), and will be reviewed by PPD and
GSK study team throughout the conduct of the study in accordance with PPD’s 
Study Deviation Rules Document.
o
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset. 
 
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o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS

There are planned examination of covariates and subgroups.

There are no planned adjustments made for multiple centres in this study.

There are no planned adjustments for multiple comparisons or multiplicity.
Table 2 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 2
Overview of Appendices
Section
Component
Section 11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
Section 11.2
Appendix 2: Time & Events
Section 11.3
Appendix 3: Assessment Windows
Section 11.4
Appendix 4: Treatment States and Study Phases
Section 11.5
Appendix 5: Data Display Standards & Handling Conventions
Section 11.6
Appendix 6: Derived and Transformed Data
Section 11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
Section 11.8
Appendix 8: Values of Potential Clinical Importance
Section 11.9
Appendix 9: Multicenter Studies
Section 11.10
Appendix 10: Examination of Covariates and Subgroups
Section 11.11
Appendix 11: Multiple Comparisons & Multiplicity
Section 11.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Section 11.13.
Appendix 13: Abbreviations & Trade Marks
Section 11.14
Appendix 14: List of Data Displays
Section 11.15
Appendix 15: Example Mock Shells for Data Displays
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on either the Safety population, the ITT 
population or the All Randomized population, unless otherwise specified. All summary 
tables will include a Total column and a Dapro Total column, unless otherwise specified. 
Table 3 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 14: List of Data Displays.
Table 3
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Disposition
Y
Reasons for Screening Failure
Y
Y
Study Treatment Discontinuation
Y
Y
Reasons for Study Withdrawal
Y
Subjects for Whom the Treatment Blind was Broken
Y
Randomized and Actual Treatment Assignment
Y
Subjects at Each Visit
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Deviations Leading to Exclusions from Per Protocol
Population
Y
[1]
Subjects with Inclusion/Exclusion Criteria Deviations
Y
Y
Populations Analyzed 
Study Populations
Y
Y
Number of Subjects by Center
Y
Subjects Excluded from Any Population
Y
Demography
Demographic and Other Baseline Characteristics
Y
Y
Race & Racial Combinations
Y
Y [2]
Summary of Race and Racial Combination Details
Y
Y[2]
Medical Condition & Concomitant Medications
Medical Conditions (Current/Past)
Y
Y
Concomitant Medication
Y
Y
Relationship Between ATC Level 1, Ingredients And 
Verbatim Text
Y
Cardiovascular Risk Assessment
Y
Family History of Cardiovascular Risk
Y
 
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Display Type
Data Displays Generated
Table
Figure
Listing
Substance Use History
Y
Y
Baseline Hemodialysis
Y
Y
Prior Erythropoiesis-Stimulating Agents
Y
Y
Y
Erythropoiesis Stimulating Agents Medications
Y
Standardized Prior Recombinant Human Erythropoietin 
Dose
Y
Concomitant Erythropoiesis-Stimulating Agents
Y
Pre-therapy Average Iron Dose
Y
On-therapy Average Iron Dose
Y
Subjects Using IV Iron Dose Between Study Treatment 
Start and Final Visit
Y
Iron Therapy
Y
Blood Products
Y
Y
Exposure and Treatment Compliance
Study Medication Overall Compliance
Y
Y
Extent of Exposure to Study Treatment
Y
Y
NOTES :
1.
Subjects with protocol deviations leading to exclusions from Per Protocol population will be listed in Listing of 
Subjects Excluded from Any Populations
2.
Listing of race will be generated, which includes both “Race and Racial Combinations” and “Race and Racial 
Combination Details”
6.2.
Display Details
6.2.1.
Subject Disposition
The number of subjects who completed the study for purpose of the disposition table will 
consist of all randomized subjects who, as documented in the eCRF, have completed all 
study visits, including the follow-up visit. 
Reasons for withdrawal from study and study treatment will be summarized for each 
treatment group and overall.  A by-subject listing of reasons for study withdrawal and a 
by-subject listing of reasons for study treatment discontinuation will be produced. 
The number and percentage of subjects who failed screening and were therefore not 
entered into the study, overall and by reason, will be summarized. A listing of the screen 
failure record for all subjects who failed screening, including the reasons for screen 
failure will be produced.
The number and percentage of subjects at each visit will be summarized for each 
treatment group and overall. 
A listing of subjects for whom the treatment blind was broken and a listing of 
randomized and actual treatment assignment will be produced. 
 
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6.2.2.
Protocol Deviations
The number and percentage of subjects who had important/significant protocol deviations 
defined in Section 11.1.1 will be summarized overall and by treatment group. (Note: 
Given that different terminologies have been used by GSK and PPD, the terms 
“important protocol deviation” and “significant protocol deviation” will be used 
interchangeably throughout the RAP.)
Protocol deviations leading to exclusion from Per Protocol population will be 
summarized overall and by treatment group. (See Section 11.1.2 for protocol deviations, 
which may lead to the exclusion of a subject from the Per Protocol population)
A listing of important protocol deviations will be produced. Subjects excluded from Per 
Protocol can be found in the listing of subjects excluded from any populations (see 
below). 
Inclusion and exclusion criteria deviations will be summarized and listed. 
6.2.3.
Populations Analyzed
The number of subjects who were randomized into the study, the number of subjects 
within each analysis population (ITT, Per Protocol, Completers, Safety and PK) will be 
summarized for each treatment group and overall. A by-subject listing showing inclusion 
within each study population and a listing of subjects excluded from any populations will 
be produced.
The number and percentage of subjects will be summarized by country and by center 
within each country for each treatment group and overall. 
6.2.4.
Demography
Demographic and baseline data will include age, gender, ethnicity, race, diabetes,
baseline height, baseline weight, baseline body mass index (BMI), prior ESA dose 
(stratification factor, Low ESA dose: <100 IU/kg/week epoetin OR <0.5 μg/kg/week 
darbepoetin OR<0.6 μg/kg/week methoxy PEG-epoetin beta vs. High ESA dose: ≥100 
IU/kg/week epoetin OR ≥0.5 μg/kg/week darbepoetin OR ≥0.6 μg/kg/week methoxy 
PEG-epoetin beta), type of ESA, standardized prior rhEPO Dose (IU/kg/Week, including 
epoetin, darbepoetin, and Mircera), baseline Hgb, baseline ferritin, baseline absolute 
reticulocyte count, baseline iron-based phosphate binder (ferric citrate and sucroferric 
oxyhydroxide), and baseline pre-dose plasma EPO.  In addition, the following data will 
be categorized and summarized for each treatment group and overall: 

Age (<65, >=65 years)

Baseline Hgb (< 10, >= 10 g/dL) 

Baseline Weight (<=Median, > Median kg) 

Baseline BMI (<27,  >=27 kg/m2) 

Race (White, African American, Asian, Other)

Standardized Prior rhEPO (<=xx.xx, >xx.xx and < xx.xx, >=xx.xx) (Tertile)

Diabetes (Yes, No) 

Iron-based Phosphate Binders (Yes, No)

Baseline Absolute Reticulocyte Count (<= Median, >Median TI/L)
 
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All the above demographic and baseline data will be summarized by treatment group and 
overall for the Safety, ITT and All Randomized populations.
A by-subject listing of demographic and baseline characteristics will also be produced. 
Summaries of race and racial combinations and race and racial combination details will 
be produced for each treatment group and overall.  A listing of race and racial 
combination details by subject will also be produced.
6.2.5.
Medical Conditions and Concomitant Medications
The number and percentage of subjects with each past and current medical condition will 
be reported for each treatment group and overall. Past conditions are those reported as 
‘past’ and current conditions are those reported as ‘current’ at screening.  Past and current 
conditions will be reported separately. Medical conditions will be coded using the 
Medical Dictionary for Regulatory Activities (current MedDRA version at the time of 
DBR) and reported by system organ class (SOC) and preferred term.
Summaries of family history of cardiovascular risk, and substance use history will be 
provided by treatment group and overall.
Furthermore, summaries of baseline hemodialysis (mode of dialysis) will be produced by 
treatment group and overall.
By-subject listings of data for past and current medical conditions, cardiovascular risk
assessments, and history of substance use will be produced separately. In addition, a 
listing of hemodialysis will be provided.
For reporting purposes, medications will be classified as prior, concomitant, and/or post-
treatment using the associated start and stop dates recorded in the eCRF and relative to 
the first and last dose dates of IP (see Section 11.4.2.3). Medications will be coded using 
the GSK Drug coding dictionary (current version at the time of DBR).
Concomitant medications will be summarised by GSK-Drug Anatomical Therapeutic 
Chemical (ATC) classification level 1 (body system) and ingredient. Drugs that are 
composed of a combination of ingredients will be displayed according to the ATC 
classifications of the ingredients, not of the combination. 
A summary of the number and percentage of subjects receiving concomitant medications 
will also be displayed using a method that presents multi-ingredient medications 
according to their combination ATC classification rather than the classifications of the 
ingredients. This display will also include single-ingredient medications. Multi-ingredient 
medications will be labelled according to the sum of their ingredients, e.g., “TYLENOL 
Cold and Flu” would appear as “CHLORPHENAMINE MALEATE + 
DEXTROMETHORPHAN HYDROBROMIDE + PARACETAMOL + 
PSEUDOEPHEDRINE HYDROCHLORIDE” under the ATC headings for “Nervous 
System” and “Respiratory System” (the combination’s ATC classifications). A multi-
ingredient drug’s component ingredients will not be summarized separately.
 
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A listing of all medications taken by subjects, including any which are only prior or post-
treatment, will be produced.  The relationship between ATC level 1, ingredients and 
verbatim text for all medications in the study will be listed.
A summary of prior erythropoiesis-stimulating agents taken in the 12 weeks prior to 
randomization will be produced. In addition, if any subject takes erythropoiesis-
stimulating agents during the 29-day treatment period of the study (prohibited medication 
for all subjects between Day 1 and Day 29) this will be tabulated by treatment group. A 
bar chart showing the proportions of subjects taking different prior erythropoiesis-
stimulating agents will be provided. A histogram of prior standardized rhEPO dose will 
also be produced.
A listing of prior erythropoiesis-stimulating agents and a listing of all (prior, concomitant, 
and post-treatment) erythropoiesis-stimulating agents will be provided.
Pre-therapy and on-therapy average iron dose (separately for oral and IV) by treatment 
group will be summarized.  In addition, a table showing the number of subjects (i) using 
IV iron at Study Treatment Start and Final visit, (ii) stopping IV iron on-therapy and (iii) 
starting IV iron after treatment start will be produced for the Safety and Completers 
population. All iron therapy data taken during the study will be listed.
A summary and a listing of any blood products or blood supportive care products taken 
during the study will be produced by treatment group.
6.2.6.
Exposure and Treatment Compliance
The complete dosing experience will be listed for all subjects. The total duration of 
exposure (number of days on study drug), average three times a week dose and 
cumulative dose will be summarized by treatment group and Dapro total.
The average three times a week dose (the cumulative actual dose divided by the expected 
number of doses during the treatment period) is calculated for each subject first and the 
summary statistics for each treatment group and for Dapro Total are calculated based on 
the subject average TIW dose.
Note: The tablet strengths are 5 mg or 25 mg for subjects randomized to dapro arms, and
0 mg for subjects randomized to placebo arm (unless the subject received daprodustat by 
mistake during the study).  
For subjects who completed the 29-day treatment period, the expected number of doses 
during the treatment period is 13. For subjects who permanently discontinued the study 
treatment and/or withdrew from the study, the expected number of doses during the 
treatment period will be calculated in the same way as the calculation of the expected 
cumulative number of tablets for each bottle described below for compliance calculation.
 
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For each subject “Days on study drug” will be calculated as Last Dose Date – First Dose 
Date +1. 
A summary and a listing of study medication compliance will be produced by treatment 
group. 
For each bottle, the compliance will be calculated for the whole study treatment period as 
the percentage of the cumulative number of tablets taken [100*(cumulative number of 
tablets taken) / (expected cumulative number of tablets for the subject’s treatment 
duration)]. For subjects who completed the 29-day treatment period, the expected 
cumulative number of tablets should be 13. For subjects who were permanently 
discontinued study treatment or early withdrew from the study, following algorithm will 
be used to calculate the “expected cumulative number of tablets” taken from each bottle 
during the treatment period:
1. Determine the expected “dose day”, where “dose day” is defined as days since the 
first dose date. (i.e. dosing date – first dose date +1)
a.
For a subject who receives dialysis 3-5 times per week and starts dosing 
on Monday or Tuesday, the expected dose days are: 1, 3, 5, 8, 10, 12, 15,
17, 19, 22, 24, 26, and 29.
b. For a subject who receives dialysis 3-5 times per week and starts dosing 
on Wednesday or Thursday, the expected dose days are: 1, 3, 6, 8, 10, 13,
15, 17, 20, 22, 24, 27, and 29.
c.
For a subject who receives dialysis 3-5 times per week and starts dosing 
on Friday or Saturday, the expected dose days are: 1, 4, 6, 8, 11, 13, 15,
18, 20, 22, 25, 27, and 29.
2. Determine the “expected cumulative number of tablets” by comparing the last 
dose day (last dose date – first dose date +1) with the expected dose days. For 
example, for a subject who received dialysis 3 times per week and started dosing 
on Wednesday, if the subject’s last dose day is day 7, then the expected 
cumulative number of tablets taken from a bottle should be 3 (because the last 
dose was administered before the fourth dose day); if the subject’s last dose day is
day 8, then the expected cumulative number of tablets taken from a bottle should 
be 4 (because the last dose was administered on the fourth dose day).
3. For all other situations which is not covered in step “1” (i.e. a subject who does 
not receive dialysis 3-5 times per week and/or  does not start dosing on Monday –
Saturday), the following formula will be used to estimate the “expected 
cumulative number of tablets” taken from each bottle during the treatment period:
Where “i” is the “last dose day”.
Overall compliance for a subject is categorized as follows: >0% and <80% if compliance 
for at least one bottle is <80%, 80% to 120% if compliance for all three bottles is between 
80% and 120%, and >120% otherwise.
 
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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Efficacy Analyses
7.1.1.
Overview of Planned Efficacy Analyses
The primary efficacy analyses will be based on the “Intent-To-Treat” population, unless 
otherwise specified.
Table 4 provides an overview of the planned Hgb efficacy analyses, with full details of 
data displays being presented in Appendix 14: List of Data Displays.
Table 4
Overview of Planned Hgb Efficacy and Sensitivity Analyses based 
on Emax Model and Other Analyses of Hgb
Endpoint and Related 
Analyses
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Analyses of Hgb change from baseline at Day 29 based on Emax Model
Posterior Estimates 
from the Bayesian 3 
Parameter Emax 
Dose-Response Model
for the Primary and 
Sensitivity Prior 
Analyses and the 
Estimates from the 
Frequentist 3 
Parameter Emax 
Dose-Response Model
Y[1]
Y[1]
Y[1]
Posterior Probability 
Distribution for 
Predicted Hemoglobin 
Change (g/dL) from 
Baseline at Day 29 
Based on Primary 
Analysis 
Y
Density Plots 
Associated with Emax 
Model Parameter, E0
Y
Density Plots 
Associated with Emax 
Model Parameter, 
Emax
Y
Density Plots 
Associated with Emax 
Model Parameter, 
ED50
Y
Density Plots 
Associated with Emax 
Model Parameter, 
Y
 
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Endpoint and Related 
Analyses
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Variance
Posterior Predictive 
Distribution for 
Hemoglobin (g/dL) 
Change from Baseline 
at Day 29 for a Future 
Subject based on 
Primary Analysis
Y
Posterior Predictive 
Probability that Day 29 
Hemoglobin (g/dL) 
Change for a Future 
Subject will be in the 
Range [−0.5, 0.5] g/dL 
by Daprodustat Dose
Y
Other Summary and Analyses of Hgb
Hgb Imputations
Y
Dose-Response Linear 
Model for Change in 
Hemoglobin at Day 29
Y[2]
Linear Model between
the corresponding QD 
and TIW doses with 
the same Change in 
Hemoglobin at Day 29
Y
Summary of Dose 
Ratio Between Three-
Times Weekly Doses 
(Observed) and QD 
Doses 
Y
Summary of Dose 
Ratio Between Three-
Times Weekly Doses 
and QD Doses at 
Selected Hgb 
Responses
Y
Summary of Posterior 
Estimates from the 
Bayesian 3 Parameter 
Emax Dose-Response 
Model and the 
Estimates from the 
Frequentist 3 
Parameter Emax 
Dose-Response Model 
for Change in 
Hemoglobin at Week 4 
(Based on PHI113633 
Y
 
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Endpoint and Related 
Analyses
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
data excluding Japan)
Dose-Response Linear 
Model for Change in 
Hemoglobin at Week 4 
(Based on PHI113633 
data excluding Japan)
Y
Scatter Plot of Hgb 
Response vs. TIW/QD 
Weekly Dose
Y
TIW Doses vs. QD 
Doses Corresponding 
Selected Hgb 
Responses
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Primary analysis based on ITT population will be repeated for completer and per protocol populations.
[2] This linear regression analysis will be repeated for ITT, completer, and per protocol populations. 
7.1.2.
Planned Hgb Efficacy Statistical Analyses
Primary Statistical Analyses
Endpoint(s)

Hgb change from baseline at Day 29
Model Specification

The primary endpoint is change in Hgb from baseline at Day 29. To model the dose-
response relationship a three-parameter Emax model is planned, where Emax is 
assumed an appropriate model based on the biology and QD-dose-response modeling 
completed to date for GSK1278863.
This model assumes the following form:
Where:

ΔHgb is the change in Hgb from baseline at Day 29

E0 is the placebo response

Emax is the maximum response
 
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Primary Statistical Analyses

ED50 is the dose that attains the intermediate response, i.e. where (E0+Emax) /
2, is attained

ε is a random error assumed to be normally distributed with mean zero and 
constant variance (σ2 )
The observed change in Hgb from baseline at Day 29 will be used as the response 
variable in the Emax model.  Subjects who have a Day 15 Hgb measurement but a 
missing Day 29 Hgb measurement will be included with a Day 29 value imputed (see 
Section 11.7.2.1).  Any subject who prematurely discontinues dosing prior to Day 15 will 
be non-evaluable for the dose-response analysis.
Prior Distribution
The Emax model will be fitted using Bayesian statistical methods (i.e. a posterior Emax 
model).  Prior distributions for each of the model parameters have been based on the 
estimates obtained from GSK study PHI113633.  This modeling provides confidence in 
setting prior distributions for E0, however, there is greater uncertainty in the estimation 
of Emax and ED50, which will be explored in sensitivity analyses with alternative 
(weaker) prior distributions.
Prior Distributions of the Primary Model
Emax Model 
Parameters
Bayesian Priors
E0
~Normal (-0.67, (0.146)2)
Emax
~Normal (5.26, (1.337)2)
ED50
~Uniform (10, 120)
Tau (1/σ2)
~Gamma (1,1)
Model Fitting in SAS
The model will be fitted in SAS using the MCMC procedure. 

Blocking: Sampling blocks of parameters instead of the parameters separately 
may speed up the convergence to the target distribution. Blocks are specified in 
the PARMS statement. 

