Clinical trial NCT02829320
Conditions: Anaemia
Keywords: efficacy hemodialysis (HD) hemoglobin (Hgb) erythropoiesis-stimulating agents (ESAs) GSK1278863
Sponsor: GlaxoSmithKline
Start date: 2016-08-08; Completion date: 2017-10-17
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This 24-week, Phase 3, open-label, non-comparative, multicentre study aims to evaluate the efficacy and safety of GSK1278863 in Japanese hemodialysis (HD) patients with renal anemia not using erythropoiesis-stimulating agents (ESAs). The primary objective is to evaluate the initial response to GSK1278863 measured by hemoglobin (Hgb) levels in HD patients not using ESAs enrolled in this study. The study is designed to evaluate the appropriateness of the starting dose of GSK1278863 and of the GSK1278863 dose adjustment regimen to achieve or maintain the target Hgb levels. This study will consist of a 4-week screening period, a 24-week treatment period (4-week fixed-dose period and a 20-week dose adjustment period), and a 2- to 4-week follow-up period.

Detailed description:

Arms: arm 1: Subjects will receive GSK1278863 once daily orally at a starting dose of 4 milligrams (mg) on Day 1, and continued until the day of Week 4. From Weeks 4 to 24, interruption of treatment or dose adjustments will be made within the maintenance dose range of 1 mg to 24 mg according to the dose adjustment algorithm to achieve and/or maintain Hgb within the target range (10.0 to 12.0 g/dL) based on the Hgb value measured every 4 weeks. Dose changes will be made every 4 weeks. Iron replacement therapy will be given according to the standard starting criteria.
Interventions: intervention 1: GSK1278863 intervention 2: Iron
Intervention descriptions: intervention 1: GSK1278863 will be provided as round, standard biconvex, white film coated tablets containing 1 mg, 2 mg, 4 mg or 6 mg of GSK1278863 as active ingredient. intervention 2: Subjects will receive supplemental iron therapy if ferritin is \<=100 ng/mL and TSAT is \<=20%. The investigator (or subinvestigator) will choose the route of administration and dose of prescription iron.

Protocol documents:
Prot_000.pdf: 
2015N266250_04 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
PHI204716 
 
- 1 - 
 
TITLE PAGE 
 
Division：Worldwide Development 
Information Type： Clinical Protocol 
 
 
Title：A 24-week, Phase III, open-label, non-comparative, multi-center study to evaluate efficacy and 
safety of GSK1278863 in Japanese hemodialysis subjects with anemia associated with chronic kidney 
disease who are not taking erythropoiesis stimulating agents. 
Compound Number： 
GSK1278863 
Development Phase 
III 
 
Effective Date： 
 
[19-JUL-2017] 
 
Protocol Amendment Number： 
04 
 
Author(s)： 
 
  
 
Amendment History 
GlaxoSmithKline Document 
Number 
Date 
Version 
2015N266250_00 
18-FEB-2016 
First version 
2015N266250_01 
13-MAY-2016 
Amendment 01 
Clarification of study procedures and Update to latest information 
2015N266250_02 
17-AUG-2016 
Amendment 02 
Clarification of inclusion criteri and clarification of study procedures.  
2015N266250_03 
08-MAR-2017 
Amendment 03 
Clarification of the timing of eligibility assessment regarding exclusion criteria, addition of the 
prohibited medication, and correction of adverse events of special interest 
2015N266250_04 
19-JUL-2017 
Amendment 04 
Change for definition of screen failures, clarification of the withdrawal criteria for prohibited 
medication, clarification of definition of overdose of GSK1278863, update of AESI, cancel of the 
interim analysis, update of the category for Hgb change from baseline at Week 4, update and 
correction of risk assessment 
 
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited. 
 
PPD


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


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


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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
[PHI204716 study] 
• 
I confirm agreement to conduct the study in compliance with the protocol and 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 Signature 
 
 
Date 
 
 
 
 


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TABLE OF CONTENTS 
Page 
1. PROTOCOL SYNOPSIS FOR STUDY PHI204716 ........................................................ 9 
2. INTRODUCTION ............................................................................................................ 12 
2.1. 
Study Rationale .................................................................................................... 12 
2.2. 
Background .......................................................................................................... 12 
3. OBJECTIVES AND ENDPOINTS .................................................................................. 13 
4. STUDY DESIGN ............................................................................................................. 14 
4.1. 
Overall Design ...................................................................................................... 14 
4.2. 
Treatment Groups and Study Periods ............................................................... 14 
4.3. 
Target Population and Sample Size ................................................................... 15 
4.4. 
Rationale for the Study Design .......................................................................... 15 
4.5. 
Rationale for the Dosage .................................................................................... 15 
4.6. 
Benefit: Risk Assessment................................................................................... 16 
4.6.1. 
Risk Assessment ........................................................................................ 16 
4.6.2. 
Benefit Assessment .................................................................................... 16 
4.6.3. 
Overall Benefit: Risk Conclusion .............................................................. 17 
5. SUBJECT SELECTION AND WITHDRAWAL CRITERIA ........................................... 18 
5.1. 
Inclusion Criteria.................................................................................................. 18 
5.2. 
Exclusion Criteria ................................................................................................ 19 
5.3. 
Screening Failures ............................................................................................... 20 
5.4. 
Withdrawal Criteria .............................................................................................. 21 
5.4.1. 
Liver Chemistry Stopping Criteria............................................................. 22 
5.4.1.1. 
Study Treatment Restart or Rechallenge......................................... 23 
5.5. 
Subject and Study Completion .......................................................................... 23 
6. STUDY TREATMENTS .................................................................................................. 24 
6.1. 
Investigational Product and Other Study Treatment ....................................... 24 
6.2. 
Treatment Assignment ........................................................................................ 24 
6.3. 
Treatment Schedule ............................................................................................ 24 
6.4. 
Blinding ................................................................................................................. 25 
6.5. 
Packaging and Labeling ...................................................................................... 25 
6.6. 
Preparation/Handling/Storage/Accountability .................................................. 25 
6.7. 
Compliance with Study Treatment Administration .......................................... 26 
6.8. 
Treatment of Study Treatment Overdose .......................................................... 26 
6.9. 
Treatment after the End of the Study ................................................................ 26 
6.10. Concomitant Medications and Non-Drug Therapies ....................................... 27 