Seed: The seed for reproducibility of results will be set to 123.
Starting Values
In order to check the validity of the Emax model fit, five separate Monte Carlo Markov 
Chain’s chains will be fitted each with the following starting points:

Chain 1) E0 = -1.2, Emax = 5.5, ED50 = 50, var = 1

Chain 2) E0 = -0.75, Emax = 7, ED50 = 22.5, var = 2

Chain 3) E0 = -1.65, Emax = 4, ED50 = 80, var = 0.5
 
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Primary Statistical Analyses

Chain 4) E0 = -1.65, Emax = 7, ED50 = 22.5, var = 1

Chain 5) E0 = -0.75, Emax = 4, ED50 = 100, var = 2 
When the starting values are taken in an area where the posterior probability is low, it 
may take a long time to escape from the starting positions and mixing could be low 
initially. In this case, other starting values could be tried.
Burn In
“Burn-in” is the portion of the chain where convergence has not yet been achieved. 
“Discarding burn-in” is the practice of discarding the initial portion of a Markov chain. 
This will be set to 5000 iterations.
Convergence Diagnostics
Convergence of the chains to the posterior distribution for each parameter will be 
assessed using: 

MCMC error of the model parameters

Autocorrelation plot to assess the autocorrelation of each parameter

Visual inspection of the trace plots for each parameter 

Gelman and Rubin Diagnostics
The following points will be reviewed and evaluated:
1. Monte Carlo Standard Error (MCSE) is the standard error of the posterior mean 
estimate and provides the measurement of the accuracy of the posterior estimates. 
All parameters MCSE/SD will be derived. All MCMC chains will be run until the 
posterior estimates of the variance, E0, the minimal effective dose (MED) and the 
target dose (TD) have  MCSE/SD values of < 0.015 and Emax, ED50 and the 
doses of GSK1278863 that achieve a -0.25, 0.25, 0.5, 0.75 and 1 g/dL change 
over 29 days have MCSE/SD of < 0.05. Note the MCSE/SD criteria for all 
parameters must be met.
2. Autocorrelation measures dependency among Markov chain samples. When the 
autocorrelation takes many sample iterations to reduce, this indicates poor mixing 
of the Markov chain. When the autocorrelation reduces more quickly over time, 
this indicates good mixing. Autocorrelation plot will be generated for all chains 
for visual inspection.
3. A visual inspection of all parameters associated trace plots will be performed to 
assess the mixing of the 5 chains – to check if each chain is independently 
realizing values similar to the other chains. This is shown by the chain having a 
constant mean and variance, and by moving around the parameter space freely 
(i.e. the plot resembles random noise).
4. Gelman and Rubin diagnostics (Gelman and Rubin, 1992; Brooks and Gelman, 
1997) are based on analysing multiple simulated MCMC chains by comparing the 
variances within each chain and the variance between chains. Large deviation 
between these two variances indicates non-convergence. A refined version of the 
 
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potential scale reduction factor (PSRF) as suggested by Brooks and Gelman, 
(1997) will be calculated for each parameter using the autocall macro %gelman in 
SAS. The significance level (alpha) of this test will be set to 0.002. A large PSRF 
indicates that the between-chain variance is substantially greater than the within-
chain variance, so that longer simulation is needed. A PSRF < 1.05 suggests that 
each of the 5 chains has stabilized, and they are likely to have reached the target 
posterior distribution.
From the above review, if it is felt the burn-in is inadequate as evidenced by (3) and (4), 
then this will be increased in increments of 5000 iterations. After which, a sample size of 
100,000 will be obtained from the estimated posterior from each of the 5 chains, for a 
total sample size of 500,000 iterations. If the chain appears to be mixing slowly as 
evidenced by (2) and (3), then re-allocation of parameters in the PARM statement or 
increasing the number of iterations in increments of 10,000 iterations will be investigated. 
By monitoring these diagnostics and making adjustments to the modelling code as stated 
above, it is anticipated that that the required parameter precision as stated in (1) will be 
achieved. If this is not the case, increases in the number of sample iterations and/or 
incorporation of thinning will be used to ensure the required level of precision is 
achieved.
Pairwise comparison plot (cross plot) of the posterior sample for all parameters will be 
created and inspected. 
The Deviance Information Criteria (DIC) for the model will also be obtained for 
reference.
Posterior Estimates
Once the dose response model has been fitted satisfactorily, the posterior distribution of 
the model parameters (E0, Emax, ED50, and variance) will be summarized through 
means, standard deviation, median, MCSE/SD and equal-sided 95% credibility intervals. 
The predicted value of Hgb value change from baseline on day 29 at a series of doses 
(range of possible doses from 0 to 50 will be sectioned off into a sequence of 0.5 
increments; i.e. dose levels of 0, 0.5, 1.0, 1.5, …, 25.0..., 50.) will also be monitored and 
the median and 95% credibility values will be obtained at each dose. The Hgb dose 
response curve will be plotted as a line through these medians and 95% credibility bands, 
and overlaid on a scatter plot of the observed data. This estimated dose response curve is 
a composite best fit at each dose and is not in itself an Emax curve. 
The model will be used to make the following inferences to describe the dose response 
relationship:

Estimation of the three-times weekly minimally effective dose (MED), defined as 
the smallest dose achieving a change of -0.5 g/dL over 29 days after being 
switched from ESA. To estimate this value a variable in the PROC MCMC code 
will be tracked with the MCMC algorithm and calculated as follows where ΔHgb 
= -0.5
 
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










Hgb
E
E
Hgb
ED
MED
max
0
50

Estimation of three-times weekly dose levels from the MED in +0.25 g/dL mean 
Hgb increments, including estimation of the target dose (TD), defined as the 
three-times weekly dose of GSK1278863 that achieves a 0 g/dL change over 29 
days after being switched from ESA will be made. These variables will be 
calculated similar to the MED, as shown above, where ∆Hgb equals -0.25, 0, 
0.25, 0.5, 0.75 and 1.
As well as the dose-response Emax curve, the following figures will be produced: 

A posterior probability distribution of predicted Hgb (g/dL) change over 29 days
for each treatment group. Seperate variables to estimate the predicted Hgb (g/dL) 
change at day 29 for doses 0, 10, 15, 25, and 30 will be derived and tracked 
within the MCMC algorithm. The mean and SD will be calculated for each 
variable. The dose, along with the mean and SD of its corresponding predicted 
Hgb change at day 29 will be output into a text file, then R or SAS will be used to 
produce the plot.

A predictive posterior probability distribution of Hgb (g/dL) change over 29 days 
anticipated for a future subject, for each treatment group. The PREDDIST 
statement will be used in PROC MCMC to predict Hgb change from baseline in 
future subjects, for each of the studied doses. 

Density plots for each Emax parameter showing the prior and posterior 
distribution for the primary and sensitivity priors analyses overlaid (Sensitivity 
priors are described below in Section Sensitivity and Supportive Statistical
Analyses.) The sample data generated from the MCMC method will be used to 
plot the posterior density. R or SAS will then be used to produce this plot for each 
Emax parameter.

A predictive posterior probability plot over the dose range to describe the 
probability that dose will maintain Hgb within the range of [-0.5, 0.5] g/dL after 
29 days for a future subject. This plot will be used to determine the probability of 
a future subject achieving Hgb in [-0.5, 0.5] range at each dose. By comparing 
across doses, evidence will be provided for the expected improvement of one dose 
over another, and may aid selection of titration doses in phase 3.
Additional Dose Response Modeling
A Frequentist 3-parameter Emax model in the model form defined as above will also be 
fitted to data. The derived data from this Emax model (estimates of E0, Emax, ED50 and 
Var along with their standard error, and 95% CI) will be tabulated and a dose-response 
curve (alongside the primary analysis curve and sensitivity prior analysis) will also be 
produced.
 
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If problems are encountered fitting a three parameter Emax model, or if the Emax shape 
is a poor fit for the data, or a linear relationship looks plausible across the three-times 
weekly dose range, then a linear model will be considered of the form: 
Other appropriate models, such as quadratic model and log-transformed dose will also be 
explored if necessary.
Dose Response Exploration

A scatter plot will be produced by study with total weekly doses as x-axis, and 
Hgb responses as y-axis including the combined QD (PHI113633 excluding 
Japan) and three-times weekly (204836) data. The pattern can be examined to 
explore whether or not the two regimens with the same weekly dose would have 
the same response. 
Dose Ratio Estimation
Dose ratio between TIW and QD doses that produce the same Hgb response will be 
estimated by different approaches. The dose ratio that will be used to make an 
informative decision about conversion of QD initial and maintenance dose regimens to 
three-times weekly doses/regimens will be based on the totality of the data obtained from 
different approaches. 

The TIW dose response estimations will be obtained from the above fitted 
models. In addition, the QD dose response estimations will also be obtained by 
fitting the same models as described above (two Emax models and a linear model) 
using GSK study PHI113633 data excluding Japan. The prior information and the 
starting values for the QD Bayesian Emax model is shown below:
Five separate Monte Carlo Markov Chain’s chains will be fitted each with the following 
starting points:

Chain 1) E0 = -1.2, Emax = 5.5, ED50 = 16, var = 1

Chain 2) E0 = -0.75, Emax = 7, ED50 = 22.5, var = 2

Chain 3) E0 = -1.65, Emax = 4, ED50 = 9.5, var = 0.5

Chain 4) E0 = -1.65, Emax = 7, ED50 = 22.5, var = 1

Chain 5) E0 = -0.75, Emax = 4, ED50 = 9.5, var = 2 
Prior Distributions for QD Bayesian Emax Model 
Emax Model 
Parameters
Bayesian Priors
E0
~Normal (-1.2, (0.45)2)
Emax
~Normal (5.5, (1.5)2)
ED50
~Uniform (5, 50)
Tau (1/σ2)
~Gamma (1,1)
 
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
For each TIW dose (10mg, 15mg, 25mg, and 30mg), the observed mean Hgb 
response (Hgb change from baseline) at day 29 can be calculated. Using the 
observed mean Hgb response values as a bridge, the corresponding QD doses will 
be estimated using Emax models or a linear model. TIW dose divided by the 
corresponding QD dose will be used to estimate the dose ratio between them. The 
TIW doses, the observed mean Hgb responses, and the corresponding estimated 
QD doses, dose ratios, and the 95% CIs (bootstrap CIs or Bayesian credibility 
intervals) will be displayed in a table.

Another way to estimate the dose ratios is to use a selected series of Hgb 
responses. For each Hgb response value (such as a change of 0.25 g/dL), the 
corresponding TIW dose and QD dose can be calculated using either an Emax 
model, or a linear model. The possible Hgb responses choices are: a change of -
0.5, -0.25, 0, 0.25, 0.5, 0.75, 1 g/dL between baseline and day 29. The Hgb 
responses, and the corresponding TIW doses, QD doses, Dose ratios, and their 
95% CIs (bootstrap CIs or Bayesian credibility intervals) will be presented in a 
table. 

In the above two methods, fairly similar dose ratios across the doses indicate the 
dose ratios is not dose-dependent. Under this assumption, the ratio between the
estimated ED50s from the TIW Emax model (this study) and the QD Emax model 
(GSK study PHI113633) would be equivalent to the dose ratio, as well as the ratio 
between the estimated slopes from the QD linear model (GSK study PHI113633) 
and three-times weekly linear model (this study). 

An additional way to explore the dose ratio is to draw a TIW dose vs. QD dose 
plot using the pair of TIW doses and QD doses obtained from the above methods. 
The appropriate models to investigate the dose ratio will be fitted based on the 
plot. If the relationship between the TIW doses and the QD doses is linear, then a 
linear model 
can be fitted. If the relationship between 
the TIW and QD doses is generally linear and the magnitude of 
dose not deviate 
from zero in a clinically meaningful way, then it suggests that the dose ratio is not 
dose dependent. Otherwise if 
shows a clinically meaningful difference from 0 
or the relationship between the TIW and QD doses is not linear, then it suggests 
that the dose ratio may be dose dependent. Additional models may be used to 
further examine how the dose ratio changes when QD dose changes.

Although the Emax models and the linear model will be explored to estimate the 
dose ratio between the TIW and the QD doses, the linear model will be more 
reliable if it is well-fitted across the TIW and the QD dose range. This is because 
the QD and TIW dose ranges are expected to only cover the beginning part of the 
Emax curves. Therefore if any doses lie outside the dose ranges (such as ED50), 
they will be poorly estimated.

The 95% bootstrap CI of the estimated dose ratios can be constructed based on the 
2.5 percentile and the 97.5 percentile of 1000 bootstrap simulations (Efron and 
 
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Tibshirani, 1993).

For Bayesian Emax models, the posterior distributions of the estimated doses will 
be obtained by the PROC MCMC procedure to estimate the dose ratios, of which 
the 95% Bayesian credibility intervals can be constructed based on the 2.5 
percentile and the 97.5 percentile of the 500,000 estimations.
Model Checking & Diagnostics

Refer to Convergence Diagnostics and Posterior Estimates
Model Results Presentation

As described above with Posterior Estimates, model parameters estimated from the 
Bayesian Emax model will be summarized through means, SD, median, MCSE/SD
and equal-sided 95% credibility intervals. 

Median and 95% credibility intervals from Bayesian analyses and the model 
estimates and 95% CIs from frequentist analysis will be presented for MED, TD, and 
selected doses corresponding to the change of -0.25, 0.25, 0.5, 0.75 and 1 g/dL in Hgb 
from baseline.

The Hgb dose response curve will be plotted as a line through the medians (of the 
predicted values of Hgb change from baseline on day 29 at a series of doses) and 95% 
credibility bands, and overlaid on a scatter plot of the observed data.

A posterior probability distribution of predicted Hgb (g/dL) change over 29 days for 
each treatment group will be generated.

A predictive posterior probability distribution of Hgb (g/dL) change over 29 days 
anticipated for a future subject, for each treatment group will be plotted.

Density plots for each Emax parameter showing the prior and posterior distribution 
for the primary analysis overlaid with sensitivity priors analyses will be generated.

A predictive posterior probability plot over the dose range to describe the probability 
that dose will maintain Hgb within the range of [-0.5, 0.5] g/dL after 29 days for a
future subject will be generated.

Dose ratios estimated by different approaches will be tabulated.   
Additional Results Presentation
Listing of Hgb (and HemoCue Hgb data), Hgb change from baseline and Hgb derived 
parameters will be provided.
Analysis Datasets

Unless otherwise specified, efficacy inference will be based on the ITT population 
using an observed case dataset, comprising of all non-missing data collected up to 
discontinuation of study drug and withdrawal from the trial.

For dose response analysis based on ITT population, the analysis dataset comprises 
(1) all observed non-missing Hgb data collected up to Day 29; and (2) imputed Hgb 
value at Day 29 for subjects who have a Day 15 Hgb measurement but a missing Day 
29 Hgb measurement. 
 
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Sensitivity and Supportive Statistical Analyses
To assess the robustness of the primary efficacy conclusions the dose-response analysis 
will be repeated using the sensitivity approaches described below. 

The primary dose-response model will be fitted based on the completer population. A 
table summarizing the results of these dose response analyses along with the dose 
response curve (alongside the primary analysis curve) will be produced on this 
population.

The primary dose-response analysis will be repeated using the PP population if it 
comprises ≤80% of the ITT population. A table summarizing the results of these dose 
response analyses along with the dose response curve (alongside the primary analysis 
curve) will be produced on this population. 

The dose-response Emax model will be fitted using alternative (weaker, less 
informative) prior distributions for the Emax model parameters. The results from this 
sensitivity prior analysis will be tabulated as previously described for the primary 
dose-response model.
Alternative Prior Distributions 
Emax Model 
Parameters
Bayesian Priors
E0
~Normal (-1.2, (1)2)
Emax
~Normal (5, (3)2)
ED50
~Uniform (2, 200)
Tau (1/σ2)
~Gamma (1,1)

A 3-parameter frequentist Emax model will be fitted based on ITT population. It will 
be fitted using PROC NLMIXED or PROC NLIN, and will be presented as described 
above.

A linear model will be fitted to the dose-response data based on ITT population, if a 
linear relationship looks plausible across the three-times weekly dose range and will 
be presented as described above. This analysis will be repeated in the Completers and 
Per Protocol populatipons. 
 
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8.
SECONDARY STATISTICAL ANALYSES
8.1.
Efficacy Analyses
8.1.1.
Overview of Planned Efficacy Analyses
The secondary efficacy analyses will be based on the Intent-To-Treat population, unless 
otherwise specified. All secondary Hgb summaries/analyses will use the ITT population 
with an observed case on-therapy dataset. If the Hgb concentration measurement from 
Quest is missing and a corresponding valid Hemocue Hgb concentration measurement is 
available, the Hemocue Hgb concentration measurement will be used for all summaries 
and analyses.
Table 5 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Appendix 14: List of Data Displays.
Table 5
Overview of Planned Efficacy Analyses
Endpoint 
Absolute
Change or %Change from Baseline
Stats Analysis
Summar
y
Individual
Stats Analysis
Summar
y
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Hemoglobin (Hgb)
Summary of 
Treatment Difference 
for Hemoglobin (g/dL) 
Change from Baseline 
at Day 29 by 
Subgroups
Y
Y
Y
Exploratory Summary 
of Repeated Measures 
Analysis for 
Hemoglobin (g/dL) 
Change from Baseline 
at Day 29
Y
Y
Summary of 
Hemoglobin (g/dL) by 
Visit
Y
Y
Y
Y
Summary of 
Hemoglobin (g/dL) 
Change from Baseline 
by Visit by Subgroups
Y
Individual Subject 
Hemoglobin Change 
from Baseline at Day 
29 with Means and 
95% CIs
Y
Y
Subjects Who Reach 
Pre-defined Hgb 
Stopping Criteria
Y
Y
Y
 
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Endpoint 
Absolute
Change or %Change from Baseline
Stats Analysis
Summar
y
Individual
Stats Analysis
Summar
y
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Subjects Meeting 
Different Hemoglobin 
Criteria
Y
Y
Subject Profiles of Hgb 
and Dose over Time
Y
Hgb Assessments: 
Quest vs. HemoCue
Y
Secondary Efficacy Endpoints
Hepcidin
Y
Y
Y
Y
CHr
Y
Y
Y
Y
Hematocrit
Y
Y
Y
Y
RBC Count
Y
Y
Y
Y
Reticulocyte Count(%)
Y
Y
Y
Y
Reticulocyte 
Count(Absolute)
Y
Y
Y
Y
Plasma EPO
Y
Y
VEGF
Y
Y
Plasma EPO and 
Hepcidin
Y
Individual Post-Dose 
EPO
Y
Individual Post-Dose 
VEGF
Y
Iron-related Parameters
Ferritin
Y
Y
Y
Y
Transferrin
Y
Y
Y
Y
Transferrin Saturation
Y
Y
Y
Y
Total Iron
Y
Y
Y
Y
UIBC
Y
Y
TIBC
Y
Y
Y
Y
Iron-related 
Parameters (Ferritin, 
Transferrin, Total Iron, 
Hepcidin)
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
 
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8.1.2.
Planned Efficacy Statistical Analyses
Secondary Statistical Analyses
Endpoint(s)

Hgb change from baseline at Day 29
Model Specification

Repeated Measures Analysis of Hgb Change from Baseline
The observed change in Hgb from baseline to Day 29 will be analyzed by a repeated measures 
model using the PROC MIXED procedure. Hgb data will be used from Day 15 and Day 29 
provided it is collected on-treatment; a subject must have a baseline value and at least one on-
treatment Hgb assessment to be included in the analysis. Model effects will include baseline 
Hgb, treatment, time, and treatment-by-time interactions. The estimation method to use will be 
Restricted Maximum Likelihood (REML). The Kenward and Roger version of the F-test will be 
used. The variance-covariance structures for repeated measures within the same subject will 
be unstructured (UN). For Day 29, least squares mean differences will be calculated as 
estimates of the difference between the GSK1278863 groups and placebo, together with 95% 
CIs. These results will be tabulated.

Subgroup Analysis
The observed change in Hgb from baseline to Day 29 by subgroups will be analyzed by a 
repeated measures model using the PROC MIXED procedure. The subgroups of interest are 
detailed in Section 11.10.1 In order to analyse a particular subgroup, at least 30% of total ITT 
subjects will be required in each subgroup (approximately 27 subjects per subgroup 
anticipated). Hgb data will be used from Day 15 and Day 29 provided it is collected on-
treatment; a subject must have a baseline value and at least one on-treatment Hgb 
assessment to be included in the analysis. Model effects will include baseline Hgb, treatment, 
time, subgroup, treatment-by-time, treatment-by-subgroup, subgroup-by-time and treatment-
by-time-by-subgroup interactions. The estimation method to use will be Restricted Maximum 
Likelihood (REML). The Kenward and Roger version of the F-test will be used. The variance-
covariance structures for repeated measures within the same subject will be unstructured (UN). 
For Day 29, the least squares mean differences will be calculated as estimates of the 
difference between each GSK1278863 treatment group and placebo for each subgroup, 
together with 95% CIs. All comparisons will be presented, irrespective of the number of 
subjects per treatment arm within each subgroup.
Note: if subgroup is baseline Hgb (<10 vs. >=10 g/dL), drop the continuous variable for 
baseline Hgb from the model. 
Model Results Presentation

For repeated measures analysis of Hgb change from baseline, model-adjusted change from 
baseline, SE, and 95% CI for dapro arms and placebo will be presented. Model-adjusted 
treatment difference and the associated 95% CI will also be presented in an analysis table. 

For subgroup analyses, a forest plot will be produced showing the placebo-corrected Hgb 
change from baseline at Day 29 for each dose and subgroups. A table of these results will also 
be provided. 
 
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Summary of Other Endpoints
Endpoint(s)

Hepcidin

CHr

Hematocrit

RBC Count

Reticulocyte Count(%)

Reticulocyte Count(Absolute)

Plasma EPO

VEGF

Ferritin

Transferrin

Transferrin Saturation

Total Iron

UIBC

TIBC
Summary Results Presentation

Summaries over time and change or percent change from baseline will be produced by 
treatment group for parameters listed above. 

For plasma erythropoietin and VEGF, summary statistics will be calculated and presented by 
visit and sample time within visit. In addition, maximum observed change / %change from 
baseline will also summarized for plasma erythropoietin and VEGF. 

Line plots of mean/geometric mean with 95 CI will be produced by visit for parameters listed 
above (except that no line plots will be created for UIBC, Plasma EPO, and VEGF).

Line plots of mean change/%change with 95% CI will be produced by visit for parameters listed 
above (except that no line plots will be created for UIBC, Plasma EPO, and VEGF).

Graphs of individual post-dose EPO at Day 15 by actual time will be plotted with a loess curve 
fitted for each treatment group

Graphs of individual post-dose VEGF at Day 15 by actual time will be plotted with a loess curve 
fitted for each treatment group. 

Graph of subject profiles of iron-related parameters with mean line by visit for each treatment 
group

Graph of subject profiles of plasma erythropoietin and hepcidin by visit for each treatment 
group 
 
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8.2.
Safety Analyses
8.2.1.
Overview of Planned Analyses
The safety analyses will be based on the Safety population, unless otherwise specified.
Table 6 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 6
Overview of Planned Safety Analyses
Endpoint / Parameter/ 
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Adverse Events
AE Overview
Y
On-therapy/Post-
therapy AEs by System 
Organ Class (SOC)
Y
Y
On-therapy/Post-
therapy AEs by 
Preferred Term (PT)
Y
Subject Numbers for 
Individual AE
Y
On-Therapy Common 
AEs by Overall 
Frequency
Y
Y
On-Therapy Common 
Non-Serious Adverse 
Events by Overall 
Frequency
Y
On-therapy Adverse 
Events by System 
Organ Class and 
Maximum Intensity
Y
On-Therapy 
Treatment-Related 
AEs by SOC
Y
Y
On-Therapy 
Treatment-Related 
AEs by PT
Y
On-Therapy Serious 
AEs by SOC
Y
On-Therapy Serious 
AEs by PT
Y
Post-Therapy Serious 
AEs by PT
Y
 
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Endpoint / Parameter/ 
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
On-Therapy 
Treatment-Related
Serious AEs by SOC
Y
On-Therapy 
Treatment-Related 
Serious AEs by PT
Y
Drug-Related Serious 
AEs
Y
On-Therapy AEs 
Leading to Withdrawal/ 
Permanent 
Discontinuation of 
Study Treatment by 
Overall Frequency (By 
System Organ Class)
Y
Y
On-Therapy AEs 
Leading to Withdrawal/ 
Permanent 
Discontinuation of 
Study Treatment by 
Overall Frequency (By 
PTs)
Y
Fatal AEs
Y
Non-Fatal SAEs
Y
Relationship of AE 
SOC, PT and Verbatim 
Text
Y
Death 
Y
Reasons for
Considering as a 
Serious AE
Y
On-Therapy AEs of 
Special Interest
Y
Y
Subjects and Number 
of Occurrences of 
Common Non-Serious 
AEs by SOC and PT
Y
Subjects and Number 
of Occurrences of 
Serious, Treatment-
Related Serious, Fatal, 
and Treatment-Related 
Fatal Serious AEs
Y
Cancer Data
Y
Patient Profile Listing 
of Arrhythmias
Y
Patient Profile Listing 
Y
 
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Endpoint / Parameter/ 
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
of Congestive Heart 
Failure
Patient Profile Listing 
of Cerebrovascular 
Events/Stroke/Transien
t Ischemic Attack
Y
Patient Profile Listing 
of Deep Venous 
Thrombosis 
/Pulmonary Embolism
Y
Patient Profile Listing 
of Myocardial 
Infarction/Unstable 
Angina
Y
Patient Profile Listing 
of Peripheral Arterial 
Thrombosis Embolism
Y
Patient Profile Listing 
of Pulmonary 
Hypertension
Y
Patient Profile Listing 
of Revascularisation
Y
Patient Profile Listing 
of Valvulopathy
Y
Possible Suicidality-
Related Adverse Event 
Data
Y
Laboratory Values
Clinical Chemistry by 
Visit
Y
Y
Y
Hematology by Visit
Y
Y
Y
Hematology Data 
Outside the Reference 
Range
Y
Hematology and 
Chemistry Data of 
Potential Clinical 
Importance at Any 
Time On-Therapy
Y
Y
Hematology and 
Chemistry Data of 
Potential Clinical 
Importance at Any 
Time Post-Therapy
Y
Y
Chemistry Changes 
from Baseline  Relative 
to the Reference 
Range (or with 
Y
 
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Endpoint / Parameter/ 
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Respect to the Normal 
Range)
Hematology Changes 
from Baseline  Relative 
to the Reference 
Range (or with 
Respect to the Normal 
Range)
Y
ECG’s
ECG Findings
Y
ECG Values
Y
All ECG Values for 
Subjects with Any 
Value of Potential 
Clinical Importance
Y
All ECG Findings for 
Subjects with an 
Abnormal Finding
Y
Vital Signs
Vital Sign Values by 
Visit
Y
Y
Y
Vital Signs of Potential 
Clinical Importance at 
Any Time On-therapy
Y
Y
Mean and 95% CI for 
Systolic and Diastolic 
Blood Pressure by Visit
Y
Hepatobiliary (Liver)
Liver Monitoring/ 
Stopping Event 
Reporting
Y
Hepatobiliary 
Laboratory 
Abnormalities
Y
Liver Function Tests by 
Visit
Y
Matrix Display of 
Maximum Liver 
Function Test Values
Y
Liver Function Test 
Values
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.     
 
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8.2.2.
Display Details
8.2.2.1.
Adverse Event Safety Analyses
All adverse event (AE) data will be summarized, sorted by the system organ class (SOC) 
and preferred term assigned by MedDRA, and presented by treatment group. The 
following summaries will be provided:

Adverse events overview

All on-therapy AEs by System Organ Class (Sorted by Dapro Total in descending 
order)

All post-therapy AEs by System Organ Class (Sorted by Dapro Total in descending 
order) 

All on-therapy AEs by Preferred Term (Sorted by Dapro Total in descending order)

All post-therapy AEs by Preferred Term (Sorted by Dapro Total in descending order)

On-therapy common adverse events by overall frequency (Common adverse event is 
defined as an AE with >= 2 subjects in any treatment group or >=2% in Dapro Total)

On-therapy common non-serious adverse events by overall frequency (Common 
adverse event is defined as an AE with >= 2 subjects in any treatment group or 
>=2% in Dapro Total)

On-therapy AEs by System Organ Class and maximum intensity

On-therapy treatment-related AEs by System Organ Class

On-therapy treatment-related AEs by Preferred Term

On-therapy serious AEs by System Organ Class

On-therapy serious AEs by Preferred Term

Post-therapy serious AEs by Preferred Term

On-therapy treatment-related serious AEs by Preferred Term

On-therapy treatment-related serious AEs by System Organ Class

On-therapy AEs leading to withdrawal from study/permanent discontinuation of 
study treatment by System Organ Class

On-therapy AEs leading to study withdrawal from study/permanent discontinuation 
of study treatment by preferred term

Subjects and number of occurrences of common on-therapy non-serious AEs by 
System Organ Class and Preferred Term with occurrences >= 5%

Subjects and number of occurrences of on-therapy serious, treatment-related serious, 
fatal serious, and treatment-related fatal serious adverse events by System Organ 
Class and Preferred Term

AEs of special interest assessed by the SRT prior to study end as:
 
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o
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) 
o
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 
o
Cardiomyopathy
o
Pulmonary artery hypertension
o
Cancer-related mortality and tumor progression and recurrence 
o
Esophageal and gastric erosions
o
Proliferative retinopathy, macular edema, choroidal neovascularization 
o
Exacerbation of rheumatoid arthritis
For reporting purposes, the AEs of special interest will be displayed as:
o
Fatal, CV and thrombotic events
o
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis
o
Cardiomyopathy  
o
Pulmonary artery hypertension  
o
Cancer 
o
Esophageal and gastric erosions  
o
Retinal and choroidal neovascularization
o
Exacerbation of rheumatoid arthritis  
For AEs reported more than once by a subject, the most severe intensity will be included 
in summaries where applicable.
Listings will be produced for:

All Adverse Events

On-Therapy Treatment-Related Adverse Events

Fatal Adverse Events

Non-Fatal Serious Adverse Events

Post-Randomization Treatment-Related Serious Adverse Events

Adverse Events Leading to Withdrawal from Study/Permanent Discontinuation of 
Study Treatment

A listing showing the relationship of AE System Organ Class, Preferred Terms, 
and Verbatim Text  

A listing of Reasons for Considering as a Serious Adverse Event
Additionally, a listing of subject numbers for the individual AEs will be presented. Any 
possible suicidality-related AE will be listed separately.
 
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A plot (sorted by Dapro Total) showing the proportion of the most frequent AEs (defined 
as at least 2 subjects in any treatment group) for each treatment group and Dapro Total 
will be presented. 
The following listings of safety data will also be produced:

Listing of Deaths

Listing of AE of Special Interest 

Listing of MACE Data

Listing of Cancer Data

Patient Profile Listing of Arrhythmias

Patient Profile Listing of Congestive Heart Failure

Patient Profile Listing of Cerebrovascular Events/Stroke/Transient Ischemic Attack

Patient Profile Listing of Deep Venous Thrombosis /Pulmonary Embolism

Patient Profile Listing of Myocardial Infarction/Unstable Angina

Patient Profile Listing of Peripheral Arterial Thrombosis Embolism

Patient Profile Listing of Pulmonary Hypertension

Patient Profile Listing of Revascularisation

Patient Profile Listing of Valvulopathy
 
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8.2.2.2.
Clinical Laboratory Safety Analyses
Hematology, clinical chemistry and additional parameters collected in this study are 
listed in Table 7 below:
Table 7
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
WBC Count with 
Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
WBC Count (absolute)
RDW
Eosinophils
Reticulocyte Count
CHr
Basophils
Clinical 
Chemistry
Potassium
AST (SGOT)
Total and direct/indirect 
bilirubin
Sodium
ALT (SGPT)
Total Protein
Glucose
Calcium (Albumin 
adjusted)
Alkaline Phosphatase
Albumin
Phosphate
Other laboratory 
Tests
Erythropoietin
Vascular Endothelial 
Growth Factor
Hepcidin
Serum ferritin
Serum iron
Serum transferrin
Transferrin saturation (% 
saturation)
Unbound iron binding 
capacity
Folate, B12
Other Screening 
Tests1
FSH
Estradiol
Serum hCG Pregnancy 
test
1As needed in women of non-child bearing potential only
Any parameters already evaluated in the efficacy section will not be reported again 
within the clinical laboratory evaluations (Note: Efficacy lab parameters will be listed in 
the clinical chemistry and hematology listings.). Efficacy lab parameters include: 
Hemoglobin, Hepcidin, Ferritin, Transferrin, Transferrin Saturation, Total Iron, 
Unsaturated (i.e. Unbound) Iron Binding Capacity, Total Iron Binding Capacity (Note: 
derived by Q2/Quest), Reticulocyte Hemoglobin (CHr), Hematocrit (in both SI (Fraction 
of 1), and conventional (%) unit), RBC count, Reticulocyte Count,  Absolute 
Reticulocyte Count, Plasma Erythropoietin, VEGF. 
Laboratory data will be reported out in SI units as listed in the CONV dataset; any 
required conversions will be carried out programmatically. Conventional units will also 
be reported for phosphate, albumin, and calcium corrected.
Folate and B12 are measured only at week -4 and will be summarized in the clinical 
chemistry by-visit table.
Laboratory values and change from baseline for hematology and clinical chemistry
parameters will be summarized by visit and by treatment group and Dapro Total in the 
following order:
 
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Clinical Chemistry: Sodium, Potassium, Glucose, Albumin (both units), Protein, Calcium 
Corrected (both units), Phosphate (both units), ALT, AST, Bilirubin, Direct Bilirubin, 
Indirect Bilirubin, Alkaline Phosphatase, Folate, and B12. 
Hematology: MCH (Mean Corpuscular Hgb), MCHC (Mean Corpuscular Hgb 
Concentration), MCV (Mean Corpuscular Volume), RDW (Erythrocytes Distribution 
Width), Leukocytes, Neutrophils, Basophils, Eosinophils, Lymphocytes, Monocytes, 
Platelets.
In addition, the number and percentage of subjects with values outside the normal range 
at each visit will be reported for hematology parameters. The number and percentage of 
subjects with values outside the potential clinical importance range at any time on-
therapy and anytime post-therapy will be summarized (potential clinical importance 
criteria is specified in Section 11.8). 
Chemistry and hematology changes from baseline relative to the reference range will be 
summarized by visit, including “Any time on-therapy”. 
Chemistry data and hematology data for all subjects and for subjects with abnormalities 
of potential clinical importance will be listed.
8.2.2.3.
Other Safety Analyses
8.2.2.3.1.
Electrocardiograms
A summary of the number and percentage of subjects who had normal, abnormal and/or 
clinically significant ECG findings will be displayed by treatment group and Dapro Total. 
For all ECG parameters, change from baseline in ECG values will be summarized by 
visit and displayed by treatment group and Dapro Total. 
A listing of ECG values for subjects with any value of potential clinical importance and a
listing of all ECG findings for subjects with an abnormal finding will also be produced.
8.2.2.3.2.
Vital Signs
Each vital sign parameter and change from baseline for each vital sign parameters will be 
summarized by visit for both pre-dialysis and post-dialysis measurements. Vital sign 
parameters will also summarized with respect to whether the observed values are of 
potential clinical importance at any time on-therapy. 
A plot of mean and 95% CI for systolic and diastolic blood pressure by visit will be 
created for both pre-dialysis and post-dialysis measurements. 
A by-subject listing of vital signs for all subjects and a listing of all vital signs for 
subjects with any value of potential clinical importance will be produced. 
8.2.2.3.3.
Hepatobiliary (Liver)
Liver monitoring/stopping event reporting will be summarized by treatment group and 
Dapro Total. A summary of hepatobiliary laboratory abnormalities will be displayed. 
 
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The following graphical displays will be created for liver function tests (LFT):

box plots over time,

matrix display of maximum LFT values

LFT subject profiles. (Note: include subjects who have normal baseline, but have 
any LFT outside normal range any time post-baseline. LFT subject profiles will 
include a separate line for dose.)
In addition, the following listings will be created:

Listing of Liver Event Results and Time of Events Relative to Treatment

Listing of Past and Current Liver Disease Medical Conditions

Listing of Alcohol Intake at Time of Liver Event

Listing of Laboratory Data from Liver Event Follow-Up
 
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8.3.
Pharmacokinetic Analyses
8.3.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the Pharmacokinetic population, 
unless otherwise specified.
Table 8 provides an overview of the planned analyses, with full details being presented in 
Appendix 14: List of Data Displays. 
Table 8
Overview of Planned Pharmacokinetic Analyses
Endpoint / Parameter/ 
Display Type
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
GSK1278863 and Metabolites
GSK1278863 and 
Metabolites Plasma 
Pharmacokinetic 
Concentration Time 
Data (ng/ml)
Y
Y1
Y1
Individual 
GSK1278863 and 
Metabolites Plasma 
Concentration-Actual 
Time Plot by 
Treatment
Y
Y
GSK1278863 and 
Metabolites Plasma 
Pharmacokinetic 
Parameter Data
Y
Y
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listings, Y = Display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.    
1. Mean and Median Plots will be generated.
8.3.2.
Drug Concentration Measures
Daprodustat (GSK1278863) and metabolites [GSK2391220 (M2), GSK2499166 (M4), 
GSK2531403 (M3), GSK2531400 (M13), GSK2531399 (M5), and GSK2531398 (M6)] 
plasma pharmacokinetic concentration will be summarized by visit and planned 
collection time point for each dose level of daprodustat, and will be listed. Standard 
summary statistics will be calculated (i.e. mean, standard deviation, median, minimum 
and maximum).  The merge of PK concentration data, randomization and CRF data will 
be performed by statistical programmers.
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. Figures for individual plasma concentrations will be presented 
 
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on both a linear and semilog scale daprodustat, and its six predominant metabolites. 
Linear and semi-log figures for mean and median plasma concentrations versus time for 
each treatment regimen will also be generated.
Overlaid individual plasma concentration-actual time profiles and median/mean plasma 
concentration-planned time profiles by dose level at visit will be plotted. All plots will 
include PK data from all visits on the same plot. Each of the figures will contain one plot 
on the untransformed scale (i.e. a linear plot) and one plot on the log transformed scale 
(i.e. log-linear plot).
8.3.3.
Pharmacokinetic Parameters
Plasma concentration-time data for daprodustat and its six metabolites (GSK2391220 
(M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), GSK2531398 (M6), 
GSK2531401 (M13)) will be analyzed by non-compartmental methods with Phoenix
WinNonlin 6.3 or higher (Pharsight Corporation, St. Louis, MO). The data from each PK 
sampling day will be combined to generate a single profile, i.e., PK concentration data 
from Days 1, 15 and 29 (taken at non-overlapping time points on these days) will be 
combined with the actual times, normalized to a 24 hour period to create a “Day 1” 
profile for non-compartmental analysis (NCA). The exposure estimates obtained from 
such an analysis will be a close approximation as compared to sampling a subject over a 
single 24 hour period with minimal patient inconvenience.
Pharmacokinetic parameters described in Table 9 will be determined from the plasma 
concentration-time data for daprodustat and its six predominant metabolites 
(GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), 
GSK2531398 (M6), GSK2531401 (M13)), as data permits.
Table 9
Derived Pharmacokinetic Parameters
Please refer to GSK “SOP_00000314000 - 1.0, Non-Compartmental Analysis of Clinical 
Pharmacokinetic Data, CPMS Global” for calculating PK parameters.
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(t)) will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid.
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity will be calculated as: 
AUC = AUC(0-t) + C(t) / lambda_z
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / lambda_z
NOTES:

Lambda_z is the terminal phase rate constant.
 
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All pharmacokinetic endpoints will be summarized in tabular form.  Descriptive statistics 
(n, arithmetic mean, standard deviation, minimum, median, maximum) will be calculated 
for all pharmacokinetic endpoints by regimen. In addition, for AUC, Cmax, t1/2, geometric 
means and geometric CVs (CVb(%)) will be calculated for each regimen. Geometric 
mean and geometric CV% will not be calculated for tmax.  A subject listing of individual 
PK parameters for each treatment group will be provided.  Pharmacokinetic parameters 
will be summarized by treatment group using descriptive statistics.
8.4.
Pharmacokinetic / Pharmacodynamic Analyses
The relationship between plasma concentrations of daprodustat and selected endpoints 
may be explored using appropriate pharmacokinetic/pharmacodynamic models.  
Exploratory modeling of the plasma EPO, VEGF and/or hepcidin concentrations also 
may be conducted, as a function of daprodustat dose or PK, and may be used to further 
characterize the effect of daprodustat.  Other PD data such as iron parameters and RBC 
indices may also be included if relevant to characterize the PD response.  Relevant 
measures of the secondary and exploratory endpoints (if meaningful) will be initially 
explored graphically and where appropriate modeling approaches will be used. 
Pharmacokinetic/Pharmacodynamic exploratory analysis will be the responsibility of 
CPMS. If additional details are needed, they will be included in a separate PK/PD RAP. 
The results of the PK/PD analyses may be reported in separate PK/PD report(s).
 
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9.
OTHER STATISTICAL ANALYSES
No other statistical analyses are planned.
 
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10.
REFERENCES
Besarab A, Reyes CM, and Hornberger J. Meta-Analysis of Subcutaneous Versus 
Intravenous Epoetin in Maintenance Treatment of Anemia in Hemodialysis Patients. 
American Journal of Kidney Diseases. 2002; 40 (No. 3): 439-446.
Brooks SP, and Gelman A. General Methods for Monitoring Convergence of Iterative 
Simulations. Journal of Computational and Graphical Statistics. 1997; 7: 434–455.
Efron, B., & Tibshirani, R. J. (1993). An introduction to the bootstrap. New York: 
Chapman & Hall.
Gelman A, and Rubin DB. Inference from Iterative Simulation Using Multiple 
Sequences. Statistical Science. 1992; 7: 457–472.
GlaxoSmithKline Document Number 2015N241222_01 Study ID 204836. A 29-day, 
randomized, double-blinded, placebo-controlled, parallel-group, multi-center study to 
evaluate the efficacy, safety and pharmacokinetics of three-times weekly dosing of
GSK1278863 in hemodialysis-dependent subjects with anemia associated with chronic 
kidney disease who are switched from a stable dose of an erythropoiesis-stimulating 
agent. 2016.
 