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6.10.1. 
Permitted Medications and Non-Drug Therapies .................................... 27 
6.10.2. 
Prohibited Medications and Non-Drug Therapies ................................... 27 
6.11. Supplemental Iron Therapy ................................................................................ 27 
7. Study Assessments and Procedures ......................................................................... 28 
7.1. 
Time and Events Table ........................................................................................ 28 
7.2. 
Screening and Critical Baseline Assessments ................................................ 31 
7.3. 
Efficacy ................................................................................................................. 31 
7.4. 
Safety .................................................................................................................... 31 
7.4.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) .................... 31 
7.4.1.1. 
Time period and Frequency for collecting AE and SAE 
information .......................................................................................... 31 
7.4.1.2. 
Method of Detecting AEs and SAEs ................................................. 32 
7.4.1.3. 
Follow-up of AEs and SAEs .............................................................. 32 
7.4.1.4. 
Cardiovascular and Death Events .................................................... 32 
7.4.1.5. 
Regulatory Reporting Requirements for SAEs ............................... 32 
7.4.2. 
Adverse Events of Special Interest ........................................................... 33 
7.4.3. 
Pregnancy .................................................................................................... 33 
7.4.4. 
Vital Signs/Height/Weight .......................................................................... 33 
7.4.5. 
Electrocardiogram (ECG) ........................................................................... 34 
7.4.6. 
Clinical Laboratory Assessments ............................................................. 34 
7.4.7. 
Ophthalmology ............................................................................................ 35 
7.5. 
Pharmacokinetics ................................................................................................ 35 
7.6. 
Genetics ................................................................................................................ 35 
8. DATA MANAGEMENT .................................................................................................. 36 
9. STATISTICAL CONSIDERATIONS AND DATA ANALYSES ..................................... 36 
9.1. 
Hypotheses ........................................................................................................... 36 
9.2. 
Sample Size Considerations .............................................................................. 36 
9.2.1. 
Sample Size Assumptions ......................................................................... 36 
9.2.2. 
Sample Size Sensitivity .............................................................................. 36 
9.2.3. 
Sample Size Re-estimation or Adjustment............................................... 37 
9.3. 
Data Analysis Considerations ............................................................................ 37 
9.3.1. 
Analysis Populations .................................................................................. 37 
9.3.2. 
Interim Analysis .......................................................................................... 37 
9.3.3. 
Final Analysis .............................................................................................. 37 
9.4. 
Key Elements of Analysis Plan .......................................................................... 37 
9.4.1. 
Efficacy Analysis ......................................................................................... 37 
9.4.1.1. 
Primary Analysis ................................................................................ 37 


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9.4.1.2. 
Secondary Analysis ........................................................................... 37 
9.4.2. 
Safety Analysis ............................................................................................ 38 
9.4.2.1. 
Exposure ............................................................................................. 38 
9.4.2.2. 
Adverse Events ................................................................................... 38 
9.4.2.3. 
Other Safety Measures....................................................................... 38 
9.4.3. 
Pharmacokinetic Analysis ......................................................................... 38 
10. STUDY GOVERNANCE CONSIDERATIONS .............................................................. 39 
10.1. Posting of Information on Publicly Available Clinical Trial Registers ........... 39 
10.2. Regulatory and Ethical Considerations, Including the Informed 
Consent Process.................................................................................................. 39 
10.3. Quality Control (Study Monitoring) .................................................................... 40 
10.4. Quality Assurance ............................................................................................... 40 
10.5. Study and Site Closure ....................................................................................... 40 
10.6. Records Retention ............................................................................................... 41 
10.7. Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ................. 41 
10.8. Study Period ......................................................................................................... 42 
10.9. Study Administrative Structure .......................................................................... 42 
11. REFERENCES ............................................................................................................... 43 
12. APPENDICES ................................................................................................................ 44 
12.1. Appendix 1: Abbreviations and Trademarks .................................................... 44 
12.2. Appendix 2: Risk Assessment ........................................................................... 46 
12.3. Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP ................................................................................................ 53 
12.4. Appendix 4: Collection of Pregnancy Information ........................................... 54 
12.5. Appendix 5: Liver Safety Required Actions and Follow up 
Assessments ........................................................................................................ 55 
12.6. Appendix 6: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events ................................................... 58 
12.6.1. 
Definition of Adverse Events ..................................................................... 58 
12.6.2. 
Definition of Serious Adverse Events ....................................................... 59 
12.6.3. 
Definition of Cardiovascular Events ......................................................... 60 
12.6.4. 
Recording of AEs and SAEs ...................................................................... 60 
12.6.5. 
Evaluating AEs and SAEs .......................................................................... 60 
12.6.6. 
Reporting of SAEs to GSK ......................................................................... 62 
12.7. Appendix 7: Genetic Research ........................................................................... 63 
12.8. Appendix 8: Protocol Changes .......................................................................... 66 


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12.8.1. 
Amendment 1 － Summary of Changes and Rationale ..................... 66 
12.8.2. 
Amendment 2 － Summary of Changes and Rationale ..................... 70 
12.8.3. 
Amendment 3 － Summary of Changes and Rationale ..................... 73 
12.8.4. 
Amendment 4 － Summary of Changes and Rationale ..................... 76 
 


2015N266250_04 
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1. PROTOCOL SYNOPSIS FOR STUDY PHI204716 
 
Rationale 
This Phase 3 clinical study (PHI204716) aims to evaluate the efficacy and safety of GSK1278863 in 
Japanese hemodialysis (HD) patients with renal anemia not using erythropoiesis-stimulating agents 
(ESAs). The primary objective is to evaluate the initial response to GSK1278863 measured by 
hemoglobin (Hgb) levels in HD patients not using ESAs enrolled in this study. The study is designed 
to evaluate the appropriateness of the starting dose of GSK1278863 and of the GSK1278863 dose 
adjustment regimen to achieve or maintain the target Hgb levels. This study is positioned as one of the 
pivotal studies to support for an approval application in Japan for GSK1278863 for the treatment of 
renal anemia. 
 
 
Objective(s)/Endpoint(s) 
Objectives 
Endpoints 
Primary  
• 
To characterize the appropriateness of the 
starting dose of GSK1278863 in HD 
patients not using ESAs 
• 
Change from baseline in Hgb at Week 4 
• 
Number (%) of subjects by Hgb change from 
baseline category at Week 4 
Secondary 
• 
To characterize overall Hgb control of 
GSK1278863 in HD patients not using 
ESAs 
 
• 
Hgb and changes from baseline 
• 
Number (%) of subjects who have a Hgb level 
within the target range (10.0–12.0 g/dL)   
• 
Time (in days) to reach the lower target Hgb 
level (10.0 g/dL)  
• 
Number (%) of subjects who have a Hgb level 
of less than 7.5 g/dL 
• 
Number (%) of subjects who have a Hgb 
increase of more than 2-g/dL over any 4 weeks 
• 
Number (%) of subjects who have a Hgb level 
of more than 13.0 g/dL and number of 
episodes 
• 
To characterize the 
pharmacokinetics (PK) of GSK1278863 
• 
Area Under Curve (AUC) and Maximum 
Concentration (Cmax) of plasma GSK1278863 
• 
To characterize the effect on iron use of 
GSK1278863 in HD patients not using 
ESAs 
• 
Dose of intravenous iron 
• 
Number (%) of subjects who used intravenous 
iron 
• 
To characterize the effect on iron 
metabolism of GSK1278863 in HD 
patients not using ESAs 
 
• 
Change from baseline in ferritin 
• 
Change from baseline in transferrin 
saturation (TSAT)  
• 
Changes from baseline in hepcidin, serum iron, 
and total iron binding capacity (TIBC) 


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Objectives 
Endpoints 
• 
To characterize dose adjustment of 
GSK1278863 in HD patients not using 
ESAs 
• 
Distribution of dose level 
• 
Duration of treatment interruption due to Hgb 
> 13 g/dL 
• 
Frequency of dose adjustments 
Safety 
• 
To assess the safety and tolerability of 
GSK1278863 in HD patients not using 
ESAs 
• 
Incidence and severity of adverse events (AEs) 
and serious adverse events (SAEs), including 
adverse events of special interest (AESIs) 
• 
fs for discontinuation of study medication 
• 
Laboratory tests, Electrocardiogram (ECG), 
vital signs, and ophthalmology assessments 
 
Study Design 
This is a 24-week, Phase 3, open-label, non-comparative, multicentre study to evaluate the efficacy 
and safety of GSK1278863 in Japanese HD patients with renal anemia not using ESAs. Subjects 
meeting the eligibility criteria will receive GSK1278863 orally once daily initially at 4 mg for 4 weeks 
from Day 1. Subsequently, subjects will receive GSK1278863 orally once a day according to a pre-
defined study treatment dose adjustment algorithm to achieve or maintain Hgb within the target range 
(10.0–12.0 g/dL). 
This study will consist of a 4-week screening period, a 24-week treatment period (4-week fixed-dose 
period and a 20-week dose adjustment period), and a 2- to 4-week follow-up period. The study design 
is illustrated as below. . 
 
 
 
 
 
 
 
 
 
 
Screening period 
(4 weeks) 
 
Fixed-dose period 
Dose adjustment period  
(target Hgb 10-12 g/dL)  
(20 weeks) 
 
Follow-up period 
(2–4 weeks) 
 
(4 weeks) 
 
 
 
 
 
 
 
 
 
Patients on 
hemodialysis or 
hemodiafiltration 
not using ESAs 
 
GSK1278863(N=22) 
 
 
 
 
 
 
 
 
 
 
Week -4                Day 1              Week 4                    Week 24              Week 26-28 
 
Study design 
 
Treatment Groups and Study Periods 
 
Screening period (4 weeks) 
After informed consent, subjects meeting the eligibility criteria at screening (Week -4) (Sections 5.1. 
and 5.2.) will be provisionally enrolled. In subjects taking oral iron before participating in the study, 
the iron dose should not be changed during the screening period (intravenous iron should not be used). 


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Fixed-dose period (4 weeks) 
Subjects meeting the eligibility criteria at the start of the treatment period (Day 1) will be formally 
enrolled, and will start administration of oral GSK1278863 once daily at the starting dose of 4 mg. In 
subjects taking oral iron before the study, their iron dose should not be changed during the fixed-dose 
period (intravenous iron should not be used). 
 
Dose adjustment period (20 weeks) 
After the starting fixed-dose period (4 weeks), GSK1278863 will be given orally once daily according 
to the dose adjustment schedule specified in Section 6.3. to achieve or maintain the target Hgb range 
(10.0–12.0 g/dL). Iron replacement therapy will be given according to the standard starting criteria as 
described in Section 6.11. 
 
Follow-up period 
Subjects will return to the study site for follow-up evaluation and observation at 2 to 4 weeks after 
completion or discontinuation of study treatment. During the follow-up period, treatment of renal 
anemia may be given as required at the discretion of the investigator. 
 
Analysis 
There will be no hypothesis testing performed in this study Two-sided 95% confidence intervals will 
be used for efficacy estimation. Since HD patients not using ESAs in Japan are limited, the sample 
size of 22 as enrolled subjects was determined based on feasibility. For the change from baseline in 
Hgb at Week 4, the summary statistics will be calculated, along with the two-sided 95% confidence 
interval based on t-distribution. The change in Hgb at Week 4 will be classified into different 
categories (i.e., -2, >-2 to -1, >-1 to 0, >0 to 1, >1 to 2, and >2 g/dL), and the number (%) of subjects 
in each category will be summarized. 


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2. INTRODUCTION 
GSK1278863 is a member of an emerging new class of drugs called hypoxia-inducible factor prolyl 
hydroxylase inhibitors (HIF-PHI), which act to promote erythropoiesis by a mechanism similar to 
intrinsic response to hypoxia, and is currently investigated for the treatment of renal anemia. 
 
2.1. 
Study Rationale  
This Phase 3 clinical study (PHI204716) aims to evaluate the efficacy and safety of GSK1278863 in 
Japanese HD patients with renal anemia not using ESAs. The primary objective is to evaluate the 
initial response to GSK1278863 measured by Hgb levels in HD patients not using ESAs enrolled in 
this study. The study is designed to evaluate the appropriateness of the starting dose of GSK1278863 
and of the GSK1278863 dose adjustment regimen to achieve or maintain the target Hgb levels. This 
study is positioned as one of the pivotal studies to support for an approval application in Japan for 
GSK1278863 for the treatment of renal anemia. 
 
2.2. 
Background 
Renal anemia is diagnosed commonly in chronic kidney disease (CKD) patients, and advanced CKD 
is associated with a higher prevalence of renal anemia [Akizawa, 2011]. Causes of anemia in CKD 
patients include absolute or relative deficiency of erythropoietin (EPO), shortened red cell life-span, 
and decreased iron availability. Anemia can further worsen because of dialysis-related chronic 
exsanguination, infection, functional hemolysis, etc. [Tsubakihara, 2010]. 
 
GSK1278863 is an HIF-PHI being investigated for the treatment of renal anemia. GSK1278863 has 
been clinically evaluated as 4-week therapy in a Japanese Phase 2 study in Japanese HD patients 
(PHI116099; 97 Japanese), 24-week therapy in a global Phase 2 study in HD patients (PHI113633; 
including 24 Japanese), and 24-week therapy in a global Phase 2 study in non dialysis (ND) patients 
(PHI113747; including 42 Japanese). Clinical data from these studies demonstrate that GSK1278863 
can increase endogenous EPO, reduce hepcidin, and increase Hgb in HD patients and ND patients 
including Japanese. Data suggest the increases in Hgb with GSK1278863 are achieved at blood EPO 
levels lower than those observed with ESAs. 
 
Data from completed clinical and clinical pharmacology studies and the pre-clinical data safety 
package are provided in the Development Core Safety Information found in the current GSK1278863 
Investigator’s Brochure. A benefit-risk assessment, including risk mitigation strategies, is outlined in 
Section 4.6. 
 