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11.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 11.2
Appendix 2: Time and Events
Section 11.3
Appendix 3: Assessment Windows
Section 11.4
Appendix 4: Treatment States & Study Phases
Section 11.5
Appendix 5: Data Display Standards & Handling Conventions
Section 11.6
Appendix 6: Derived and Transformed Data
Section 11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
Section 11.8
Appendix 8: Values of Potential Clinical Importance
Section 11.9
Appendix 9: Multicentre Studies
Section 11.10
Appendix 10: Examination of Covariates and Subgroups
Section 11.11
Appendix 11: Multiple Comparisons and Multiplicity
Section 11.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 11.13
Appendix 13: Abbreviations & Trade Marks
Section 11.14
Appendix 14: List of Data Displays
Section 11.15
Appendix 15: Example Mock Shells for Data Displays
 
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11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
11.1.1.
Important Protocol Deviation
All deviations are to be tracked in PPD CTMS. PPD is responsible for collating all 
identified deviations and, after internal review, for sending this list to GSK on monthly 
basis. Protocol deviations will be reviewed by PPD and GSK study team and 
important/significant protocol deviations will be identified according to PPD’s Study 
Deviation Rules Document. (Note: Given that different terminologies have been used by 
GSK and PPD, the terms “important protocol deviation” and “significant protocol 
deviation” will be used interchangeably throughout the RAP.)
11.1.2.
Exclusions from Per Protocol Population
The following criteria define the protocol deviations, which may lead to the exclusion of 
a subject from the per protocol (PP) population (refer to Section 4 for population 
definitions). These are the deviations that are considered to affect interpretation of the 
primary endpoint (Hgb change from baseline at Day 29). Protocol deviations will be 
recorded and documented in the PPD’s protocol deviation capturing tool. Potential 
protocol deviations listed below will be reviewed by the clinical team to establish 
whether subjects meeting these criteria should be excluded from the PP population. This 
review will occur before the clinical database has been locked for the final analysis. 
Number
Exclusion Description
01
Inclusion/Exclusion criteria not met. 

Subjects who deviate from any inclusion or exclusion criteria, as recorded in the 
eCRF)
02
Not withdrawn after meeting the following stopping criteria prior to Day 29

receiving blood transfusion

receiving kidney transplant

having active GI bleed

liver stopping criteria

patient not discontinued from the study treatment despite having missed two or more 
consecutive dialysis sessions

diagnosis of cancer, with the exception of squamous cell and basal cell carcinoma

pregnancy
03
Prohibited medication taken during study treatment phase, prior to Day 29

Subject taking single dose of long-acting darbepoetin or Mircera during the study (Day 
1 – Day 29)

Subject taking more than one dose of Epoetin, or more than 2 non-consecutive 
Epoetin administrations
 
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Number
Exclusion Description

Subject taking the prohibited medications (inhibitor or inducer of CYP2C8: gemfibrozil 
and rifampin/rifampicin) during the 29-day study treatment phase and 7 days after last 
dose of study treatment).
04
Incorrect study treatment or Non- compliance 

Dispensed incorrect study treatment at Day1 

Incorrect bottle used for administration to the patient

Expired study drug administered to the patient

Administration of study drug that was incorrectly stored and was not approved by GSK 
for use (Study drug stored incorrectly/ temperature monitoring not documented/ 
storage temperature excursion)

Non-compliance for IP (defined as < 80% or > 120%; refer to RAP Section 6.2.6 for 
treatment compliance definition) for any single bottle of study treatment between Day 1 
and Day 29. Note: <80% is equal to 3 or more doses over 29 days

Two or more consecutive missed doses, or 3 or more non-consecutive missed doses

Patient takes more than the scheduled number of tablets or doses of Study treatment, 
e.g. more than 3 tablets per dose or more than 3 doses per week.

Patient did not receive one tablet from each of 3 bottles (e.g., took 3 tablets from single 
bottle).
05
Error in Randomization procedure

Subject randomized in error. (This should capture any protocol deviation which is not 
covered by another protocol deviation category such as deviation to eligibility criteria.) 
(Note: Randomization to incorrect stratum will not lead to the exclusion of a subject from 
the per protocol (PP) population.)
06
Other (lack of PI oversight)

Exclude subject(s) if failed audit/compliance
07
If Day15 visit or Day 29 visit is done on first dialysis session of the week (we would check 
each patient’s estimated dry weight (EDW) to see if there is a greater than 4% difference in 
EDW between the first dialysis session of the week and the dialysis session at mid or end 
of the week).
08
Informed Consent

Patient not consented prior to screening procedure

ICF not properly completed (Consideration should be given to whether the ICF was 
later completed properly, and whether a valid consent was in place.)

Patient not consented with a current ICF version (e.g. inappropriate re-consenting 
 
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Number
Exclusion Description
process). (Consideration should be given to what new information is contained in the 
revised ICF, and whether any procedures/assessments were performed to which the 
subject had not given consent, as a result of not using a current ICF version.)
09
Dialysis modality changed from hemodialysis (HD, hemofiltration or hemodiafiltration) to 
peritoneal dialysis during the study
 
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11.2.
Appendix 2: Time & Events
11.2.1.
Protocol Defined Time & Events
Protocol Activity 1, 2
Screening
Day 1
Treatment Period
Follow-
up
Week 
-4 
Week 
-2 
Day 15 
Day 29 
Un-
schedule
d
Early 
Withdra
wal
Day 43 ± 
3 6
Informed Consent
X
Entry Criteria
X
X
Physical, Medical History, 
Demography
X
HemoCue Hgb
X
X
X
X
X
X
X
IVWRS Call
X
X
X
X
X
X
X
X
Females Only: Serum Pregnancy 
Test 3
X
X
X
Females Only: Estradiol and 
FSH (if required) 3
X
ECG
X
X
X
Vitals (Pre-dialysis and Post-
dialysis) 4
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Folate and Vitamin B12
X
Ferritin, transferrin, total iron, 
UIBC
X
X
X
X
X
Pharmacokinetic/Pharmacodyna
mic Samples
X
X
X
X 5
Blood draw for PGx
X
Adverse Events Assessment 7
X
X
X
X
X
X
Review Concomitant Medications
X
X
X
X
X
X
X
1 All assessments should be done pre-dialysis except as noted.
2 Allowable time window of ± 2 days for all study visits, except the follow-up visit for which it is ± 3 days.
3 As detailed in Inclusion Criteria in study protocol Section 5.2
4 Weight measured post-dialysis only & height measured at screening only.
5 Obtain samples as per the Day 29 visit in Table 2 of the study protocol. If subject does not receive a dose of study 
medication at this early withdrawal visit, no post-dose PK/PD samples should be obtained.
6 Subjects who withdraw early from treatment should attend a follow-up visit 14 days ± 3 days after the last dose of 
study treatment.
7 Serious adverse events are assessed from the time of consent as stated in study protocol Section 7.4.1.1
 
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Pharmacokinetic/Pharmacodynamic Time and Events Table
PK/PD 
Sample
Day 1
(dose study 
med at clinic)
Day 15
(dose study med at home1)
Day 29
(dose study med at clinic)
Plasma 
PK2
Pre-dose
1st sample collected approx 6-10 hr post-
dose on arrival.
Additional sampling: 1, 2, and 3 h after 
this 1st sample
Pre-dose, 1, 2, and 3 h post 
dose
EPO & 
VEGF2
Pre-dose
1st sample collected approx 6-10 h post-
dose on arrival.
Additional sampling: 1, 2, and 3 h after 
this 1st sample
Pre-dose and 3 h post dose
Hepcidin3
Pre-dose
Single sample during visit
Single sample during visit
1 Subject to take their dose of study medication at home and arrive for clinic visit approx 6-10 h post-dose.  Subjects 
may take their Day15 dose the evening prior to the Week 2 study visit to accommodate the 6-10 h PK/PD sampling 
window
2 Sample to be collected within 30 minutes of planned collection time
3 Sample can be pre- or post-GSK1278863 administration
 
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11.3.
Appendix 3: Assessment Windows
11.3.1.
Assessment Windows Assignment
For efficacy data, laboratory data, vital signs, and ECG measurements to be summarized 
or analyzed by visit, unscheduled and early withdrawal (EW) data measurements will be 
assigned to one of the protocol specified visits using the following algorithm:
1. Determine Study Day of assessment (refer to Section 11.6.1) 
2. Based on the Study Day, assessment will be assigned as shown in Table 10 below
Table 10
Assessment Windows
Study Day of Assessment 
Assessment Window
Target Study Day of Window
1
Day 1
1
2 to 22
Day 15
15
23 to 36
Day 29
29
This will not be slotted
Day 43 (Follow-up)
Note: If an unscheduled value is recorded prior to Day 1 then this will be slotted as 
follows (Table 11; Refer to Section 11.5.2 for the derivation of Baseline):
Table 11
Assessment Windows for Screening
Study Day of Assessment
Assessment Window
<= -22 
Week -4
-21 to -1
Week -2
As specified in the protocol, if a subject does not receive a dose of study medication at 
the early withdrawal visit, no post-dose PK/PD samples should be obtained. Hence if we 
do have EW EPO, hepcidin and VEGF values, it will be slotted to the appropriate visit as 
specified in Table 10 and summarized.  These parameters are collected at scheduled time 
points (e.g. 6 to10 hrs post-dose) within a visit and so this data will be reported as pre-
specified for the tables and by actual time for graphics.
Local laboratory assessments (efficacy or safety) will not be slotted and will not be 
summarized. Only central lab assessments will be summarized. For parameters which are 
not scheduled to be assessed at particular visits, the all-inclusive windows defined in 
Table 10 and Table 11 above will still be used.  However, if a value is slotted to a visit 
unscheduled for a parameter, it will not be summarized but will be included in data 
listings. Assessments at unscheduled visits will be included for ‘any time on-treatment’ 
time points and “any time post-treatment”, and in data listings, as well any algorithms 
that make use of additional data.
 
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11.3.2.
Multiple Assessments
For assessments on or after Day 1, if after window assignment there are multiple valid 
assessments of a parameter from the central lab within the same window (nominal and 
slotted visit data), then the scheduled assessment at a nominal visit takes precedence over 
any unscheduled assessments and will be reported for summary statistics/analyses. If the 
scheduled assessment is missing for the target visit within the same window, then the last 
on-treatment value in the window will be reported for on-treatment summary 
statistics/analyses, and the last post-treatment value in the window will be reported for 
post-treatment summary statistics/analyses. 
For assessments during the screening period prior to Day1, if after window assignment 
there are multiple valid assessments of a parameter from the central lab within the same 
window (nominal and slotted visit data), then the last/most recent values will be reported 
for summary statistics/analyses.
For the primary endpoint, Hemoglobin (Hgb), if the scheduled Hgb concentration 
measurement during the study (including screening, treatment, and follow-up period) 
from the central lab is missing and a corresponding valid HemoCue Hgb concentration 
measurement is available, then the HemoCue Hgb concentration measurement takes 
precedence over unscheduled Hgb concentration measurements within the same window 
and will be used for all summaries and analyses.
ECG values and vital signs measured at the local sites will be slotted and selected 
following the same algorithm applied to the central lab assessments described above and 
will be reported for summary statistics/analyses, unless otherwise specified.  
All assessments, including local lab assessments, will still appear in the associated 
listings.
 
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11.4.
Appendix 4: Treatment States and Study Phases
11.4.1.
Study Phases

Screening Period: Day -28 to Day -1

Treatment Period: Day 1 to Day 29/study treatment stop date

Follow-up period: Study treatment stop date + 1 to follow-up visit date (study 
treatment stop date + 14 if follow-up visit date is missing)
11.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment as either pre-treatment, on-treatment, or post-
treatment.
11.4.2.1.
Treatment States for Laboratory Data, Vital Signs, ECG Data
For laboratory data, pre-dialysis vital signs, and ECGs, treatment state will be defined as:
Treatment State
Definition
Pre-Treatment
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date + 1
Post-Treatment
Date > Study Treatment Stop Date +1
NOTES: 

If the study treatment stop date is missing then any assessment after study treatment Start Date will be 
considered to be On-Treatment.

Post-dialysis vital signs measured on the “Study Treatment Start Date” will be considered to be On-Treatment. 
11.4.2.2.
Treatment States for AE Data
For adverse events (AEs), treatment state will be defined as:
Treatment State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date
On-Treatment
If AE onset date is on or after treatment start date & on or before treatment stop date
+1.
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date + 1
Post-Treatment
If AE onset date is after the treatment stop date + 1.
AE Start Date > Study Treatment Stop Date + 1
Onset Time  
Since 1st Dose
(Days)
If Treatment Start Date ˃AE Onset Date = AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date +1
Missing otherwise.
Onset Time Since 
Last Dose (Days)
If Treatment Stop Date + 1 ≤ AE onset date: AE onset date – treatment stop date + 1
If Treatment Stop Date + 1 > AE onset date: AE onset date – treatment stop date
Missing otherwise.
Duration (Days) 
AE Resolution Date/AE End Date – AE Onset Date + 1
 
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NOTES: 

If the study treatment stop date is missing then any AEs with a start date on or after study treatment start date will 
be considered to be On-Treatment.

In the case of a completely missing AE start date, the event will be considered to have started on-treatment 
unless an end date for the AE is provided which is before start of investigational product; in such a case the AE is 
assigned as pre-treatment.
11.4.2.3.
Classification of Prior, concomitant, an Post-Therapy Medications
Prior medications are those taken (i.e., started) before the start date of study treatment. 
Concomitant medications are those taken (i.e., started or continued) at any time between 
the start date and stop date of study treatment, inclusive. Prior medications that were 
continued during the study treatment period are also considered as concomitant 
medications. Post-treatment medications are those started after the stop date of study 
treatment. Concomitant medications that were continued after the stop date of the study 
treatment are also considered as post-treatment medications.
It will be assumed that medication has been taken on the date in which it is reported as 
started or stopped.  Also, for any medication starting on the same date as study treatment, 
it will be assumed that the medication was taken after the subject started taking the study 
treatment.
Table 12 below illustrates how a medication is classified as prior, concomitant, or post-
treatment.
 
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Table 12
Prior, Concomitant, and Post-treatment Classification of Medications
Pre-
treatment
On-treatment
Post-treatment
Prior
Conco-
mitant
Post
(a)
xx
Study Treatment Start Date
Study Treatment Stop Date
Study Treatment Stop Date+1
Y
N
N
(b)
x
x
Y
Y
N
(c)
x

x
Y
Y
Y
(d)
xx
N
Y
N
(e)
x
x
N
Y
Y
(f)
xx
N
N
Y
(g)
?x
Y
N
N
(h)
?
x
Y*
Y
N
(i)
?

x
Y*
Y*
Y
(j)
x

?
Y
Y**
Y**
(k)
x
?
N
Y
Y**
(l)
x?
N
N
Y
(m)
?

?
Y***
Y***
Y***
(n)
x
x
Y
Y
N
(o)
?
x
Y*
Y
N
(p)
x
x
N
Y
N
(q)
x

x
N
Y
N
(r)
x

x
N
Y
Y
(s)
x

?
N
Y
Y**
(t)
x
x
N
N
Y
(u)
x
?
N
N
Y
(v)
x

x
N
Y
Y
1.
x = start/stop date of medication
2.
? = missing start/stop date of medication
3.
* If a medication is stopped On-treatment or Post-treatment and no start date is recorded it will be 
assumed that the medication was ongoing from the Pre-treatment phase
4.
** If a medication is started Pre-treatment or On-treatment and no stop date is recorded then usage will 
be assumed to be ongoing for the remainder of the study
5.
*** If a medication has no start and stop date it will be assumed that the medication was ongoing from 
the Pre-treatment phase to the Post-treatment phase
 
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11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
PPD Randomization System
Data Displays for Reporting[3][4]
Code
Description
Description
Order [1]
1
10 mg GSK1278863 three-times weekly
Dapro 10 mg[2]
2
2
15 mg GSK1278863 three-times weekly
Dapro 15 mg[2]
3
3
25 mg GSK1278863 three-times weekly
Dapro 25 mg[2]
4
4
30 mg GSK1278863 three-times weekly
Dapro 30 mg[2]
5
5
Placebo three-times weekly
Placebo
1
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
2.
When display space is limited, 10 mg, 15 mg, 25 mg, and 30 mg can used as the description under an overall 
column/row title, “Dapro”.
3.
“Dapro Total” will be used as the description when the four Daprodustat groups are pooled. 
4.
“Total” will be used as the description when the five treatment groups are pooled.
11.5.2.
Baseline Definition & Derivations
11.5.2.1.
Baseline Definitions
For Hgb the average of Hgb measured by the central lab, Quest, at Week -2 and Day 1 
visits will serve as the baseline value.  If an unscheduled Hgb value is taken pre-treatment 
then this will be slotted following the algorithm in Section 11.3.1 and Section 11.3.2.
Vital signs will be measured both pre-dialysis and post-dialysis. The baseline values for 
vital signs will be defined as:
Pre-dialysis baseline = vital sign value obtained pre-dialysis on Day 1
Post-dialysis baseline = vital sign value obtained post-dialysis at Week -2
Weight baseline= post-dialysis weight measured at Week -2.  
Unless stated otherwise, the baseline value for all other lab parameters and ECG are 
defined as the last pre-treatment value observed. This is generally expected to be from the 
Day 1 visit (except for Folate, B12 and ECG, which are only measured at Week -4), 
although such values may be missing or unscheduled assessments may be performed 
before treatment start.
 
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Parameter
Study Assessments Considered As Baseline
Baseline Used in 
Data Display
Week -4
Week -2
Day 1 (Pre-Dose)
Safety 
Vital Signs
X
X
See description 
above [1]
ECG
X
Week -4
Laboratory (clinical 
chemistry and 
hematology)
X
X
Day 1
Folate, Vitamin B12
X
Week -4
Ferritin, Transferrin, 
Total Iron, UIBC
X
X
Day 1
Efficacy
Hgb
X
X
Mean (Quest)
See description 
above
PK/PD
PK Plasma, EPO & 
VEGF, Hepcidin
X
Day 1
NOTES:
1.
Three measurements of SBP, DBP and HR will be recorded at each study-specified visit and the mean of the 
replicate assessments will be used as the baseline value. 
11.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Baseline Visit Value – Baseline) / Baseline]
Maximum Change from Baseline
= Calculate the change from baseline at each given post-
baseline timepoint and determine the maximum change
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 11.5.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

For this study %Change from Baseline (without log transformation) will be calculated only for “Absolute 
Reticulocyte Count.”
Some lab parameters will be log-transformed and percent change from baseline will be 
reported for these parameters: Hepcidin, Transferring Saturation, and VEGF.
To calculate a geometric mean for baseline measurement or at a specified timepoint, the 
following steps are used:
1.
Log-transform the data points
 
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2.
Calculate the mean and standard error (SE) of the log-transformed data
3.
Exponentiate the mean, (if required, the mean – SE, mean + SE) and the endpoints of 
the confidence interval back to the original scale in order to obtain the geometric 
mean, (the geometric mean – SE, the geometric mean + SE) and the confidence 
interval for the geometric mean.
4.
Coefficient of variation will be calculated as 
1
)
exp(
log


scale
Var
CV
100%
To calculate a geometric mean for the ratio of a specific timepoint to baseline (expressed 
as a percent change from baseline), the following steps are used:
1.
Log-transform the data at both the baseline and the specified timepoint 
2.
For each subject, calculate a change from baseline using the log-transformed data
3.
Calculate the mean and standard error (SE) of the log-transformed data
4.
Exponentiate the mean, (if required, the mean – SE, the mean + SE) and the 
endpoints of the confidence interval, back to the original scale and then subtract 1, 
then multiply everything by 100% in order to express the geometric mean, (the 
geometric mean – SE, the geometric mean + SE) and the confidence interval (CI) as 
the  percent change from baseline.
So, geometric mean for percent change from baseline =
     [ Exp( ∑ {log(value at specified time point_i) – log(baseline value_i) }/n) – 1 ] x 100,
Where i = subject, n=  total number of subjects, and ∑ represents the sum over all 
subjects.
To calculate the minimum, median and maximum for the ratio of a specific timepoint to 
baseline (expressed as a percent change from baseline), the following steps are used:
1.
Log-transform the data at both the baseline and the specified timepoint 
2.
For each subject, calculate a change from baseline using the log-transformed data
3.
Calculate the minimum (median and maximum) of change from baseline using the 
log transformed data.
4.
Exponentiate the minimum (median and maximum), back to the original scale and 
then subtract 1, then multiply everything by 100% in order to express the minimum 
(median and maximum) as the percent change from baseline. 
So, minimum percent change from baseline =
     [ Exp( min {log(value at specified time point_i) – log(baseline value_i) }) – 1 ] x 100,
Where i = subject.
 
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11.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software, version 9.3. or higher will be used for all 
analyses unless otherwise specified. Additionally, R version 3.1.1 or higher may be used, if 
necessary, for analysis and the production of graphics. 
Reporting Area
HARP Server
: UK1SALX00175
HARP Area
: /arenv/arprod/gsk1278863/mid204836/final/
QC Spreadsheet
: /arenv/arprod/gsk1278863/mid204836/final/qc/
Analysis Datasets

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.1.3 & 
ADaM IG Version 1.1.
Generation of RTF Files

RTF files will be generated.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits (including early withdrawal visit) will be included in summary tables after 
 
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Reporting Standards
they are slotted to the planned visits, as described in Section 11.3.1.