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3. OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary  
• 
To characterize the appropriateness of the 
starting dose of GSK1278863 in HD 
patients not using ESAs 
• 
Change from baseline in Hgb at Week 4 
• 
Number (%) of subjects by Hgb change from 
baseline category at Week 4 
Secondary  
• 
To characterize overall Hgb control of 
GSK1278863 in HD patients not using 
ESAs 
 
• 
Hgb and changes from baseline  
• 
Number (%) of subjects who have a Hgb level 
within the target range (10.0–12.0 g/dL)   
• 
Time (in days) to reach the lower target Hgb 
level (10.0 g/dL)  
• 
Number (%) of subjects who have a Hgb level 
of less than 7.5 g/dL 
• 
Number (%) of subjects who have a Hgb 
increase of more than 2 g/dL over any 4 weeks 
• 
Number (%) of subjects who have a Hgb level 
of more than 13.0 g/dL and number of 
episodes 
• 
To characterize the PK of GSK1278863 
• 
AUC and Cmax of plasma GSK1278863 
• 
To characterize the effect on iron use of 
GSK1278863 
• 
Dose of intravenous iron 
• 
Number (%) of subjects who used intravenous 
iron 
• 
To characterize the effect on iron 
metabolism of GSK1278863 
 
• 
Change from baseline in ferritin  
• 
Change from baseline in TSAT  
• 
Changes from baseline in hepcidin, serum iron, 
and TIBC 
• 
To characterize dose adjustment of 
GSK1278863 
• 
Distribution of dose level 
• 
Duration of treatment interruption due to Hgb 
> 13 g/dL 
• 
Frequency of dose adjustments 
Safety 
• 
To assess the safety and tolerability of 
GSK1278863 
• 
Incidence and severity of AEs and SAEs, 
including AESIs 
• 
Reasons for discontinuation of study 
medication 
• 
Laboratory tests, ECG, vital signs, and 
ophthalmology assessments 


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4. STUDY DESIGN 
4.1. 
Overall Design 
This is a 24-week, Phase 3, open-label, non-comparative, multicentre study to evaluate the efficacy 
and safety of GSK1278863 in Japanese HD patients with renal anemia not using ESAs. Subjects 
meeting the eligibility criteria will receive GSK1278863 orally once daily initially at 4 mg for 4 weeks 
from Day 1. Subsequently, subjects will receive GSK1278863 orally once a day according to a pre-
defined study treatment dose adjustment algorithm to achieve or maintain Hgb within the target range 
(10.0–12.0 g/dL). 
This study will consist of a 4-week screening period, a 24-week treatment period (4-week fixed-dose 
period and a 20-week dose adjustment period), and a 2- to 4-week follow-up period. The study design 
is illustrated in Figure 1. 
 
 
 
 
 
 
 
 
 
 
Screening period 
(4 weeks) 
 
Fixed-dose period 
Dose adjustment period  
(target Hgb 10-12 g/dL)  
(20 weeks) 
 
Follow-up period 
(2–4 weeks) 
 
(4 weeks) 
 
 
 
 
 
 
 
 
 
Patients on 
hemodialysis or 
hemodiafiltration 
not using ESAs 
 
GSK1278863(N=22) 
 
 
 
 
 
 
 
 
 
 
Week -4                Day 1              Week 4                    Week 24              Week 26-28 
 
Figure 1    Study design 
 
4.2. 
Treatment Groups and Study Periods 
Individual study periods and study treatment are detailed below. A point-of-care Hgb measurement 
device (i.e., HemoCue®) will be uniformly used to measure Hgb for determination of subject 
eligibility, assessment against withdrawal criteria, and GSK1278863 dose adjustment in this study. 
 
Screening period (4 weeks) 
After informed consent, subjects meeting the eligibility criteria at screening (Week -4) (Sections 5.1. 
and 5.2.) will be provisionally enrolled. In subjects taking oral iron before participating in the study, 
the iron dose should not be changed during the screening period (intravenous iron should not be used). 
 
Fixed-dose period (4 weeks) 
Subjects meeting the eligibility criteria at the start of the treatment period (Day 1) will be formally 
enrolled, and will start administration of oral GSK1278863 once daily at the starting dose of 4 mg. In 
subjects taking oral iron before the study, their iron dose should not be changed during the fixed-dose 
period (intravenous iron should not be used). 
 
Dose adjustment period (20 weeks) 
After the starting fixed-dose period (4 weeks), GSK1278863 will be given orally once daily according 
to the dose adjustment schedule specified in Section 6.3. to achieve or maintain the target Hgb range 


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(10.0–12.0 g/dL). Iron replacement therapy will be given according to the standard starting criteria as 
described in Section 6.11. 
 
Follow-up period 
Subjects will return to the study site for follow-up evaluation and observation at 2 to 4 weeks after 
completion or discontinuation of study treatment. During the follow-up period, treatment of renal 
anemia may be given as required at the discretion of the investigator. 
 
4.3. 
Target Population and Sample Size 
This study will enrol at least 22 Japanese HD patients with renal anemia not using ESAs. Assuming a 
25% drop-out rate during the screening period, approximately 30 patients should be screened. 
Assuming a 20% drop-out rate after the start of study treatment, the number of subjects who complete 
the 24-week study treatment is estimated to be 17. 
 
Table 1   Target Sample Size 
Screened 
30 
Enrolled 
22 
Completed fixed-dose period (Week 4) 
20 
Completed dose adjustment period (Week 24) 
17 
 
4.4. 
Rationale for the Study Design 
This is a Phase 3 study to evaluate the efficacy and safety of GSK1278863 in Japanese HD patients 
with renal anemia not using ESAs. The primary objective is to evaluate the initial response to 
GSK1278863 in HD patients not using ESAs. The target Hgb in this study range has been set with 
reference to the 2008 Japanese guideline for renal anemia in chronic kidney disease, issued by the 
Japanese Society for Dialysis Therapy [Tsubakihara, 2010]. The study has been designed to evaluate 
the appropriateness of the starting dose of GSK1278863 and of the GSK1278863 dose adjustment 
regimen to achieve or maintain the target Hgb levels. 
 
4.5. 
Rationale for the Dosage 
GSK1278863 starting dose and dose adjustment 
The starting dose of GSK1278863 (4 mg) and the dose adjustment steps (maintenance dose range, 1–
24 mg) are described in Section 6.3. 
The GSK1278863 starting dose and the dose adjustment algorithm selected for this study in Japanese 
HD patients not using ESAs are based on the analysis results of longitudinal modelling of Hgb data 
and clinical data from a total of 6 Phase 2 studies conducted inside or outside Japan (PHI112844, 
PHI116581, PHI116582, PHI113633, PHI113747, and PHI116099). The data set used in the model 
analysis included GSK1278863 therapy data in a wide dose range (0–25 mg) from the studies, 
including the 4-week Japanese Phase 2 study (PHI116099) and 24-week global Phase 2b studies 
which Japanese subjects participated in (PHI113633 and PHI113747). 
 
Starting dose 
The longitudinal model simulation results and clinical study results from HD patients indicated that, in 
patients not using ESAs, 4 mg is the dose of GSK1278863 producing a modest increase in the Hgb 


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level (mean, 0.5 g/dL) without rapid increase by > 2 g/dL after 4 weeks of therapy. Covariate analyses 
elucidated that baseline Hgb, body weight, and prior ESA dose were the most relevant covariates of 
Hgb response to GSK1278863. However, the effect of these factors was smaller than the effect of 
inter-individual variability in the response to GSK1278863. Thus, the appropriate starting dose of 
GSK1278863 was considered to be 4 mg. 
 
Maintenance dose range and dose adjustment algorithm 
The longitudinal model simulation results indicated that the response to GSK1278863 greatly varies 
among different subjects, and the doses required to achieve and maintain the target Hgb levels range 
from 1 to 24 mg. Using 4 mg as the standard dose in patients with a standard therapeutic response, 8 
different maintenance doses (1, 2, 4, 6, 8, 12, 18, 24 mg) were selected. 
The dose adjustment algorithm was selected to maintain the target Hgb range (10.0–12.0 g/dL), which 
was set in line with the Japanese Guideline for Renal Anemia in Chronic Kidney Disease[Tsubakihara, 
2010]. Since the guideline recommends that the Hgb increase per week should be limited to  0.5 g/dL 
for prevention of adverse reactions, if the Hgb level shows a > 2 g/dL increase over the past 4 weeks, 
the dose will be reduced to the next lower dose level. In subjects with Hgb levels warranting 
improvement of anemia ( 7.5, < 10.0 g/dL), if the increase over the past 4 weeks is within 0.5–2 g/dL, 
the dose will be maintained, and if the increase over the past 4 weeks is < 0.5 g/dL, the dose will be 
increased to the next higher dose level. 
 
4.6. 
Benefit: Risk Assessment 
Summaries of findings from clinical and nonclinical studies of GSK1278863 can be found in the 
Investigator’s Brochure (IB) and IB supplement. The risk assessment and risk minimization strategies 
for the present study are outlined in the following sections:  
 
4.6.1. 
Risk Assessment 
Based on the results of completed clinical and nonclinical studies of GSK1278863, the potential risks 
of clinical significance and the risk minimization strategies for the present study are outlined in 
Section 12.2. 
 
4.6.2. 
Benefit Assessment  
Study PHI204716 is a Phase 3 study in Japanese HD subjects with renal anemia not using ESAs. 
Previous clinical studies of GSK1278863 administered for up to 24 weeks in ND or HD subjects have 
demonstrated clinical efficacy (increase in and/or maintenance of Hgb) with serum EPO 
concentrations increased within the normal physiologic range in CKD subjects. Data obtained in 
Study PHI204716 will evaluate safety and efficacy data in Japanese HD subjects with renal anemia 
who are not using ESA, for a 24-week treatment period. Study participants who will receive 
GSK1278863 may benefit from the expected clinical efficacy.  
GSK1278863 may have important advantages over existing ESAs. GSK1278863, which is orally 
administered and requires no cold chain management unlike ESAs, is more convenient to patients. 
GSK1278863 is shown to increase Hgb at lower EPO concentrations than ESAs. Since increased 
exposure to EPO following administration of ESAs may be associated with an increased 


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cardiovascular (CV) risk [Szczech, 2008], GSK1278863 may increase Hgb without increasing the CV 
risk.  
 
4.6.3. 
Overall Benefit: Risk Conclusion 
GSK1278863 is shown to have a positive benefit-risk balance based on the following findings: in 
studies of GSK1278863 administered for up to 24 weeks, treatment with GSK1278863 resulted in 
achievement of target Hgb, and no adverse events have been identified as related to treatment with 
GSK1278863.  
 
The present study is intended to evaluate the efficacy and safety of GSK1278863 administered for 24 
weeks in Japanese HD subjects with renal anemia who are not using ESA, and designed to administer 
GSK1278863 to all enrolled subjects; therefore, subjects enrolled are expected to benefit from the 
treatment.  
 
This protocol employs precautions to mitigate known and potential risks to enrolled subjects (see 
Section 12.2.). Given these precautions, as well as the potential benefit that GSK1278863 holds for the 
treatment of renal anemia compared with the current standard treatment, the overall benefit-risk 
balance is considered to be positive.  
 


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5. SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
Specific information regarding warnings, precautions, contraindications, adverse events, and other 
pertinent information on the study treatment, which is possible to affect subject’s eligibility, is 
provided in the Investigator’s Brochure (IB)/IB supplement(s) and other pertinent documents. 
 
Deviations from inclusion and exclusion criteria are not allowed because compliance with the 
protocol-specified inclusion and exclusion criteria is most important from the viewpoints of scientific 
integrity of the study, regulatory acceptability or subject safety. 
 
5.1. 
Inclusion Criteria  
A subject will be eligible for inclusion in this study only if all of the following criteria apply at 
provisional enrollment (Screening) and formal enrollment (Day 1) unless otherwise specified. 
 
1. 
Age (at the time of informed consent): 20 years 
2. 
Dialysis: Patients on HD or hemodiafiltration (HDF) 
3. 
Use of any ESA:  
• 
Newly started dialysis (Dialysis newly started < 12 weeks before screening): Patients not 
using ESAs after the start of dialysis 
• 
Maintenance dialysis (Dialysis started  12 weeks before screening): Patients not using 
ESAs within 8 weeks before screening [including patients who are on treament/interruption 
of ESA theyapy and planned to intruppt ESA therapy for at least 8 weeks prior to Screening 
exam (at the time of informed consent)]  
4. 
Hemoglobin (Hgb):  8.0 to < 10.0 g/dL [measured using a point-of-care Hgb measurement 
device (HemoCue) at the study site on Day 1] 
5. 
Iron parameter: Ferritin > 100 ng/mL or TSAT > 20% (at screening only)  
6. 
Gender (at screening only): Female or male 
A female subject is eligible to participate if she is not pregnant (as confirmed by a negative 
serum human chorionic gonadotropin [hCG] test for females of reproductive potential [FRP] 
only), not breastfeeding, and at least one of the following conditions applies: 
1） Females of non-reproductive potential defined as: 
• 
Pre-menopausal with one of the following and no plans to utilise assisted reproductive 
techniques (e.g., in vitro fertilisation or donor embryo transfer): 
• 
documented bilateral tubal ligation or salpingectomy 
• 
documented hysteroscopic tube occlusion procedure with follow-up confirmation of 
bilateral tubal occlusion 
• 
documented hysterectomy 
• 
documented bilateral oophorectomy 
• 
Post-menopausal defined as 1) females 60 years of age or older or 2) In females < 60 years 
of age, 12 months of spontaneous amenorrhea [In questionable cases, a blood sample with 
simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with 
menopause is confirmatory (the reference values are provided separately)]. 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 


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their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
post-menopausal status prior to study enrollment. 
2） Females of reproductive potential who agree to follow one of the options listed in the “GSK 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (Section 12.3.)” from 28 days before the first dose of study treatment 
until completion of the follow-up visit.  
7. 
Informed consent: Subjects who can provide written informed consent to the study, involving 
compliance with the requirements and patient responsibilities stated in the consent form and the 
protocol, as described in Section 10. 
 
5.2. 
Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria apply at 
provisional enrollment (Screening) or formal enrollment (Day 1) unless otherwise specified. 
 