Assessments at unscheduled visits will be included for ‘any time on-treatment’ time points and 
any time post-treatment, and in data listings, as well any algorithms that make use of additional 
data, as described in Section 11.3.1.

Unscheduled visits will be included in figures after they are slotted to the planned visits, as 
described in Section 11.3.1.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.

Y-axis breaks will be implemented in order to best show the distribution of values in the y-
dimension. GSK Study PHI113747 figures will provide examples of the y-axis break levels, and 
clinical scientist review feedback will be provided on proposed y-axis breaks positions at the 
Dry Run Review.  

SAS goptions will be set to provide hardware fonts wherever possible.  

A color scheme will be established that is similar to that used for GSK Study PHI113747 (e.g., 
Orange for daprodustat, Blue for Placebo).  

GSK Programming will work with PPD programming to establish default SAS goptions.
 
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11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Multiple Measurements at One Time Point

Three pre-dialysis measurements and three post-dialysis measurements of SBP, DBP and HR 
will be recorded at each study-specified visit. Mean of the measurements will be calculated and 
used in any derivation of summary statistics but if listed, all data will be presented.

After window assignment, if there are two or more values within a time window, the algorithm 
described in Section 11.3.2 will be followed.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Calculated as the number of days from randomisation date :

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Randomisation Date   → Study Day = Ref Date – Randomisation Date    

Ref Data ≥ Randomisation Date   → Study Day = Ref Date – (Randomisation Date) + 1    
Randomization Date

Date subject was randomized
Treatment Start Date

The date of first dose of study treatment
Treatment Stop Date

Calculated as the date of final dose of study treatment received. If treatment stop date is 
missing, then, for purposes of calculating exposure, it will be imputed using the date of last visit 
or the recorded date of withdrawal/completion, whichever is earlier. Note that the follow-up visit 
date must not be used as the date of last visit or recorded date of withdrawal/completion 
because this date will be off-treatment. 
Study Completion/Withdrawal Date

Date of withdrawal for subjects withdrawing (i.e., subjects who actively withdraw or are deemed 
lost to follow-up) from study or date of completion of study for subjects who complete the study, 
as documented in the eCRF.

Note: Subjects who die while on study are considered as having completed the study
Time Definitions (per GSK standard principles)

1 week = 7 days

1 month = 30.4375 days

1 year = 365.25 days
 
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11.6.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Missing date and month will be imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2
Standardized rhEPO
For this study, ESA dose can be administered in five different ways: epoetin IV 
(Intravenous), epoetin SC (Subcutaneous), darbepoetin IV, darbepoetin SC or Mircera IV.  
The dose of ESA will be standardized to obtain a continuous single unit of prior ESA dose 
in terms of epoetin IV IU/kg/week. The standardization will be carried out using the 
formula: 

Weekly darbepoetin IV or SC dose (mcg) = Weekly epoetin IV dose (IU)/200 

113 epoetin IV = 161 epoetin SC [Besarab et al]
1. For subjects taking epoetin IV no adjustment is needed.
Standardized  rhEPO IV dose (IU/kg/week) = epoetin IV dose (IU) / 
(frequency*weight (kg) )
2. For subjects taking darbepoeitin (IV or SC ), their dose will be converted as follows:
Standardized  rhEPO IV dose (IU/kg/week) = (darbepoeitin dose (mcg) * 200) / 
(frequency* weight (kg))
3. For subjects taking epoetin SC, their dose will be converted as follows:
Standardized rhEPO IV dose (IU/kg/week) = 161/113 * (epoetin SC dose (units)) / 
(frequency* weight (kg)) 
4. For subjects taking Mircera (IV), their dose will be converted as follows:
Standardized  rhEPO IV dose (IU/kg/week) = (Mircera dose (mcg) ) / (1.2*frequency* 
weight (kg))
Where frequency = 4 if the subject takes the Mircera dose once every 4 weeks (Note: Once 
a month (QM) will be handled same as once every 4 weeks.), 2 if the subject takes the 
darbepoeitin or Mircera dose once every 2 weeks, 1 if the subject takes the darbepoeitin 
dose once a week, 0.5 if the subject takes the epoetin dose 2 times a week, 0.333 if the 
 
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Demographics
subject takes the epoetin dose 3 times a week etc. (For dose frequency = ONCE, please see 
the algorithm described later in this section.) Note, weight is the weight recorded at 
screening Week -2. If the screening weight is missing, the baseline weight will be used.
If a subject has multiple doses of prior ESA during the 12 weeks prior to randomization, the 
weighted mean would be calculated to obtain the standardized rhEPO. 
In order to account for changes in ESA dose and pauses in ESA dose, the following 
algorithm will be used to determine the average weekly dose per subject over the 12-week 
period prior to randomization:
1. Derive the standardized weekly dose in terms of Epoetin IV (IU/kg/week) for each dose 
recorded in the eCRF during the 12-week period of interest, as detailed above. (Note, 
where the first dose started after the cutoff date for the 12-week period, defined by 
“randomization date – 12 weeks”, the dose prior to the first dose start date will be 
assumed to be 0. When the first dose started before the cutoff date defined by 
“randomization date – 12 weeks”, first day of the period (i.e. Randomization date – 12 
weeks) is defaulted as the start date of that dose.)
2. Convert dose into units of dose per day (IU/kg/day) by dividing the weekly dose from 
step 1 by 7.
Standardized  rhEPO IV Daily Dose (IU/kg/day) = Standardized  rhEPO IV weekly 
dose IU/kg/week) / 7
3. Identify whether a pause in dosing has occurred, i.e. a period of time deemed to be a 
break from the planned treatment regimen, for each dose recorded. A pause in dosing 
will be identified as follows. In the table below, Dose 1 refers to the dose received before 
the pause (if one exists), and Dose 2 to the dose received after the pause (if one exists).
Dosing 
Regimen
Definition 
of a pause in 
dosing
Criteria for dosing pause
Gap factor 
(days) (to be 
added to stop 
date if dose 
pause exists)
3 times 
per week
3 or more 
days where 
no dose is 
administered
(Start Date Dose 2) – (Stop Date Dose 1) 
> 3 
2
2 times 
per week
5 or more 
days where 
no dose is 
administered
(Start Date Dose 2) – (Stop Date Dose 1) 
> 5
4
1 times 
per week
8 or more 
days where 
no dose is 
(Start Date Dose 2) – (Stop Date Dose 1) 
> 8
7
 
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Demographics
administered
0.5 times 
per week
15 or more 
days where 
no dose is 
administered
(Start Date Dose 2) – (Stop Date Dose 1) 
> 15 
14
0.33 
times 
per week
22 or more 
days where 
no dose is 
administered
(Start Date Dose 2) – (Stop Date Dose 1) 
> 22
21
0.25 
times 
per week
29 or more 
days where 
no dose is 
administered
(Start Date Dose 2) – (Stop Date Dose 1) 
> 29
28
4. Calculate the duration of dose for each dose received. (Note that the duration of a dose 
will be capped at the start date of a new dose (Start Date Dose 2) or at randomization 
date.)
If a pause was identified between doses, the duration of dosing will be defined as follows:
(Duration of Dose 1) = (Stop Date Dose 1) + (Gap Factor) – (Start Date Dose 1) + 1
= Min(Randomization Date,  Start Date Dose 2, Stop Date Dose 1+ Gap Factor + 1) – Start 
Date Dose 1 
If no pause was identified between doses, the duration of dosing will be defined as follows:
(Duration of Dose 1) = (Stop Date Dose 1+ Gap factor) – (Start Date Dose 1) + 1
= Min(Randomization Date, Start Date Dose 2, Stop Date Dose 1 + Gap Factor +1) – (Start 
Date Dose 1)
5. Calculate the actual dose received for each dose, by multiplying the daily dose from step 
2 by the duration of dose derived in step 4:
Actual Dose (IU/kg) = Daily Dose (IU/kg/day) x Duration of Dose (days)
6. Calculate the total cumulative dose received over the subject’s 12-week period prior to 
randomization:
Cumulative Dose (IU/kg) = Sum of all Actual Doses from step 5 (IU/kg)
7. Calculate the average weekly dose over the 12-week period prior to randomization, by 
dividing the cumulative dose from step 6 by the duration of the 12-week period
 
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Demographics
Average Dose (IU/kg/week) = Cumulative Dose (IU/kg)/12
For the special situation of dose frequency = “ONCE”, the following algorithm will be 
followed: (Note: Only for dosing within the 12-week period prior to randomization (i.e. 
randomization date – 12 weeks)). 
1. Calculate the standardized rhEPO IV dose (IU/kg) for this specific prior ESA use
1) For subjects taking epoetin IV no adjustment is needed.
Standardized  rhEPO IV dose (IU/kg) = epoetin IV dose (IU) / (weight (kg) )
2) For subjects taking darbepoetin (IV or SC), their dose will be converted as 
follows:
Standardized  rhEPO IV dose (IU/kg) = (darbepoetin dose (mcg) * 200) / (weight 
(kg))
3)  For subjects taking epoetin SC, their dose will be converted as follows:
Standardized rhEPO IV dose (IU/kg) = 161/113 * (epoetin SC dose (units)) / (weight 
(kg)) 
4)  For subjects taking Mircera (IV), their dose will be converted as follows:
Standardized  rhEPO IV dose (IU/kg) = (Mircera dose (mcg) ) / (1.2*weight (kg))
2. If all the records of prior ESA use during the 12-week period prior to randomization 
have dose frequency = “ONCE”, then:
Standardized  rhEPO IV dose (IU/kg/week) = Sum of Standardized rhEPO IV dose (s) 
(IU/kg) calculated from Step 1 / 12 
Note: This includes the situations when either a subject has only one prior ESA use record 
with dose frequency = “ONCE” or a subject has more than one prior ESA use records and 
all of them have dose frequency = “ONCE”. 
3. If, in addition to the prior ESA use record(s) with dose frequency = “ONCE”, a subject 
has other ESA use record(s) with different dose frequency during the 12-week period 
prior to randomization, then the Standardized rhEPO IV doses calculated from Step 1 in 
terms of epoetin IV (IU/kg) will contribute directly (without considering “Gap Factor”) 
to the total Cumulative Dose derived in Step 6 of calculation of average weekly dose. 
 
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Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – Treatment Start Date + 1

Subjects who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum (Each dose taken recorded in the eCRF, including the dose 
taken on or prior to PK day Day 15 study visit)
11.6.3.
Safety
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘x’ or ‘x’ is present, then the corresponding numeric value will 
be set equal to x.

The following will be used to convert laboratory values from SI units to conventional unit:

Phosphate: Divide the mmol/L value by 0.32290 to get the mg/dL value

Albumin: Divide the g/L value by 10 to get the g/dL value

Calcium corrected: Divide the mmol/L value by 0.2495 to get the mg/dL value

Hematocrit: Divid the Fraction of 1 by 0.01 to get the %
 
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11.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (as specified in the protocol Section 5.8) was defined 
as completing all phases of the study including the follow-up visit, with the 
following exception: subjects who die while on study are also considered as 
having completed the study.The number of subjects who completed the study 
for purpose of the disposition table will consist of all randomized subjects who, 
as documented in the eCRF, have completed all study visits, including the 
follow-up visit.

Withdrawn subjects will not be replaced in the study.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
11.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument :
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.7.2.1.
Handling of Missing Hgb and Other Data
Element
Reporting Detail
Hgb

The Hgb concentration analyzed by Quest Diagnostics is referred to as Hgb 
throughout this document. These data will be summarized and analyzed. If the 
Hgb concentration measurement is missing and a corresponding valid HemoCue 
Hgb concentration measurement is available, the Hemocue Hgb concentration 
measurement will be used for all summaries and analyses.

The dose response dataset will be based on the ITT population using an 
observed case dataset, comprising all non-missing data collected up to Day 29. 
For subjects who have a Day 15 Hgb measurement but a missing Day 29 Hgb 
measurement, a change from baseline at Day 29 value will be imputed using 2 * 
(Day 15 Hgb – Baseline Hgb). The assumption is deemed appropriate based on 
phase 2a data indicating linear response over time. Any subject who prematurely 
 
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Element
Reporting Detail
discontinues dosing prior to Day 15 will be non-evaluable for the dose-response 
analysis. In general, the imputed data for the dose response analysis will not be 
used in summaries and figures, except for those generated specifically for dose 
response results. However, for descriptive summaries of Hgb over time, raw Day 
29 Hgb will be summarised as well as Day 29 Hgb including imputations. The 
number of imputed Day 29 Hgb values will be summarized by treatment group.

All other efficacy inference will be based on the ITT population using an 
observed case dataset.
Other Data

For laboratory data no imputation for missing data or premature discontinuation 
will be performed and the observed values will be used. The same approach 
applies to other assessments such as vital signs and electrocardiograms (ECGs) 
examination data.
 
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11.7.2.2.
Handling of Missing/Partial Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day and Non-missing End Date: If the day in a start date is 
missing, e.g. - -JUN2006, and the month is the one in which treatment 
started, assign the day to the day treatment started (i.e. the event is 
considered on-treatment as per Appendix 4, Section 11.4.2.2) if treatment
start date <= AE end date).  Otherwise, set to the first of the month, 
01JUN2006.
o
Missing Stop Day and Non-missing Start Date: Last day of the month (28th, 
29th, 30th, or 31st as appropriate for the month and year) will be used. If the 
last day of the month is after the stop date of study treatment in the same 
month and treatment stop date >= AE start date, then study treatment stop 
date will be used.
o
Missing Start Day and Missing End Day: If both the day in a start date and 
the day in an end date are missing, set them to the first day of the month 
and the last day of the month, respectively. 

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.

The recorded partial date will be displayed in listings
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the missing/unknown 
day and 'Jan' will be used for the missing/unknown month.
o
If the partial date is a stop date, last day of the month (28, 29, 30, 31, 
dependent on the month and year) will be used for the missing/unknown 
day and 'Dec' will be used for the missing/unknown month.

The recorded partial date will be displayed in listings.
 
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11.8.
Appendix 8: Values of Potential Clinical Importance
11.8.1.
Laboratory Values
Haematology
Laboratory Test
Unit
PCI  Value 
White Blood Cell Count
GI/L
>1 x GI/L below the lower limit of reference range 
(LLRR) or
>5 x GI/L above the upper limit of reference range 
(ULRR)
Total Neutrophils
GI/L
<0.5x LLRR
Lymphocytes
GI/L
<0.5x LLRR
Platelet Count
GI/L
<80 or >500 x GI/L
Clinical Chemistry
Laboratory Test
Unit
PCI  Value 
Total Bilirubin 
umol/L
≥2x ULRR
Total Protein
g/L
>15 g/L above or below the RR
Albumin
g/L
>5 g/L above or below the RR
Aspartate Aminotransferase
IU/L
≥3x ULRR
Alanine Aminotransferase 
IU/L
≥3x ULRR
Alkaline Phosphatase 
IU/L
≥3x ULRR
Sodium
mmol/L
>5 mmol/L above ULRR or below LLRR
Potassium
mmol/L
>0.5 mmol/L below the LLRR or >1.0 mmol/L above 
the ULRR
Glucose 
mmol/L
<3.9 or >22 mmol/L
Phosphorus (phosphate)
mmol/L
0.323 mmol/L above ULRR or below LLRR
Calcium (Albumin adjusted)
mmol/L
<1.8 or >3.0 mmol/L
PD Markers
Laboratory Test
Unit
PCI  Value 
Ferritin
ng/mL
<100 or > 800 ng/mL
Transferrin Saturation
%
< 20% or  >40%
 
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11.8.2.
Vital Signs
Vital Sign
PCI Range 
Unit
Systolic Blood Pressure
< 85 or > 170
mmHg
Diastolic Blood Pressure
< 45 or > 100
mmHg
Heart Rate
< 40 or > 110
bpm
11.8.3.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Change from Baseline
Increase from Baseline QTc
msec
> 60 
 
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11.9.
Appendix 9: Multicenter Studies
11.9.1.
Methods for Handling Centres
This study will be conducted in Germany, Russia, Spain, Canada and the US. There will 
be a large number of centres and a relatively small number of subjects per centre, hence 
data will be summarized for all centres combined. Statistical analyses will not be adjusted 
for centre. A summary of the number of subjects by centre will be produced.
 
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11.10.
Appendix 10: Examination of Covariates and Subgroups
11.10.1.
Handling of Covariates and Subgroups

The following is a non-exhaustive list of covariates that may be used in descriptive 
summaries and statistical analyses, some of which may also be used for subgroup 
analyses (See Section 8.1.1 and Section 8.1.2 for further details).

Additional covariates of clinical interest may also be considered. 

If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to unblinding the trial.  
Category
Covariates and / or Subgroups
Baseline Hgb
<10, >=10 g/dL
Weight
<=Median, >Median kg
Body Mass Index (BMI)
<27, 27 to <30, >=30 kg/m2
Type of Prior ESA
Epoetin IV, Darbepoetin, Mircera
Standardized Prior rhEPO dose
standardized dose by tertile (<=xx.xx, >xx.xx and < xx.xx, 
>=xx.xx)
Prior ESA dose (stratification 
factor)
Low ESA dose: <100 IU/kg/week epoetin OR <0.5 μg/kg/week 
darbepoetin OR<0.6 μg/kg/week methoxy PEG-epoetin beta
High ESA dose: ≥100 IU/kg/week epoetin OR ≥0.5 μg/kg/week 
darbepoetin OR≥0.6 μg/kg/week methoxy PEG-epoetin beta
Ethnicity
Not Hispanic or Latino, Hispanic or Latino
Race
White, African American, Asian, Other
Gender
Male, Female
Age
<65, >=65 to < 75, >=75 years
Region
North America, Europe
Diabetes
Yes, No
Phosphate Binders
Yes, No
Baseline Absolute Reticulocyte 
Count
<= Median, >Median TI/L
NOTES :

Subgroup summaries will only be produced if there are at least 30% of total ITT subjects in 
each subgroup.
 
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11.11.
Appendix 11: Multiple Comparisons & Multiplicity
11.11.1.
Handling of Multiple Comparisons & Multiplicity
No adjustment for multiplicity will be made because (1) all statistical analyses are 
estimation based, and (2) the focus of this study is on characterizing the Hgb-three-times 
weekly dose-response relationship and using the results to estimate the dose ratio 
between three-times weekly and QD doses that produce the same Hgb response, not on 
formal testing of hypotheses.
 
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11.12.
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses
Refer to Section 7.1.2 for “Convergence Diagnostics” and “Posterior Estimates”.
 
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11.13.
Appendix 13 – Abbreviations & Trade Marks
11.13.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
ALT
Alanine Transaminase
AST
Aspartate Transaminase
ATC
Anatomical Therapeutic Chemical classification
BMI
Body Mass Index
CDISC
Clinical Data Interchange Standards Consortium
CHr
reticuloctye Hgb
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CRO
Contract Research Organization
CSR
Clinical Study Report
CTMS
Clinical Trial Management System
CV
Coefficient of Variation 
DBP
Diastolic Blood Pressure
DBR
Database Release 
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
EPO
Erythropoietin
ESA
Erythropoiesis-Stimulating Agent
EW
Early Withdrawal
FSH
follicle stimulating hormone
GSK
GlaxoSmithKline
HD
Hemodialysis
Hgb
Hemoglobin
HR
Heart Rate
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
ICF
Informed Consent Form
IP
Investigational Product
ITT
Intent-To-Treat
IU
International Unit
IV
Intravenous 
IVWRS
Interactive Voice/Web Response System
LFT
Liver Function Test
MCV
Mean Corpuscular Volume
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MedDRA
Medical Dictionary for Regulatory Activities
PCI
Potential Clinical Importance 
 
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Abbreviation
Description
PD
Pharmacodynamic
PI
Principal Investigator
PK
Pharmacokinetic
PP
Per Protocol
PT
Preferred Term
QC
Quality Control
QD
Once daily
QTc
QT Interval Corrected for Heart Rate
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RBC
Red Blood Cell
RDW
Red cell distribution width
rhEPO
Recombinant Human Erythropoietin
SAC
Statistical Analysis Complete
SBP
Systolic Blood Pressure
SDTM
Study Data Tabulation Model
SE
Standard Error
SI
International System of Units
SOC
System Organ Class
TFL
Tables, Figures & Listings 
TIBC
Total iron-binding capacity
TIW
Three-times weekly
UIBC
unsaturated iron-binding capacity
Var
Variance
VEGF
Vascular endothelial growth factor
WBC
White Blood Cell
11.13.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
HemoCue
R
SAS
WinNonlin
 
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11.14.
Appendix 14: List of Data Displays
11.14.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Efficacy
2.1 to 2.n
2.1 to 2.n
Safety
3.1 to 3.n
3.1 to 3.n
Pharmacokinetic
4.1 to 4.n
4.1 to 4.n
Section
Listings
ICH Listings
1 to 50
Other Listings
51 to 81
11.14.2.
Mock Example Shell Referencing
IDSL and Non-IDSL shells will be referred by either the IDSL example shell name (e.g. 
ES6) or a TFL number (e.g. Table 6.03) from study PHI113633, to which the result of a 
similar, corresponding TFL created for this study will be compared.  Example TFL shells 
will be provided in Appendix 15.
 