CKD related criteria 
1. 
Kidney transplant: Planned living kidney transplant during the study period 
 
Anemia-related criteria 
2. 
Aplasia: History of bone marrow aplasia or pure red cell aplasia 
3. 
Other causes of anemia: Pernicious anemia, thalassaemia, sickle cell disease, or myelodysplastic 
syndrome 
4. 
Gastrointestinal bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal ulcer 
disease or clinically significant gastrointestinal bleeding within 8 weeks before screening or 
during a period from screening to Day 1. 
 
Cardiovascular disease-related criteria 
5. 
History of myocardial infarction, acute coronary syndrome, stroke or transient ischemic attack: 
Diagnosed within 8 weeks before screening or during a period from screening to Day 1. 
6. 
Heart failure: Class IV heart failure, as defined by the New York Heart Association (NYHA) 
functional classification system 
7. 
Q-T Interval Corrected for Heart Rate (QTc) (at screening only): QTc > 500 msec, or QTc > 530 
msec in subject with bundle branch block 
Note: Corrected QT interval using Bazett’s formula (QTcB) (machine-read or manually) will be 
used. 
 
Other disease-related criteria 
8. 
Liver disease (if any of the following occurs): 
• 
(Screening verification only): Alanine Aminotransferase (ALT) > 2 x upper limit of 
normal (ULN) 
• 
(Screening verification only): Bilirubin > 1.5 x ULN (If bilirubin fractions are measured and 
direct bilirubin is < 35%, isolated bilirubin > 1.5 x ULN will be acceptable.) 


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• 
Current unstable active liver or biliary disease (generally defined by the onset of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, persistent 
jaundice, or cirrhosis) 
Note: Stable liver disease (including asymptomatic gallstones, chronic hepatitis B/C, or 
Gilbert’s syndrome) is acceptable if the subject otherwise meets entry criteria. 
9. 
Malignancy: History of malignancy within the two years prior to screening, known complex 
kidney cyst > 3 cm (II F, III or IV based on the Bosniak classification) or currently receiving 
treatment for cancer. 
Note: The only exception is squamous cell or basal cell carcinoma of the skin that has been 
definitively treated  8 weeks before screening. 
 
Concomitant medications and other study treatment-related criteria 
10. Iron medication: Planned use of any intravenous iron preparation during the screening period or 
from Day 1 to Week 4 
Note: 
• 
Patients on oral iron may be enrolled if the iron dose regimen is unchanged during the 
screening period and from Day 1 to Week 4. 
• 
Patients on anti-hyperphosphatemia medication containing iron (e.g., ferric citrate 
hydrate) for at least 12 weeks before screening may be enrolled if the medication is 
continued during the screening and from Day 1 to Week 4. 
11. Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity 
to any excipients in the investigational product (see GSK1278863 Investigator’s Brochure) 
12. Drugs and dietary supplements: Current use of prohibited prescription drugs, non-prescription 
drugs, or dietary supplements or planned use of any of these drugs during the study period 
(prohibited drugs: strong Cytochrome P450 (CYP2C8) inducers and inhibitors; see Section 
6.10.2.) 
13. Exposure to any other investigational product: Use of an investigational product within the past 
30 days or five half lives of that investigational product (whichever is longer). 
14. Prior treatment with GSK1278863: Prior treatment with GSK1278863 for > 30 days 
 
General health-related criteria 
15. 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. 
 
5.3. 
Screening Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial, but are not 
subsequently officially enrolled in the study. A minimum set of information including Demography, 
Screen Failure details, Eligibility Criteria, and SAEs is required from screen failure subjects in order 
to report screen failures in a reliable manner, satisfy the requirements for publication defined by the 
Consolidated Standards of Reporting Trials (CONSORT), and respond to requests of the regulatory 
authorities.  


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Subjects that fail screening are eligible to be rescreened up to 3 times as soon as the investigator (or 
subinvestigator) assesses they may meet study entry criteria.  In the rescreening case, the re-exams of 
the ophthalmology at the rescreening are not required if the investigator judges it appropriate to use 
the previous screening result (see Table 6).   
 
5.4. 
Withdrawal Criteria 
If subjects meet one of the following criteria, study treatment should be permanently discontinued and 
withdrawal reason should be recorded.  
 
• 
Hgb <7.5 g/dL 
Note: HemoCue Hgb values will be employed. If an initial Hgb value meets the Hgb stopping 
criteria, measurement will be repeated at the same study visit (using the same sample) to 
calculate the average. If the average meets the Hgb stopping criteria, study treatment will be 
discontinued.  
• 
Kidney transplant 
• 
Subject becomes pregnant or intends to become pregnant during the study. 
• 
Diagnosis of new or recurrent cancer 
• 
Liver chemistry abnormalities exceeding the threshold criteria (see Section 5.4.1.)  
• 
Need for chronic (more than 14 days) use of prohibited medication (strong inhibitors/ inducers of 
CYP2C8 meet this criteria) 
• 
When the investigator (or subinvestigator) considers necessary to withdraw the subject from the 
study for other reasons  
 
Subjects who meet any of the withdrawal criteria or are withdrawn for other reasons during the 
treatment phase should be assessed at withdrawal visit after study treatment is discontinued, and will 
then enter the follow-up phase.  
Should a subject fail to attend a required study visit, the investigator (or subinvestigator) should take 
the following measures:  
• 
The investigator (or subinvestigator) or designee should attempt to contact the subject and re-
schedule the missed visit as soon as possible.  
• 
The investigator (or subinvestigator) should counsel the subject on the importance of maintaining 
the assigned visit schedule and determine whether the subject is willing to continue his/her 
participation in the study and/or whether the subject should remain in the study.  
• 
The investigator (or subinvestigator) or designee should make every effort to regain contact with 
a subject who is deemed “Lost to Follow-up”. All efforts to contact the subject should be 
documented in the subject’s clinical charts.  
• 
Should the subject continue to be unreachable, then and only then will he/she be considered 
“Lost to Follow-up.” 
 
A subject may withdraw from the study at any time at his/her own request. The investigator (or 
subinvestigator) may withdraw a subject from the study at any time for safety or compliance reasons 
or study conduct considerations. If a subject withdraws from the study, he/she may request destruction 


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of any clinical samples taken, and the investigator (or subinvestigator) must document this in the site 
study records. 
 
5.4.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to assure subject 
safety and evaluate liver event etiology (in alignment with the Food and Drug Administration [FDA] 
premarketing clinical liver safety guidance). 
 
Liver Chemistry Stopping and Increased Monitoring Algorithm 
 
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
➢Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
➢Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
 
 


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Liver Chemistry Increased Monitoring Algorithm with Continued Therapy for ALT 3xULN 
but <8xULN 
 
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
➢Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
➢Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
➢Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
 
Liver Safety Required Actions and Follow up Assessments can be found in Section 12.5. 
 
5.4.1.1. 
Study Treatment Restart or Rechallenge 
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by any subject 
participating in this study is not allowed. 
 
5.5. 
Subject and Study Completion 
A completed subject is one who has completed all periods of the study including the follow-up visit. 
The study will be completed with the last subject’s last study visit.  
 


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6. STUDY TREATMENTS 
6.1. 
Investigational Product and Other Study Treatment 
The term ‘study treatment’ is used throughout the protocol to describe any products received by the 
subject as per the protocol design.  
 
The study drug GSK1278863 will be supplied as fast-release film coated tablets for oral 
administration containing 1 mg, 2 mg, 4 mg, or 6 mg of GSK1278863 (Table 2). There are two sizes 
of GSK1278863 tablets. 
 
Table 2   Description of GSK1278863 Tablets 
GSK1278863 tablets of specific 
content 
Description 
1 mg tablets, 2 mg tablets, 4 mg 
tablets 
7.0 mm round, standard biconvex, white film coated tablets containing 1 mg, 2 mg, 
or 4 mg of GSK1278863 as active ingredient 
6 mg tablets 
9.0 mm round, standard biconvex, white film coated tablets containing 6 mg of 
GSK1278863 as active ingredient 
 
GSK1278863 tablets of specific content are packed in high density polyethylene (HDPE) bottles, with 
35 tablets per bottle. Subjects are to take one to four tablets (Table 3) with water once daily according 
to the dose level indicated at each study visit. Subjects can take GSK1278863 tablets without regard to 
food or hemodialysis. The administration schedule (starting dose and dose adjustment) described in 
Section 6.3. should be followed.  
 
Table 3    Dose Levels of GSK1278863 and Number of Tablets Taken 
Dose level of 
GSK1278863 
(once daily) 
1 mg 
2 mg 
4 mg 
6 mg 
8 mg 
12 mg 
18 mg 
24 mg 
Number of 
GSK1278863 
tablets taken 
1 mg tablet 
×1 
2 mg tablet 
×1 
4 mg tablet 
×1 
6 mg tablet 
×1 
4 mg tablet 
×2 
6 mg tablet 
×2 
6 mg tablet 
×3 
6 mg  
tablet 
×4 
 
Subjects should be instructed to bring GSK1278863 tablets with bottles at each study visit, and all 
unused GSK1278863 tablets will be collected from subjects at each study visit. 
 
6.2. 
Treatment Assignment 
This is an open-label, non-comparative study. All eligible subjects will take GSK1278863. Refer to 
Study Reference Manual (SRM) regarding details such as allocation of randomization number. 
 
6.3. 
Treatment Schedule 
Starting dose (Day 1 to Week 4) 
In the Japanese HD patients not using ESAs enrolled in the study, oral administration of GSK1278863 
once daily at the starting dose of 4 mg will be started (Day 1), and continued until the day of Week 4. 
 


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Maintenance Dose (Week 4 to Week 24) 
From Weeks 4 to 24, interruption of treatment or dose adjustments will be made within the 
maintenance dose range of 1-24 mg (Table 4) according to the dose adjustment algorithm (Table 5) to 
achieve and/or maintain Hgb within the target range (10.0-12.0 g/dL) based on the HemoCue Hgb 
value measured every 4 weeks. Dose changes will be made every 4 weeks. If any of the one-step dose 
reduction criteria is met during treatment at the minimum maintenance dose (1 mg), treatment should 
be interrupted; once the one-step dose increase criteria are met, treatment at 1 mg will be resumed. If 
the one-step dose increase criterion is met during treatment at the maximum maintenance dose 
(24 mg), treatment at 24 mg should be continued.  
 
Table 4    Maintenance Dose of GSK1278863 
Dose step 
1 
2 
3 
4 
5 
6 
7 
8 
Dose level of 
GSK1278863 
(once daily) 
1 mg 
2 mg 
4 mg 
6 mg 
8 mg 
12 mg 
18 mg 
24 mg 
Number of 
GSK1278863 
tablets taken 
1 mg tablet 
×1 
2 mg tablet 
×1 
4 mg tablet 
×1 
6 mg tablet 
×1 
4 mg tablet 
×2 
6 mg tablet 
×2 
6 mg tablet 
×3 
6 mg tablet 
×4 
 
Table 5   Dose Adjustment Algorithm (GSK1278863) 
Hgb 
(g/dL) 
Hgb increase over 4 weeks 
(g/dL) 
Treatment 
>13.0 
NA 
Interrupt treatment until Hgb decreases to less than 
12.0 g/dL 
Resume treatment at the one lower dose level (resume 
treatment at 1 mg once the one-step dose increase criteria 
are met, if interrupted at 1 mg ) 
12.0-13.0 
NA 
One-step dose reduction 
10.0-<12.0 
>2.0 
One-step dose reduction 
 
2.0 
Continue treatment at the current dose level 
7.5-<10.0 
>2.0 
One-step dose reduction 
 
0.5-2.0 
Continue treatment at the current dose level 
 
<0.5 
One-step dose increase 
<7.5 
NA 
Discontinue treatment permanently * and initiate another 
appropriate treatment 
*: If an initial Hgb value is less than 7.5 g/dL, measurement will be repeated at the same study visit (using the same sample) to 
calculate the average. If the average meets the Hgb stopping criteria, study treatment will be discontinued. 
 
6.4. 
Blinding 
This is an open-label study.  
 
6.5. 
Packaging and Labeling 
The contents of the label will be in accordance with all applicable regulatory requirements. 
 
6.6. 
Preparation/Handling/Storage/Accountability 
• 
No special preparation of study treatment is required.  


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• 
Only subjects enrolled in the study may receive study treatment and only authorized site staff 
may supply study treatment. All study medications must be stored in a secure environmentally 
controlled and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator (or subinvestigator) and authorized site staff. 
• 
Subjects must bring all of supplied study medication bottles of GSK1278863 at each study visit. 
Study staff will collect all of study medication bottles supplied at the previous study visit and 
supply new study medication bottles.  
• 
The investigator (or subinvestigator), institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).  
• 
Under normal conditions of handling and administration, study medication is not expected to 
pose significant safety risks to site staff. GSK will provide an information related to  
occupational hazards and recommended handling precautions either to the investigator (or 
subinvestigator) when necessary or upon request of the medical institution.  
• 
Further details are provided in the SRM.  
 
6.7. 
Compliance with Study Treatment Administration 
Since GSK1278863 is self-administered, compliance with GSK1278863 treatment will be assessed 
through an interview with subjects at each study visit and recorded in the source document and eCRF. 
A record of the number of GSK1278863 tablets dispensed to and taken by each subject will be 
maintained and reconciled with study treatment and compliance records. In addition, the number of 
GSK1278863 doses dispensed, used, and unused, as well as study treatment start and stop dates will 
be recorded in the eCRF (the number of doses returned and unreturned will also be recorded 
separately). 
6.8. 
Treatment of Study Treatment Overdose 
In this study, an overdose of GSK1278863 is defined as any dose greater than the highest daily dose 
included in the protocol. There is no specific antidote for overdose with GSK1278863. The expected 
manifestations of GSK1278863 overdosage include signs and symptoms associated with an excessive 
and/or rapid increase in Hgb concentration. GSK1278863 is highly protein bound; thus, clearance of 
GSK1278863 by hemodialysis or peritoneal dialysis is very low and this is not an effective method to 
enhance the elimination of GSK1278863. GSK1278863 metabolites are, in part, cleared via 
hemodialysis. In the event of a suspected overdose, it is recommended that the appropriate supportive 
clinical care be instituted, as dictated by the subject’s clinical status. Additionally, subjects should be 
monitored closely for CV events, increased heart rate and hematologic abnormalities. 
 