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11.14.3.
Data Display Convention
The table, figure and listing shells are for guidance only and programming notes have been included to indicate how these outputs will 
look for this study.
Treatment Labels
The approved generic name for GSK1278863 is daprodustat, and its abbreviation, dapro, will be used in the displays. The five treatment 
groups in this study with the Total and Dapro Total will be displayed as shown below. Some of the templates/shells provided show less 
treatment groups, this is for guidance purposes and the tables should show the treatment groups shown below. 
a)
For Study population
                                                                     Dapro
                                                     --------------------------------------------
                      Placebo    Total    Dapro Total  10 mg      15 mg      25 mg      30 mg       
                      (N=39)     (N=216)    (N=177)    (N=39)     (N=40)     (N=39)     (N=40)   
     --------------------------------------------------------------------------------------------
b) For Safety and Efficacy
                                                           Dapro
                                                ------------------------------------------
                      Placebo    Dapro Total    10 mg      15 mg      25 mg      30 mg       
                      (N=39)       (N=177)      (N=39)     (N=40)     (N=39)     (N=40)   
       -----------------------------------------------------------------------------------
Note: When possible, display all treatment columns on the same page regardless of how they are shown on the templates.
Note: To be consistent with CDISC, USUBJID will be used for all listings even when SUBJID or SUBJ etc are shown in the listing shells. 
 
 
 
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11.14.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Subject Disposition
1.1.
All 
Randomized
Table 6.03
Summary of Subject Disposition
1.2.
All Screened
ES6
Summary of Reasons for Screen Failure
1.3.
Safety
Table 6.04
Summary of Study Treatment Discontinuation
Use the primary reasons and the subreasons for IP 
discontinuation collected from the eCRF. The ones on 
the shell are for guidance purposes only.   
1.4.
All 
Randomized
Table 6.05
Summary of Subjects at Each Visit
Protocol Deviations
1.5.
All 
Randomized
DV1A
Summary of Important Protocol Deviations
See RAP Section 11.1.1 for categories of important 
protocol deviations
1.6.
ITT
SA2
Summary of Deviations Leading to Exclusions from Per Protocol 
Population
See RAP Section 11.1.2 for categories of protocol 
deviations leading to exclusions from PP population
1.7.
All 
Randomized
Table 6.12
Summary of Inclusion/Exclusion Criteria Deviation
See eCRF and study protocol Section 5.2 and Section 
5.3 for inclusion and exclusion criteria 
Populations Analyzed
1.8.
All 
Randomized
Table 6.01
Summary of Study Populations
1.9.
All 
Randomized
Table 6.02
Summary of Number of Subjects by Center
Countries will be ordered in descending order of the 
Dapro Total column.  Centres will be ordered within 
each country by descending order of Dapro Total 
 
 
 
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
column.
Demography
1.10.
Safety
DM1
Summary of Demographic and Other Baseline Characteristics
Age, Gender, Ethnicity, Race, Diabetes, Weight, 
Height, BMI, Prior ESA Dose (Low ESA dose: <100 
IU/kg/week epoetin OR <0.5 μg/kg/week darbepoetin 
OR <0.6 μg/kg/week methoxy PEG-epoetin beta vs. 
High ESA dose: ≥100 IU/kg/week epoetin OR ≥0.5 
μg/kg/week darbepoetin OR  ≥ 0.6 μg/kg/week 
methoxy PEG-epoetin beta), Type of ESA, 
Standardized Prior rhEPO Dose, Baseline Hgb, 
Baseline Ferritin, Baseline Absolute Reticulocyte 
count, Baseline Pre-dose Plasma EPO, Baseline iron-
based phosphate binder (ferric citrate and sucroferric 
oxyhydroxide)
For details on Race categories shown in this table, 
please see GSK IDSL Demography Statistical Display 
Standards, Section 1.1.1 Summary of Demographic 
Characteristics
1.11.
ITT
DM1
Summary of Demographic and Other Baseline Characteristics
Age, Gender, Ethnicity, Race, Diabetes, Weight, 
Height, BMI, Prior ESA Dose (Low ESA dose: <100 
IU/kg/week epoetin OR <0.5 μg/kg/week darbepoetin 
OR <0.6 μg/kg/week methoxy PEG-epoetin beta vs. 
High ESA dose: ≥100 IU/kg/week epoetin OR ≥0.5 
μg/kg/week darbepoetin OR  ≥ 0.6 μg/kg/week 
methoxy PEG-epoetin beta), Type of ESA, 
 
 
 
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Standardized Prior rhEPO Dose, Baseline Hgb, 
Baseline Ferritin, Baseline Absolute Reticulocyte 
count, Baseline Pre-dose Plasma EPO, Baseline iron-
based phosphate binder (ferric citrate and sucroferric 
oxyhydroxide)
For details on Race categories shown in this table, 
please see GSK IDSL Demography Statistical Display 
Standards, Section 1.1.1 Summary of Demographic 
Characteristics
 
 
 
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
1.12.
All 
Randomized
DM1
Summary of Demographic and Other Baseline Characteristics
Age, Gender, Ethnicity, Race, Diabetes, Weight, 
Height, BMI, Prior ESA Dose (Low ESA dose: <100 
IU/kg/week epoetin OR <0.5 μg/kg/week darbepoetin 
OR <0.6 μg/kg/week methoxy PEG-epoetin beta vs. 
High ESA dose: ≥100 IU/kg/week epoetin OR ≥0.5 
μg/kg/week darbepoetin OR  ≥0.6 μg/kg/week 
methoxy PEG-epoetin beta), Type of ESA, 
Standardized Prior rhEPO Dose, Baseline Hgb, 
Baseline Ferritin, Baseline Absolute Reticulocyte 
count, Baseline Pre-dose Plasma EPO, Baseline iron-
based phosphate binder (ferric citrate and sucroferric 
oxyhydroxide)
For details on Race categories shown in this table, 
please see GSK IDSL Demography Statistical Display 
Standards, Section 1.1.1 Summary of Demographic 
Characteristics
1.13.
ITT
Table 6.10
Summary of Race & Racial Combinations
For details on Race categories shown in this table, 
please see GSK IDSL Demography Statistical Display 
Standards, Section 1.1.2 Summary of Race and Racial 
Combinations
1.14.
ITT
Table 6.11
Summary of Race and Racial Combination Details
For details on Race categories shown in this table, 
please see GSK IDSL Demography Statistical Display 
Standards, Section 1.2.1 Summary of Race and Racial 
Combination Details
1.15.
All 
Randomized
Table 6.11
Summary of Race and Racial Combination Details
For details on Race categories shown in this table, 
please see GSK IDSL Demography Statistical Display 
Standards, Section 1.2.1 Summary of Race and Racial 
 
 
 
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Combination Details
Medical Condition & Concomitant Medications
1.16.
Safety
Table 6.14
Summary of Past Medical Conditions
Categories of medical conditions will be sorted in 
descending order of “Total” incidence, and medical 
conditions within each category will be sorted in 
descending order of “Total” incidence. If the “Total” 
incidence for any two or more medical conditions is 
equal, then they will be presented in alphabetical 
order.
1.17.
Safety
Table 6.15
Summary of Current Medical Conditions
Categories of medical conditions will be sorted in 
descending order of “Total” incidence, and medical 
conditions within each category will be sorted in 
descending order of “Total” incidence. If the “Total” 
incidence for any two or more medical conditions is 
equal, then they will be presented in alphabetical 
order.
1.18.
Safety
Table 6.21
Summary Concomitant Medication ATC Level 1 by Ingredient
Medications will be sorted in descending order of total 
incidence of “Dapro Total” for the ATC level 1 and in 
descending order of total incidence for the ingredient 
within each ATC level. If the total incidence of “Dapro 
Total” for any two or more ingredients is equal, the 
events will be presented in alphabetical order.
See GSK IDSL “CONCOMITANT MEDICATIONS 
STATISTICAL DISPLAY STANDARDS” (Version 12), 
Section 1.1.1  
 
 
 
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No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
1.19.
Safety
Table 6.21
Summary Concomitant Medication ATC Level 1 by Ingredient 
and Ingredient Combinations
Medications will be sorted in descending order of total 
incidence of “Dapro Total” for the ATC level 1 and in 
descending order of total incidence for the ingredient 
within each ATC level. If the total incidence of “Dapro 
Total” for any two or more ingredients is equal, the 
events will be presented in alphabetical order.
See GSK IDSL “CONCOMITANT MEDICATIONS 
STATISTICAL DISPLAY STANDARDS” (Version 12), 
Section 1.1.2  
1.20.
Safety
Table 6.16
Summary of Family History of Cardiovascular Risk
The frequency count (%) for “First degree relatives” 
are the number (%) of subjects with any first degree 
relatives (biologic father, mother, brother, and sister) 
who have cardiovascular risk factors. It should be 
derived from the four categories of first degree 
relatives captured on the eCRF. 
1.21.
Safety
Table 6.17
Summary of Substance Use History
.
1.22.
Safety
Table 6.18
Summary of Baseline Hemodialysis
1.23.
Safety
Table 6.23
Summary of Prior Erythropoiesis-Stimulating Agents
1.24.
Safety
Table 6.24
Summary of Concomitant Erythropoiesis-Stimulating Agents 
1.25.
Safety
Table 6.26
Summary of  On-Therapy Average Iron Dose 
IV: weekly average
Oral: daily average
1.26.
Safety
Table 6.26
Summary of  Pre-therapy Average Iron Dose 
IV: weekly average
 
 
 
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No.
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Example Shell
Title
Programming Notes
Oral: daily average
“Pre-therapy” include 4-week screening period and 4-
week period prior to the screening period. 
1.27.
Safety
Table 6.29
Summary of Subjects Using IV Iron Dose Between Study 
Treatment Start and Final Visit
First row title: “Using iron at Treatment Start and Day 
29”
1.
The subjects who used IV iron between Study 
Treatment Start and final on-treatment visit 
must fall into one and only one of the 3 
categories in this table (i.e. they capture all 
types of IV iron users):
a.
Using Iron at Treatment Start and 
Day 29 (completers) or Using Iron at 
Treatment Start and Last Available 
Visit (Safety pop) (Note: Day 29 or 
Last Available Visit must be on-
treatment visit. These are the 
subjects who were on IV iron at 
treatment start AND at the last on-
treatment visit).   
b.
Stopping iron on-therapy. (Note: 
These are the subjects who were on 
IV iron at treatment start but stopped 
before the last on-treatment visit
c.
Starting iron after treatment start. 
(Note: These are the subjects who 
were not on IV iron at treatment 
start, but started taking iron after 
treatment start.)
 
 
 
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No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.
The study subjects can be categorized using 
an algorithm that is similar to the one shown 
below:
a.
(1) Using iron at treatment start: 
“Any IV Iron Therapy -Iron Start 
Date” <= “Treatment Start Date” and 
(“Any IV Iron Therapy -Iron End 
Date” >= “Treatment Start Date” or 
ongoing). (2) Using iron at Day 29 or 
Last Available On-treatment Visit: 
“Any IV Iron Therapy -Iron End 
Date” >= “Last on-treatment visit 
date” (Note: The IV iron used at 
treatment start does not have to be 
the same IV iron used at Day 29 or 
the Last Available On-treatment 
Visit)
b.
Stopping iron on-therapy: “Any IV 
Iron Therapy - Iron Start Date” <= 
“Treatment Start Date” and Any IV 
Iron Therapy - “Iron End Date” >= 
“Treatment Start Date” and “All IV 
Iron Therapy-Iron End Date” < “Last 
on-treatment visit date”” (Note: The 
IV iron used at treatment start does 
not have to be the same IV iron that 
stopped prior to the last on-
treatment visit date (i.e. We are 
 
 
 
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
flagging the subjects and not the 
Iron therapy.))
c.
Starting iron after treatment start: 
“Iron Start Date” > “Treatment Start 
Date” with no other IV Iron therapy 
at treatment start.
1.28.
Completer
Table 6.29
Summary of Subjects Using IV Iron Dose Between Study 
Treatment Start and Final Visit
First row title: “Using iron at Treatment Start and Day 
29”
Also see the programming notes above for the 
previous table 
1.29.
Safety
Table 6.32
Summary of Blood Products
Exposure and Treatment Compliance
1.30.
Safety
Table 6.33
Summary of Study Medication Overall Compliance 
1.31.
Safety
Table 8.01
Summary of Extent of Exposure to Study Treatment
 
 
 
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11.14.5.
Study Population Figures
Study Population Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
1.1.
Safety
Figure 6.05
Bar Chart of Prior Erythropoiesis Stimulating Agents
1.2.
Safety
Figure 6.06
Histogram of Standardized Prior Recombinant Human 
Erythropoietin Dose
 
 
 
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11.14.6.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Summary and Analysis of Hemoglobin
2.1.
ITT
Table 7.001
Summary of Hemoglobin (g/dL) by Visit
Show Week-2, Day 1, Baseline, Day 15, Day 29, Day 
29 Including Imputed, Day 43 Follow-up
Only on-treatment Hgb will be summarized for Day 15 
and Day 29 visits.  
2.2.
ITT
Table 7.002
Summary of Hemoglobin (g/dL) Change from Baseline by Visit
Baseline is the average of Hgb values  measured by 
Quest at Week -2 and Day 1 visits
Show Baseline, Change from baseline at Day 15, Day 
29, Day 29 Including Imputed,  Day 43 Follow-up
Only on-treatment Hgb will be summarized for Day 15 
and Day 29 visits.  
2.3.
ITT
Table 7.004
Summary of Hemoglobin (g/dL) Change from Baseline by Visit 
by Subgroups
Baseline is the average of Hgb values  measured by 
Quest at Week -2 and Day 1 visits
Use the subgroups defined in RAP Section 11.10.1
Show Baseline, Change from baseline at Day 15, Day 
29, Day 43 Follow-up
Only on-treatment Hgb will be summarized for Day 15 
and Day 29 visits.  
 
 
 
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No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.4.
ITT
Table 7.005
Summary of Treatment Difference for Hemoglobin (g/dL) 
Change from Baseline at Day 29 by Subgroups
Baseline is the average of Hgb values  measured by 
Quest at Week -2 and Day 1 visits
Only on-treatment Hgb will be included in this analysis
Use the subgroups defined in RAP Section 11.10.1
2.5.
ITT
Table 7.010
Summary of Posterior Estimates from the Bayesian 3 Parameter 
Emax Dose-Response Model for Change in Hemoglobin at Day 
29 for the Primary and Sensitivity Prior Analyses and the 
Estimates from the Frequentist 3 Parameter Emax Dose-
Response Model
There are 3 analyses (1) based on the prior defined for 
the primary analysis (2) weak priors (3) frequentist 
analysis
Based on both observed on-treatment Hgb and 
imputed Hgb at Day 29 visit. If Day 29 Hgb is imputed 
using Day 15 Hgb, Day 15 Hgb must be measured on-
treatment.
Will be performed by GSK
2.6.
Completers
Table 7.011
Sensitivity Summary of Posterior Estimates from the Bayesian 3 
Parameter Emax Dose-Response Model for Change in 
Hemoglobin at Day 29
Same as template 7.010, just based on different pop
Will be performed by GSK
 
 
 
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Population
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Example Shell
Title
Programming Notes
2.7.
Per-Protocol
Table 7.012
Sensitivity Summary of Posterior Estimates from the Bayesian 3 
Parameter Emax Dose-Response Model for Change in 
Hemoglobin at Day 29
Same as template 7.010, just based on different pop
Based on both observed on-treatment Hgb and 
imputed Hgb at Day 29 visit. If Day 29 Hgb is imputed 
using Day 15 Hgb, Day 15 Hgb must be measured on-
treatment.
Will be performed by GSK
2.8.
ITT
Linear_DR
Dose-Response Linear Model for Change in Hemoglobin at Day 
29
Based on both observed on-treatment Hgb and 
imputed Hgb at Day 29 visit. If Day 29 Hgb is imputed 
using Day 15 Hgb, Day 15 Hgb must be measured on-
treatment.
Will be performed by GSK
2.9.
Completers
Linear_DR
Dose-Response Linear Model for Change in Hemoglobin at Day 
29
Based on observed on-treatment Hgb at Day 29 visit. 
  
Will be performed by GSK
2.10.
Per Protocol
Linear_DR
Dose-Response Linear Model for Change in Hemoglobin at Day 
29
Based on both observed on-treatment Hgb and 
imputed Hgb at Day 29 visit. If Day 29 Hgb is imputed 
using Day 15 Hgb, Day 15 Hgb must be measured on-
treatment.
Will be performed by GSK
2.11.
ITT
Dose_Ratio_1
Summary of Dose Ratio Between Three-Times Weekly Doses 
(Observed) and QD Doses (Estimated by Bayesian Emax 
Model)
Will be performed by GSK when the dose-response 
model is appropriate
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.12.
ITT
Dose_Ratio_1
Summary of Dose Ratio Between Three-Times Weekly Doses 
(Observed) and QD Doses (Estimated by Frequentist Emax 
Model)
Will be performed by GSK when the dose-response 
model is appropriate
2.13.
ITT
Dose_Ratio_1
Summary of Dose Ratio Between Three-Times Weekly Doses 
(Observed) and QD Doses (Estimated by Linear Model)
Will be performed by GSK when the dose-response 
model is appropriate
2.14.
ITT
Dose_Ratio_2
Summary of Dose Ratio Between Three-Times Weekly Doses 
(Estimated by Bayesian Emax Model) and QD Doses (Estimated 
by Bayesian Emax Model) at Selected Hgb Responses
Will be performed by GSK when the dose-response 
models are appropriate
2.15.
ITT
Dose_Ratio_2
Summary of Dose Ratio Between Three-Times Weekly Doses 
(Estimated by Bayesian Emax Model) and QD Doses (Estimated 
by Frequentist Emax Model) at Selected Hgb Responses
Will be performed by GSK when the dose-response 
models are appropriate
2.16.
ITT
Dose_Ratio_2
Summary of Dose Ratio Between Three-Times Weekly Doses 
(Estimated by Bayesian Emax Model) and QD Doses (Estimated 
by Linear Model) at Selected Hgb Responses
Will be performed by GSK when the dose-response 
models are appropriate
2.17.
ITT
Dose_Ratio_2
Summary of Dose Ratio Between Three-Times Weekly Doses 
(Estimated by Frequentist Emax Model) and QD Doses 
(Estimated by Bayesian Emax Model) at Selected Hgb 
Responses
Will be performed by GSK when the dose-response 
models are appropriate
2.18.
ITT
Dose_Ratio_2
Summary of Dose Ratio Between Three-Times Weekly Doses 
(Estimated Frequentist Emax Model) and QD Doses (Estimated 
by Frequentist Emax Model) at Selected Hgb Responses
Will be performed by GSK when the dose-response 
models are appropriate
2.19.
ITT
Dose_Ratio_2
Summary of Dose Ratio Between Three-Times Weekly Doses 
(Estimated by Frequentist Emax Model) and QD Doses 
(Estimated by Linear Model) at Selected Hgb Responses
Will be performed by GSK when the dose-response 
models are appropriate
2.20.
ITT
Dose_Ratio_2
Summary of Dose Ratio Between Three-Times Weekly Doses 
(Estimated by Linear Model) and QD Doses (Estimated by 
Bayesian Emax Model) at Selected Hgb Responses
Will be performed by GSK when the dose-response 
models are appropriate
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.21.
ITT
Dose_Ratio_2
Summary of Dose Ratio Between Three-Times Weekly Doses 
(Estimated by Linear Model) and QD Doses (Estimated by 
Frequentist Emax Model) at Selected Hgb Responses
Will be performed by GSK when the dose-response 
models are appropriate
2.22.
ITT
Dose_Ratio_2
Summary of Dose Ratio Between Three-Times Weekly Doses 
(Estimated Linear Model) and QD Doses (Estimated by Linear 
Model) at Selected Hgb Responses
Will be performed by GSK when the dose-response 
models are appropriate
2.23.
ITT
Model_ratio
Summary of Dose Ratio between Three-Times Weekly Dose 
and QD Dose Estimated by Emax Model and Linear Model
Will be performed by GSK
2.24.
ITT
Linear_TQ
Linear Model between the corresponding QD and TIW doses 
with the same Change in Hemoglobin at Day 29
Will be performed by GSK
2.25.
ITT
(PHI113633)
Emax633
Summary of Posterior Estimates from the Bayesian 3 Parameter 
Emax Dose-Response Model and the Estimates from the 
Frequentist 3 Parameter Emax Dose-Response Model for 
Change in Hemoglobin at Week 4 (Based on PHI113633 data 
excluding Japan)
Will be performed by GSK
2.26.
ITT
(PHI113633)
Linear633
Dose-Response Linear Model for Change in Hemoglobin at 
Week 4 (Based on PHI113633 data excluding Japan)
Will be performed by GSK
2.27.
ITT
Table 7.013
Summary of Hemoglobin Imputations
“n(%)”s in this table reflect the number(%) of subjects 
who are included in the primary efficacy analyses. 
Therefore the post-baseline “n(%)”s should be the 
number(%) of subjects who are on-treatment at Day 15 
visit and/or at Day 29 visit.
2.28.
ITT
PHI116581
Table 7.23
Summary of Subjects who Reach Pre-defined Hemoglobin 
Stopping Criteria
Based on Hgb measured by Quest
“≥2.0 decrease” and “≥1.0 increase” refer to change 
over 2 weeks. See protocol Section 5.6.2. 
 
 
 
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Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.29.
ITT
Table 7.054
Exploratory Summary of Repeated Measures Analysis for 
Hemoglobin (g/dL) Change from Baseline at Day 29
2.30.
ITT
Ac hoc 
Table 
67.01601
Summary of Subjects Meeting Different Hemoglobin Criteria
Based on on-treatment Hgb
Summary and Analyses of Other Efficacy Parameters
2.31.
ITT
Table 7.021
Summary of Hepcidin (ug/L) by Visit
Show summary stat at Day1, Day 15, and Day 29
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.  
2.32.
ITT
Table 7.022
Summary of Hepcidin (ug/L) Percent Change from Baseline by 
Visit
Show Baseline, % Change from baseline at Day 15, 
and Day 29
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.  
2.33.
ITT
Table 7.023
Summary of Ferritin (ug/L) by  Visit
Show summary stat at Week -4, Day1, Day 29,and 
Day 43 Follow-up
Only on-treatment assessment will be summarized for 
Day 29 visit.  
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.34.
ITT
Table 7.024
Summary of Ferritin (ug/L) Change from Baseline by Visit
Show Baseline, Change from baseline at Day 29, Day 
43 Follow-up
Only on-treatment assessment will be summarized for 
Day 29 visit.  
2.35.
ITT
Table 7.023
Summary of Transferrin (g/L) by Visit
Show summary stat at Week -4, Day1, Day 29,and 
Day 43 Follow-up
Only on-treatment assessment will be summarized for 
Day 29 visit.  
2.36.
ITT
Table 7.024
Summary of Transferrin (g/L) Change from Baseline by Visit
Show Baseline, Change from baseline at Day 29, Day 
43 Follow-up
Only on-treatment assessment will be summarized for 
Day 29 visit.  
2.37.
ITT
Table 7.021
Summary of Transferrin Saturation (%) by Visit
Show summary stat at Week -4, Day1, Day 29,and 
Day 43 Follow-up
Only on-treatment assessment will be summarized for 
Day 29 visit.  
2.38.
ITT
Table 7.022
Summary of Transferrin Saturation (%) Percent Change from 
Baseline by Visit
Show Baseline, % Change from baseline at Day 29, 
Day 43 Follow-up
Only on-treatment assessment will be summarized for 
Day 29 visit.  
 
 
 
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No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.39.
ITT
Table 7.023
Summary of Total Iron (umol/L) by Visit
Show summary stat at Week -4, Day1, Day 29,and 
Day 43 Follow-up
Only on-treatment assessment will be summarized for 
Day 29 visit.  
2.40.
ITT
Table 7.024
Summary of Total Iron (umol/L) Change from Baseline by Visit
Show Baseline, Change from baseline at Day 29, Day 
43 Follow-up
Only on-treatment assessment will be summarized for 
Day 29 visit.  
2.41.
ITT
Table 7.023
Summary of Unsaturated Iron Binding Capacity (umol/L) by Visit
Show summary stat at Week -4, Day1, Day 29,and 
Day 43 Follow-up
Only on-treatment assessment will be summarized for 
Day 29 visit.  
2.42.
ITT
Table 7.024
Summary of Unsaturated Iron Binding Capacity (umol/L) Change 
from Baseline by Visit
Show Baseline, Change from baseline at Day 29, Day 
43 Follow-up
Only on-treatment assessment will be summarized for 
Day 29 visit.  
2.43.
ITT
Table 7.023
Summary of Total Iron Binding Capacity (umol/L) by Visit
Show summary stat at Week -4, Day1, Day 29,and 
Day 43 Follow-up
Only on-treatment assessment will be summarized for 
Day 29 visit.  
 
 
 
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Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.44.
ITT
Table 7.024
Summary of Total Iron Binding Capacity (umol/L) Change from 
Baseline by Visit
Show Baseline, Change from baseline at Day 29, Day 
43 Follow-up
Only on-treatment assessment will be summarized for 
Day 29 visit.  
2.45.
ITT
Table 7.023
Summary of Reticulocyte Hemoglobin (CHr) (pg) by Visit
Show summary stat at Week -2, Day1, Day 15, Day 
29,and Day 43 Follow-up
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
2.46.
ITT
Table 7.024
Summary of Reticulocyte Hemoglobin (CHr) (pg) Change from 
Baseline by Visit
Show Baseline, Change from baseline at Day 15, Day 
29, Day 43 Follow-up
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
2.47.
ITT
Table 7.023
Summary of Hematocrit (Fraction of 1) by Visit
Show summary stat at Week -2, Day1, Day 15, Day 
29,and Day 43 Follow-up
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
2.48.
ITT
Table 7.024
Summary of Hematocrit (Fraction of 1) Change from Baseline by 
Visit
Show Baseline, Change from baseline at Day 15, Day 
29, Day 43 Follow-up
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
 
 
 
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No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.49.
ITT
Table 7.023
Summary of Hematocrit (%) by Visit
Show summary stat at Week -2, Day1, Day 15, Day 
29,and Day 43 Follow-up
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
2.50.
ITT
Table 7.024
Summary of Hematocrit (%) Change from Baseline by Visit
Show Baseline, Change from baseline at Day 15, Day 
29, Day 43 Follow-up
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
2.51.
ITT
Table 7.023
Summary of Red Blood Cell Count (10^12/L) by Visit
Show summary stat at Week -2, Day1, Day 15, Day 
29,and Day 43 Follow-up
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
2.52.
ITT
Table 7.024
Summary of Red Blood Cell Count (10^12/L) Change from 
Baseline by Visit
Show Baseline, Change from baseline at Day 15, Day 
29, Day 43 Follow-up
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
2.53.
ITT
Table 7.023
Summary of Reticulocyte Count (%) by Visit
Show summary stat at Week -2, Day1, Day 15, Day 
29,and Day 43 Follow-up
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
 
 
 
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Population
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Example Shell
Title
Programming Notes
2.54.
ITT
Table 7.024
Summary of Reticulocyte Count (%) Change from Baseline by 
Visit
Show Baseline, Change from baseline at Day 15, Day 
29, Day 43 Follow-up
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
2.55.
ITT
Table 7.023
Summary of Absolute Reticulocyte Count (10^12/L) by Visit
Show summary stat at Week -2, Day1, Day 15, Day 
29,and Day 43 Follow-up
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
2.56.
ITT
Table 7.024
Summary of Absolute Reticulocyte Count (10^12/L) Percent 
Change from Baseline by Visit
Show Baseline, Percent Change from baseline at Day 
15, Day 29, Day 43 Follow-up
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
%Change = 100 x [(Post-Baseline Visit Value –
Baseline) / Baseline] 
2.57.
ITT
Table 7.047
Summary of Plasma Erythropoietin (IU/L) by Visit and Sample 
Time
Show summary stat at scheduled visit and sample time 
specified in Protocol Section 7
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
 
 
 
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IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.58.
ITT
Table 7.048
Summary of Plasma Erythropoietin (IU/L) Change from Baseline 
by Visit and Sample Time
Show Baseline and Change from baseline at 
scheduled visit and sample time specified in Protocol 
Section 7
Only on-treatment assessments will be summarized for 
Day 15 and Day 29 visits.
2.59.
ITT
Table 7.049
Summary of Plasma Erythropoietin (IU/L) Maximum Observed 
Change from Baseline
Only on-treatment assessments will be summarized
2.60.
ITT
Table 7.050
Summary of VEGF (ng/L) by Visit and Sample Time
Show summary stat at scheduled visit and sample time 
specified in Protocol Section 7
2.61.
ITT
Table 7.051
Summary of VEGF (ng/L) Percent Change from Baseline by 
Visit and Sample Time
Show Baseline and %Change from baseline at 
scheduled visit and sample time specified in Protocol 
Section 7
2.62.
ITT
Table 7.052
Summary of VEGF (ng/L) Maximum Observed Percent Change 
from Baseline
Only on-treatment assessments will be summarized
11.14.7.
Efficacy Figures
Programming notes:

If the horizontal x axis label in the figure template is “Visit (weeks)” (copied from study PHI113633), replace it with “Visit 
(days)”, and make the corresponding changes on the tick mark values.

If the horizontal x axis label in the figure template is “Dose (mg)” (copied from study PHI113633), replace it with “Three-Times 
Weekly Dose (mg)”. 
 
 
 
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Hemoglobin
2.1.
ITT
Figure 7.002
Mean and 95% CI for Hemoglobin by Visit
Show pre-baseline data, baseline data, “on-treatment” 
data for on-treatment visits (Day 15 and Day 29), and 
data at day 43 follow-up  
2.2.
ITT
Figure 7.004
Mean and 95% CI for Hemoglobin Change from Baseline by Visit
Show on-treatment data for on-treatment visits (Day 15 
and Day 29) and data at day 43 follow-up
2.3.
ITT
Figure 7.007
Subject Profiles of Hemoglobin and Exposure over Time
Remove the right Y-axis from the shell. Show Hgb 
profile, but do not show “Dose”. Instead, add a 
horizontal line to show exposure time.
Including baseline, on-treatment, and post-treatment 
data
2.4.
ITT
Figure 7.012
Scatter plot of Hemoglobin Assessments: Quest vs. HemoCue
Use different symbols and show 5 regression lines for 
the 5 different countries. In the footnote, show the fitted 
overall regression model.
Based on all data collected at any time in the study
2.5.
ITT
Figure 7.013
Posterior Emax Dose−Response Curve for Hemoglobin (g/dL) 
Change from Baseline at Day 29
Replace “Note: Bayesian 4−parameter Emax model is 
presented.” with “Note: Bayesian 3−parameter Emax 
model is presented.”
X axis: 0 to 50
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.6.
Completer
Figure 7.015
Posterior Emax Dose−Response Curve for Hemoglobin (g/dL) 
Change from Baseline at Day 29 for Primary Analysis and 
Completers Sensitivity Analysis
Replace “Note: Bayesian 4−parameter Emax model is 
presented.” with “Note: Bayesian 3−parameter Emax 
model is presented.”
Replace “Note: Solid grey lines: 95% credible bands 
associated with Week 4 Completers Analysis.” with”
Note: Solid grey lines: 95% credible bands associated 
with Completers Analysis.”
X axis: 0 to 50
Create it in house at GSK
2.7.
ITT
Figure 7.016
Posterior Emax Dose−Response Curve for Hemoglobin (g/dL) 
Change from Baseline at Day 29 for Primary Analysis and 
Sensitivity Priors and Frequentist Sensitivity Analyses
Replace “Note: Bayesian 4−parameter Emax, model for 
Primary ITT [Sensitivity Prior] analyses and Frequentist 
3−parameter Emax model are presented.” with “Note: 
Bayesian 3−parameter Emax, model for Primary ITT 
[Sensitivity Prior] analyses and Frequentist 
3−parameter Emax model are presented.”
X axis: 0 to 50
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.8.
Per Protocol
Figure 7.017
Posterior Emax Dose−response Curve for Hemoglobin Change 
at Day 29 for Primary Analysis and Per Protocol Sensitivity 
Analysis
Replace “Note: Bayesian 4−parameter Emax model is 
presented.” with “Note: Bayesian 3−parameter Emax 
model is presented.”
X axis: 0 to 50
Create it in house at GSK
2.9.
ITT
Figure 7.018
Posterior Probability Distribution for Predicted Hemoglobin 
Change (g/dL) from Baseline at Day 29 Based on Primary 
Analysis
Replace “Note: Posterior probability distributions reflect 
Hemoglobin change from  baseline over 4 weeks, on 
average, and do not reflect probability for any single 
patient” with “Note: Posterior probability distributions 
reflect Hemoglobin change from  baseline over 29 days, 
on average, and do not reflect probability for any single 
patient”
Create it in house at GSK
2.10.
ITT
Figure 7.019
Density Plots Associated with Emax Model Parameter, E0
Create it in house at GSK
2.11.
ITT
Figure 7.020
Density Plots Associated with Emax Model Parameter, Emax
Create it in house at GSK
2.12.
ITT
Figure 7.021
Density Plots Associated with Emax Model Parameter, ED50
Create it in house at GSK
2.13.
ITT
Figure 7.024
Density Plots Associated with Emax Model Parameter, Variance
Create it in house at GSK
 
 
 
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.14.
ITT
Figure 7.026
Posterior Predictive Distribution for Hemoglobin (g/dL) Change 
from Baseline at Day 29 for a Future Subject based on Primary 
Analysis
Replace “Note: Posterior predictive probability 
distributions reflect the Hemoglobin change from 
baseline at week 4 for a future subject.” with “Note: 
Posterior predictive probability distributions reflect the 
Hemoglobin change from baseline at Day 29 for a 
future subject.”
Create it in house at GSK
2.15.
ITT
Figure 7.027
Posterior Predictive Probability that Day 29 Hemoglobin (g/dL) 
Change for a Future Subject will be in the Range [−0.5, 0.5] g/dL
by Daprodustat Dose
Replace “Note: The probability describes the likelihood 
that a future subject will be maintained within the range 
+/− 0.5 g/dL from Baseline over 4 Weeks, by dose” with 
“Note: The probability describes the likelihood that a 
future subject will be maintained within the range +/− 
0.5 g/dL from Baseline over 29 days, by dose”
Create it in house at GSK
2.16.
ITT
Figure 7.028
Individual Subject Hemoglobin Change from Baseline at Day 29 
with Means and 95% CIs
Don’t distinguish Japan from Non-Japan. Show data 
from different countries by different symbols
On-treatment Hgb only
Create it in house at GSK
2.17.
ITT
Hgb_Scatter
Scatter Plot of Hgb Responses vs. Three-Times Weekly Doses 
and QD Weekly Doses
Add jittering to the plot if there are too many dots at a 
specific dose level
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.18.
ITT
TIW_QD
Three-Times Weely Doses vs. QD Doses Corresponding to 
Selected Hgb Responses
Create it in house at GSK
2.19.
ITT
Figure 7.031
Forest plot of Model−Adjusted Treatment Difference for 
Hemoglobin at Day 29
Delete “Note: results for race group=Other are provided 
in Table 7.005”  
Based the corresponding repeated measures analysis 
sas output
Other Efficacy Parameters
2.20.
ITT
Figure 7.036
Geometric Mean and 95% CI for Hepcidin by Visit
See programming notes for the corresponding 
summary table
2.21.
ITT
Figure 7.037
Mean and 95% CI for Hepcidin Percent Change from Baseline by 
Visit
See programming notes for the corresponding 
summary table
2.22.
ITT
Figure 7.039
Mean and 95% CI for Ferritin by Visit
See programming notes for the corresponding 
summary table
2.23.
ITT
Figure 7.040
Mean and 95% CI for Ferritin Change from Baseline by Visit
See programming notes for the corresponding 
summary table
2.24.
ITT
Figure 7.041
Mean and 95% CI for Transferrin by Visit
See programming notes for the corresponding 
summary table
2.25.
ITT
Figure 7.042
Mean and 95% CI for Transferrin Change from Baseline by Visit
See programming notes for the corresponding 
summary table
2.26.
ITT
Figure 7.043
Geometric Mean and 95% CI for Transferrin Saturation by Visit
See programming notes for the corresponding 
summary table
2.27.
ITT
Figure 7.044
Mean and 95% CI for Transferrin Saturation Percent Change 
from Baseline by Visit
See programming notes for the corresponding 
summary table
 
 
 
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.28.
ITT
Figure 7.045
Mean and 95% CI for Total Iron by Visit
See programming notes for the corresponding 
summary table
2.29.
ITT
Figure 7.046
Mean and 95% CI for Total Iron Change from Baseline by Visit
See programming notes for the corresponding 
summary table
2.30.
ITT
Figure 7.049
Mean and 95% CI for Total Iron Binding Capacity by Visit
See programming notes for the corresponding 
summary table
2.31.
ITT
Figure 7.050
Mean and 95% CI for Total Iron Binding Capacity Change from 
Baseline by Visit
See programming notes for the corresponding 
summary table
2.32.
ITT
Figure 7.051
Mean and 95% CI for Reticulocyte Hemoglobin Content by Visit
See programming notes for the corresponding 
summary table
2.33.
ITT
Figure 7.052
Mean and 95% CI for Reticulocyte Hemoglobin Content Change 
from Baseline by Visit
See programming notes for the corresponding 
summary table
2.34.
ITT
Figure 7.053
Mean and 95% CI for Hematocrit by Visit
See programming notes for the corresponding 
summary table
2.35.
ITT
Figure 7.054
Mean and 95% CI for Hematocrit Change from Baseline by Visit
See programming notes for the corresponding 
summary table
2.36.
ITT
Figure 7.055
Mean and 95% CI for Red Blood Cell Count by Visit
See programming notes for the corresponding 
summary table
2.37.
ITT
Figure 7.056
Mean and 95% CI for Red Blood Cell Count Change from 
Baseline by Visit
See programming notes for the corresponding 
summary table
2.38.
ITT
Figure 7.057
Mean and 95% CI for Reticulocyte Count (%) by Visit
See programming notes for the corresponding 
summary table
2.39.
ITT
Figure 7.058
Mean and 95% CI for Reticulocyte Count (%) Change from 
Baseline by Visit
See programming notes for the corresponding 
summary table
 
 
 
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.40.
ITT
Figure 7.059
Mean and 95% CI for Reticulocyte Count (Absolute) by Visit
See programming notes for the corresponding 
summary table
2.41.
ITT
Figure 7.060
Mean and 95% CI for Reticulocyte Count (Absolute) Percent 
Change from Baseline by Visit
See programming notes for the corresponding 
summary table
2.42.
ITT
Figure 7.067
Subject Profiles of Iron−related Parameters with Mean Line by 
Visit
Replace the horizontal x axis label “Weeks Since First 
Dose” with “Days Since First Dose”
2.43.
ITT
Figure 7.068
Subject Profiles of Plasma Erythropoietin and Hepcidin by Visit
Delete “with Mean Line” from shell title. 
2.44.
ITT
Figure 7.069
Individual Post−Dose Plasma Erythropoietin at Day 15
Plotted with a loess curve fitted for each treatment 
group based on Day 15 data.
2.45.
ITT
Figure 7.070
Individual Post−Dose VEGF at Day 15
Plotted with a loess curve fitted for each treatment 
group based on Day 15 data
11.14.8.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Adverse Events
3.1.
Safety
EXAMPLE 
AE13
Adverse Event Overview
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
3.2.
Safety
Table 8.07
Summary of On-Therapy Adverse Events by System Organ 
Class 
For details on how to sort the AEs in AE summary 
tables, please see GSK IDSL “Adverse Event 
Statistical Display Standards”. For this study, AEs will 
be sorted by the incidence of “Dapro Total” 
(unrounded), instead of “total incidence (i.e., summed 
across all treatment groups)”, in descending order.
Re-confirm the MedDRA version number (19.0) in the 
footnote
3.3.
Safety
Table 8.07
Summary of Post-Therapy Adverse Events by System Organ 
Class 
Sorted by Dapro Total (unrounded) in descending 
order
3.4.
Safety
Table 8.05
Summary of On-therapy Adverse Events by Preferred Term
Sorted by Dapro Total (unrounded) in descending 
order
Re-confirm the MedDRA version number (19.0) in the 
footnote
3.5.
Safety
Table 8.05
Summary of Post-therapy Adverse Events by Preferred Term
Sorted by Dapro Total (unrounded) in descending 
order
3.6.
Safety
Table 8.05
Summary of On-Therapy Common Adverse Events by Overall 
Frequency
Common AE is defined as an AE with >=2 subjects in 
any treatment group or >=2% (based on unrounded 
value) in the Dapro Total group.
3.7.
Safety
Table 8.07
Summary of On-Therapy Common Non-Serious Adverse Events 
by Overall Frequency 
Common AE is defined as an AE with >=2 subjects in 
any treatment group or >=2% (based on unrounded 
value) in the Dapro Total group.
3.8.
Safety
Table 8.10
Summary of On-therapy Adverse Events by System Organ 
Class and Maximum Intensity
3.9.
Safety
Table 8.07
Summary of On-Therapy Treatment-Related Adverse Events by 
System Organ Class
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
3.10.
Safety
Table 8.05
Summary of On-Therapy Treatment-Related Adverse Events by 
Preferred Term
3.11.
Safety
Table 8.07
Summary of On-Therapy Serious Adverse Events by System 
Organ Class
3.12.
Safety
Table 8.05
Summary of On-therapy Serious Adverse Events by Preferred 
Term
3.13.
Safety
Table 8.05
Summary of Post-therapy Serious Adverse Events by Preferred 
Term
3.14.
Safety
Table 8.05
Summary of On-Therapy Treatment-Related Serious Adverse 
Events by Preferred Term
3.15.
Safety
Table 8.07
Summary of On-Therapy Treatment-Related Serious Adverse 
Events by System Organ Class
3.16.
Safety
Table 8.07
Summary of On-Therapy Adverse Events Leading to 
Withdrawal/Permanent Discontinuation of Study Treatment by 
Overall Frequency (By System Organ Class)
3.17.
Safety
Table 8.05
Summary of On-Therapy Adverse Events Leading to 
Withdrawal/Permanent Discontinuation of Study Treatment by 
Overall Frequency (By Preferred Term)
3.18.
Safety
Table 8.18
Summary of On-Therapy Adverse Events of Special Interest
AESI: Defined in PSAP Section 8.6.1.1. 
The identification of AESI will be based on SRT in-
stream, blinded review of AEs
Footnotes of the shell need to be modified according to 
the AESI identified for this study. See RAP Section 
8.2.2.1.
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
3.19.
Safety
EudraCTNon-
serious
Summary of Subjects and Number of Occurrences of Common 
On-therapy Non-Serious Adverse Events by System Organ 
Class and Preferred Term (with Occurrences >=5%)
Total number of subjects having any non-serious AE at 
or above >=5% within any treatment group
3.20.
Safety
EudraCTSAE
Summary of Subjects and Number of Occurrences of On-
therapy Serious, Treatment-related Serious, Fatal Serious,  and 
Treatment-related Fatal Serious Adverse Events by System
Organ Class and Preferred Term
Laboratory Parameters
3.21.
Safety
Table 8.20
Summary of Chemistry by Visit    
3.22.
Safety
LB1
Summary of Chemistry Change from Baseline  by Visit    
Includes Baseline values
3.23.
Safety
Table 8.21
Summary of Hematology by Visit    
3.24.
Safety
LB1
Summary of Hematology Change from Baseline  by Visit    
Includes Baseline values
3.25.
Safety
Table 8.22
Summary of Hematology Data Outside the Reference Range
3.26.
Safety
Table 8.23
Summary of Hematology and Chemistry Data of Potential 
Clinical Importance at Any Time On-Therapy
3.27.
Safety
Table 8.23
Summary of Hematology and Chemistry Data of Potential 
Clinical Importance at Any Time Post-Therapy
. 
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
3.28.
Safety
LB3
Summary of Chemistry Changes from Baseline  Relative to the 
Reference Range (or with Respect to the Normal Range)
Use normal ranges provided by Quest/Q2 as the 
reference ranges. 
On-treatment assessment only
Generate one table for each scheduled visit, and one 
for “any time on-therapy”
See GSK IDSL Laboratory Statistical Display 
Standards, Section 1.2.1 for additional details. 
3.29.
Safety
LB3
Summary of Hematology Changes from Baseline  Relative to the 
Reference Range (or with Respect to the Normal Range)
Use normal ranges provided by Quest/Q2 as the 
reference ranges. 
On-treatment assessment only
Generate one table for each scheduled visit and one 
for “any time on-therapy”.
See GSK IDSL Laboratory Statistical Display 
Standards, Section 1.2.1 for additional details.
ECGs
3.30.
Safety
EG1
Summary of ECG Findings by Visit
3.31.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
Include all ECG parameters collected. 
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Vital Signs
3.32.
Safety
Table 8.25
Summary of Vital Signs by Visit
Summarize both pre and post-dialysis vital signs in 
separate tables
SBP, DBP, Heart Rate, and Weight (Weight is 
measured post-dialysis only)
3.33.
Safety
Table 8.26
Summary of Change from Baseline in Vital Signs by Visit
Summarize both pre and post-dialysis vital signs in 
separate tables
SBP, DBP, Heart Rate, and Weight (Weight is 
measured post-dialysis only)
3.34.
Safety
Table 8.27
Summary of Vital Signs of Potential Clinical Importance at Any 
Time On-therapy
Summarize both pre and post-dialysis vital signs in 
separate tables. 
SBP, DBP, and Heart Rate
Hepatobiliary (Liver)
3.35.
Safety
Example 
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
3.36.
Safety
Example: 
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
Follow the following treatment order:
Placebo, Dapro Total, 10 mg, 15 mg, 25 mg and 30 mg
 
 
 
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11.14.9.
Safety Figures
Safety : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
[Insert Endpoint Category]
3.1.
Safety
F8.02
Most Frequent Adverse Events Sorted by Total Daprodustat 
Proportion 
Remove the RR section in the template. For the 
“Proportion” section, add each Dapro arm in addition to 
Dapro Total and placebo.
3.2.
Safety
F8.23
Boxplot of Liver Function Tests by Visit
3.3.
Safety
F8.24
Matrix Display of Maximum Liver Function Test Values
Y-axis Scale of liver function tests set to a common 
value across pages selected to show the data in the 
range of the clinical concern levels.  Outliers beyond 
the y-axis are described in a footnote.
3.4.
Safety
F8.25
Subject Profiles: Liver Function Test Values
Include subjects who have normal baseline, but have 
any LFT outside normal range any time post-baseline. 
Add "dose" in the plot.
3.5.
Safety
F8.27
Mean and 95% CI for Systolic and Diastolic Blood Pressure by 
Visit
Placebo vs. Dapro Total
Display pre- and post-dialysis BP in separate plots with 
the same figure number
 
 
 
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11.14.10.
Pharmacokinetic Tables
Pharmacokinetic : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
4.1.
Pharmacoki
netic
Table 14.01
Summary of GSK1278863 and Metabolites Plasma 
Pharmacokinetic Concentration Time Data (ng/ml)
4.2.
Pharmacoki
netic
PK Table 4.2
Summarized Daprodustat Plasma Concentrations (ng/mL) by 
Scheduled Time for Each Treatment Group
4.3.
Pharmacoki
netic
PK Table 4.3
Summarized Daprodustat Plasma Pharmacokinetic Parameters 
for Each Treatment Group
11.14.11.
Pharmacokinetic Figures
Pharmacokinetic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
4.1.
Pharmacoki
netic
Figure 14.02
Individual GSK1278863 and Metabolites Plasma Concentration-
Actual Time Plot by Treatment
4.2.
Pharmacoki
netic
Figure 14.03
Mean GSK1278863 and Metabolites Plasma Concentration-
Planned Time Plot (Linear and Semi-Log)
4.3.
Pharmacoki
netic
Figure 14.04
Median GSK1278863 and Metabolites Plasma Concentration-
Planned Time Plot (Linear and Semi-Log)
 
 
 
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11.14.12.
ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Subject Disposition
1.
All Screened
ES7
Listing of Reasons for Screen Failure
For “Did not meet inclusion/exclusion criteria”, the 
corresponding inclusion/exclusion criteria should also 
be reported.
For “Investigator discretion” and “Withdrew consent”, 
the free-text captured in eCRF should also be reported 
with “Investigator discretion” and “Withdrew consent”
2.
All 
Randomized
ES2
Listing of Reasons for Study Withdrawal
See PHI113633 Listing 6.01 about “Subreason”. For 
“Withdrew consent” and “Investigator discretion”, use 
free-text as the subreason. Otherwise, repeat the 
primary reason as the subreason. 
3.
All 
Randomized
Listing 6.02
Listing of Reasons for Study Treatment Discontinuation
Subreason should be displayed with the primary 
reason when it is captured in the eCRF. For example, 
when the primary reason is “Adverse Event” and “GI 
Bleeding” or “Cancer Event” is selected as the 
subreason, then it should be displayed under 
“Subreason”
4.
All 
Randomized
BL1
Listing of Subjects for Whom the Treatment Blind Was Broken
“Remove “Time Blind Broken” from shell if not 
collected. 
5.
All 
Randomized
Listing 6.10
Listing of Randomized and Actual Treatment Assignment
Protocol Deviations
6.
All 
Randomized
Example DV2
Listing of Important Protocol Deviations
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
7.
All 
Randomized 
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
Populations Analyzed
8.
All 
Randomized
SA3a
Listing of Subjects Excluded from Any Populations
Including those excluded from Safety, ITT, Completer, 
PP and PK population
Demography
9.
All 
Randomized
DM2
Listing of Demographic and Baseline Characteristics
The following demographic and baseline 
characteristics will be included in this listing: Year of 
birth, age, age category, sex, ethnicity, Geographic 
Ancestry, Rescreened, Child bearing potential, 
Diabetes,, Weight, Baseline Weight Category, Height, 
BMI,Type of ESA, Standardized Prior ESA dose, 
Standardized Prior ESA Category(actual eCRF value), 
Prior ESA (stratification factor from IVRS), Baseline 
Heart Rate, Baseline Diastolic Blood Pressure, 
Baseline Systolic Blood Pressure, Baseline Hgb, 
Baseline Hgb Category, Baseline Ferritin, Baseline 
Absolute Reticulocyte Count, Baseline Pre-dose 
Plasma Erythropoietin, Baseline iron-based phosphate 
binder (ferric citrate and sucroferric oxyhydroxide), 
Country.
10.
All 
Randomized
Listing 6.08
Listing of Race
Please make sure that the details shown on the 
template will be included in this listing.
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Medical Condition & Concomitant Medications
11.
All 
Randomized
Listing 6.17
Listing of Concomitant Medications
This listing displays all data captured in the
concomitant medications dataset, including 
medications used prior to screening and post-
treatment.
Exposure 
12.
Safety
EX3
Listing of Exposure Data
Efficacy 
13.
ITT
Listing 7.01
Listing of Hemoglobin Data
Hemocue Hgb is not used for calculation of “Change 
from Baseline”. When scheduled Quest Hgb at Day 29 
visit is missing, “Change from Baseline” can be 
calculated using imputed Hgb. Slotted post-treatment 
Hgb cannot be used for calculation of “Change from 
Baseline”
14.
ITT
Listing 7.01
Listing of Hemoglobin Data for Subjects Who Reach Pre-defined 
Hemoglobin Stopping Criteria
Based on the HemoCue Hgb stopping criteria 
described in study protocol Section 5.6.2 Hemoglobin 
Stopping Criteria.
For programming purpose (1) compare Hemocue Hgb 
at a scheduled visit to Hemocue Hgb at previous 
scheduled visit (i.e. compare Day 15 back to Day 1, 
and Day 29 back to Day 15); (2) compare Hemocue 
Hgb at an unscheduled visit to that measured at 
previous scheduled/unscheduled visit within 2 weeks.
Remove the following columns from the template: (1) 
Imputed Day 29 Hgb (2) Change From Baseline
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
15.
ITT
Listing 7.03
Listing of Markers of Iron Metabolism and Utilization
ferritin, hepcidin, total iron binding capacity (TIBC), 
unsaturated iron binding capacity (UIBC), total iron,  
reticulocyte Hgb (CHr),transferrin,  transferrin 
saturation.
“Visit” shown in the listing should be corresponding to 
those in the RAP Section 11.2.1 Protocol Defined Time 
& Events Table
16.
ITT
Listing 7.04
Listing of Indices of Hematopoiesis
hematocrit, RBC (erythrocyte) count and reticulocyte 
count.
“Visit” shown in the listing should be corresponding to 
those in the RAP Section 11.2.1 Protocol Defined Time 
& Events Table
17.
ITT
Listing 7.05
Listing of Plasma Erythropoietin and VEGF Data
See protocol Section 7.1 Table 2 for visit and planned 
timepoint
“Visit” shown in the listing should be corresponding to 
those in the RAP Section 11.2.1 Protocol Defined Time 
& Events Table and PK/PD Time and Events Table
Adverse Events
18.
Safety
AE8
Listing of All Adverse Events
Modification to AE8:Added another line to All “AE8” 
listings to show “Treatment State” (whether a AE is on-
treatment or post-treatment)
19.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
20.
Safety
AE8
Listing of On-therapy Treatment-Related Adverse Events
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
21.
Safety
AE8
Listing of Fatal Adverse Events
22.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
23.
Safety
AE8
Listing of Post-Randomization Treatment-Related Serious 
Adverse Events
24.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal/Permanent 
Discontinuation of Study Treatment
25.
Safety
AE2
Listing of Relationship of Adverse Event System Organ Classes, 
Preferred Terms, and Verbatim Text
26.
Safety
SAE
Listing of Reasons for Considering as a Serious Adverse Event
27.
Safety
Listing 8.20
Listing of Deaths
28.
AE8
Listing of AE of Special Interest
In AE8 template, replace “Preferred Term/VERBATIM 
TEXT” with “AESI Category/Preferred Term”
29.
Safety
Listing 8.10
Listing of MACE Data
MACE data is not collected in a specific eCRF form 
MACE will be collected as AEs, and will be part of 
AESI. AESI will be identified and documented by SRT.
30.
Safety
Listing 8.21
Listing of Cancer Data
31.
Safety
Listing 8.11
Patient Profile Listing of Arrhythmias
32.
Safety
Listing 8.12
Patient Profile Listing of Congestive Heart Failure
33.
Safety
Listing 8.13
Patient Profile Listing of Cerebrovascular 
Events/Stroke/Transient Ischemic Attack
34.
Safety
Listing 8.14
Patient Profile Listing of Deep Venous Thrombosis /Pulmonary 
Embolism
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
35.
Safety
Listing 8.15
Patient Profile Listing of Myocardial Infarction/Unstable Angina
36.
Safety
Listing 8.16
Patient Profile Listing of Peripheral Arterial Thrombosis 
Embolism
37.
Safety
Listing 8.17
Patient Profile Listing of Pulmonary Hypertension
38.
Safety
Listing 8.18
Patient Profile Listing of Revascularisation
39.
Safety
Listing 8.19
Patient Profile Listing of Valvulopathy
Laboratory
40.
Safety
LB5
Listing of Chemistry Data for Subjects with Abnormalities of 
Potential Clinical Importance
41.
Safety
LB5
Listing of Hematology Data for Subjects with Abnormalities of 
Potential Clinical Importance
ECGs
42.
Safety
CP_EG3
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance
See Section 11.8.3 for ECG value of potential clinical 
importance: Increase from baseline QTc > 60 msec
43.
Safety
CP_EG5
Listing of All ECG Findings for Subjects with an Abnormal 
Finding
Vital Signs
44.
Safety
CP_VS4
Listing of All Vital Signs for Subjects with any Value of Potential 
Clinical Importance
Hepatobiliary (Liver)
45.
Safety
Example 
LIVER5
Listing of Liver Event Results and Time of Events Relative to 
Treatment
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
46.
Safety
MH2
Listing of Past and Current Liver Disease Medical Conditions
Data from Liver Form: 1. Medical Conditions at Onset 
of Liver Event. 2. Other Medical Conditions. 3. Other 
Liver Disease Conditions - Liver Event.
47.
Safety
L8.43
SU2
Listing of Alcohol Intake at Time of Liver Event
48.
Safety
Listing 8.44
Listing of Laboratory Data from Liver Event Follow-Up
Pharmacokinetics
49.
Pharmacoki
netic
Listing 14.01
Listing of GSK1278863 and Metabolites Pharmacokinetic 
Plasma Concentration-Time Data
50.
Pharmacoki
netic
PK Parameter 
Listing
Daprodustat Plasma Pharmacokinetic Parameters for Each 
Treatment Group
 
 
 
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11.14.13.
Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Additional listings in 204836
51.
All 
Randomized
Listing 6.09
Listing of Study Populations 
Include All Randomized, ITT, PP, Completers, Safety, 
and PK populations
52.
All 
Randomized
Listing 6.07
Listing of Prior Erythropoiesis Stimulating Agents Medications
53.
All 
Randomized
Listing 6.11
Listing of Current and Past Medical History
54.
All 
Randomized
Listing 6.12
Listing of Cardiovascular Risk Assessment
55.
All 
Randomized
Listing 6.13
Listing of Hemodialysis
Display hemodialysis data captured on “Haemodialysis 
History form (on Day 1) and Haemodialysis on Study 
form at each visit.
56.
All 
Randomized
Listing 6.16
Listing of Substance Use History
We collect smoking data, but do not collect alcohol 
drink data
57.
All 
Randomized
Listing 6.18
Listing of Relationship Between ATC Level 1, Ingredients And 
Verbatim Text
58.
All 
Randomized
Listing 6.19
Listing of Erythropoiesis Stimulating Agents Medications
Including prior, concomitant and post-treatment ESA
59.
All 
Randomized
Listing 6.20
Listing of Iron Therapy
60.
All 
Randomized
Listing 6.22
Listing of Blood Product
61.
All 
Randomized
Listing 6.23
Listing of Study Medication Compliance
 
 
 
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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
62.
ITT
Listing of SAS Output from the Bayesian 3 Parameter Emax 
Dose-Response Model for Hemoglobin Change at Day 29
Will be generated by GSK
63.
Completers
Listing of SAS Output from the Bayesian 3 Parameter Emax 
Dose-Response Model for Hemoglobin Change at Day 29
Will be generated by GSK
64.
ITT
Listing of SAS Output from the Bayesian 3 Parameter Emax 
Dose-Response Model for Hemoglobin Change at Day 29 
(Sensitivity Priors)
Will be generated by GSK
65.
ITT
Listing of SAS Output from the Frequentist 3 Parameter Emax 
Dose-Response Model for Hemoglobin Change at Day 29
Will be generated by GSK
66.
Per Protocol
Listing of SAS Output from the Bayesian 3 Parameter Emax 
Dose-Response Model for Hemoglobin Change at Day 29
Will be generated by GSK
67.
ITT
Listing of SAS Output from the Dose-Response Linear Model for 
Change in Hemoglobin at Day 29
Will be generated by GSK
68.
Completers
Listing of SAS Output from the Dose-Response Linear Model for 
Change in Hemoglobin at Day 29
Will be generated by GSK
69.
Per Protocol
Listing of SAS Output from the Dose-Response Linear Model for 
Change in Hemoglobin at Day 29
Will be generated by GSK
70.
ITT
Listing of SAS Output from the Linear Regression Analysis: Hgb 
response vs. TIW/QD Weekly Dose
Will be generated by GSK
71.
ITT
(PHI113633)
Listing of SAS Output from the Bayesian 3 Parameter Emax 
Dose-Response Model for Change in Hemoglobin at Week 4 
(Based on PHI113633 data excluding Japan)
Will be generated by GSK
72.
ITT
(PHI113633)
Listing of SAS Output from the Frequentist 3 Parameter Emax 
Dose-Response Model for Change in Hemoglobin at Week 4 
(Based on PHI113633 data excluding Japan)
Will be generated by GSK
73.
ITT
(PHI113633)
Listing of SAS Output from Dose-Response Linear Model for 
Change in Hemoglobin at Week 4 (Based on PHI113633 data 
excluding Japan)
Will be generated by GSK
 
 
 
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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
74.
ITT
Listing of SAS Output for Treatment Difference for Hemoglobin 
(g/dL) Change from Baseline at Day 29
75.
Safety
PSRAE1
Listing of Possible Suicidality-Related Adverse Event Data : 
Event and Description (Section 1-Section 2)
76.
Safety
PSRAE3
Listing of Possible Suicidality-Related Adverse Event Data : 
Possible Cause(s) (Section 3)
77.
Safety
PSRAE4
Listing of Possible Suicidality-Related Adverse Event Data 
(Section 4)
78.
Safety
PSRAE5
Listing of Possible Suicidality-Related Adverse Event Data 
(Section 5-Section 8)
79.
Safety 
Listing 8.29
Listing of Chemistry Data
All lab parameters 
“Visit” shown in the listing should be corresponding to 
those in the RAP Section 11.2.1 Protocol Defined Time 
& Events Table
80.
Safety
Listing 8.30
Listing of Hematology Data
All lab parameters 
“Visit” shown in the listing should be corresponding to 
those in the RAP Section 11.2.1 Protocol Defined Time 
& Events Table
81.
Safety
Listing 8.32
Listing of Vital Signs
Include both pre- and post-dialysis vital signs. 
“Visit” shown in the listing should be corresponding to 
those in the RAP Section 11.2.1 Protocol Defined Time 
& Events Table
 
 
 
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