6.9. 
Treatment after the End of the Study 
Since the target disease studied is not life-threatening or severely debilitating and there are alternative 
treatments for the target disease, subjects will not receive any additional treatment from GSK after 
completion of the study. Regardless of whether the sponsor provides specific treatments after the 
completion of the study, the investigator (or subinvestigator) is responsible for ensuring that 
consideration has been given to post-study care of the subject’s medical condition.  
 


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6.10. Concomitant Medications and Non-Drug Therapies 
Concomitant medications, including over-the-counter medications and supplements, taken during the 
study will be recorded in the eCRF. Start/stop dates will be recorded for general concomitant 
medications, while additional details, including dose, route of administration, and dosing frequency, 
will be recorded for certain medications (e.g., ESAs, iron). Refer to SRM for further details. 
 
6.10.1. 
Permitted Medications and Non-Drug Therapies 
Unless specified as a prohibited medication in Section 6.10.2, all concomitant medications should be 
considered permitted provided they are not contraindicated for the individual subject concerned. 
Regular multivitamins (at recommended daily allowance) and other supplements such as calcium and 
vitamin D may be used if permitted by the investigator or his/her designee.  
CYP2C8 is involved in the primary route of metabolism of GSK1278863. Accordingly, co-
administration of GSK1278863 with moderate CYP2C8 inhibitors (e.g., clopidogrel, teriflunomide, 
deferasirox) should be performed with caution. If one of these medications is started, stopped or the 
dose is changed, Hgb should be monitored every 4 weeks for 12 weeks using a point-of-care Hgb 
analyzer (Hemocue).  
Antihyperphosphatemic agents containing iron (e.g., ferric citrate hydrate) may be started from 
Week 4 onwards unless any other antihyperphosphatemic agents are appropriate. Once started, iron-
containing antihyperphosphatemic agents should be continued until the end of the study wherever 
possible.  
 
6.10.2. 
Prohibited Medications and Non-Drug Therapies 
Use of any of the following drugs from screening until 7 days after the last dose of study treatment is 
prohibited: 
• 
Strong inhibitors of CYP2C8 (e.g., gemfibrozil) 
• 
Strong inducers of CYP2C8 (e.g., rifampin/rifampicin) 
 
Use of the following drug; from HD induction until the end of the treatment period for newly started 
dialysis, from 8 weeks prior to screening until the end of the treatment period for maintenance HD: 
• 
Erythropoietin (e.g., epoetin/ darbepoetin alfa/ epoetin beta pegol) 
 
6.11. Supplemental Iron Therapy 
Supplemental iron therapy will be administered if ferritin is ≤100 ng/mL and TSAT is ≤20%, 
according to the Guidelines for Renal Anemia [Tsubakihara, 2010]. The investigator (or 
subinvestigator) should choose the route of administration and dose of prescription iron.  
 


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7. Study Assessments and Procedures 
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the Time and 
Events Table, are essential and required for study conduct. 
 
7.1. 
Time and Events Table 
Time and Events Tables are provided in Table 6 and Table 7 for the overall study and for 
pharmacokinetic assessments. For subjects on dialysis twice or more per week, throughout the study 
period, including the screening, treatment and follow-up periods, the study visit days should occur on 
the first dialysis session day of the week (e.g., if Monday-Wednesday-Friday schedule, the study visit 
should be on Monday). Visit days are counted from.the day of first dose of study treatment (Day 1). 
To allow for a flexible schedule, the allowable window for Screening Visit will be “4 weeks  7 days 
prior to Day 1”, and that for the visits after Day 1 will be “ 3 days”. In any case, the study visit 
should occur on the first dialysis session day of the week. Unless otherwise specified, all assessments 
should occur before dialysis on the day. 
 


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Table 6    Time and Events Table  
Period 
Screening 
Treatment 
Follow-up 
Visits 
All assessments pre-dialysis, unless 
noted. 
 
Week  
-4 
Day 1 
Week  
4 
Week  
8 
Week  
12 
Week  
16 
Week  
20 
Week  
24 
Early 
withdraw
al 10 
2–4 weeks 
after Week 24 
or early 
withdrawal  
Allowable window (days) 
 
7 
- 
3 
3 
3 
3 
3 
3 
- 
3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
 
X 
X 
 
 
 
 
 
 
 
 
Medical history, demography, height, 
body weight 1 
 
X 
 
 
 
 
 
 
 
 
 
Interactive Web Recognition System 
(IWRS) call 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study medication dispensing 2 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Study medication compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs (before and after dialysis) 3 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Ophthalmology examination 4 
 
X 11 
 
 
 
 
 
 
 
 
 
ECG 
 
X 
 
 
 
X 
 
 
X 
 
 
HemoCue Hgb 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology 
 
X 12 
X 
X 
Hgb 
only 
X 
Hgb 
only 
Hgb 
only 
X 
X 
X 
Clinical chemistry 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Ferritin, TSAT 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
Serum iron, TIBC, Unsaturated iron 
Binding Capacity (UIBC), serum 
transferrin, hepcidin 
 
 
X 
X 
 
X 
 
 
X 
X 
 
Serum pregnancy test 5 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Estradiol 5, FSH 6 
 
X 
 
 
 
 
 
 
 
 
 
Pharmacokinetics 7 
 
 
 
 
 
X 
 
 
X 
 
 
Intact Parathyroid Hormone (iPTH) 
 
 
X 
X 
 
X 
 
 
X 
 
 
Genetics sample 8 
 
 
X 
 
 
 
 
 
 
 
 
Adverse event assessment 9 
 
 
 
Concomitant medication assessment  
 
 


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1. 
Body weight is measured after dialysis. 
2. 
If a subject visit the study site only to receive study medication, only the IWRS call, study medication dispensing, and study medication compliance will be required 
3. 
At visits without dialysis, only one measurement of each parameter will be obtained. 
4. 
Ophthalmology exams should be conducted at the following time points. 
• 
Screening: anytime after consenting and prior to first dose of study medication (Day 1) 
• 
Week 12: window from weeks 10-14 (inclusive) 
• 
End of study: window from weeks 20-24 (inclusive) 
• 
Early study medication discontinuation or study withdrawal: withdrawal eye exam as close to the last dose as possible.  Re-conduct is not required if the exam is conducted within two weeks 
prior to withdrawal visit. 
5. 
Only for females of reproductive potential. 
6. 
Only at determination of menopausal status in female subjects (Section 5.1.). 
7. 
See Table 7 
8. 
For optional genetic research, informed consent should be obtained before the specimen collection. 
9. 
See Section 7.4.1. 
10. For examination at early withdrawal, the specified assessments should be performed as far as possible. 
11. In the rescreening case, the previous result of ophthalmology exam at the screening may be used and the ophthalmology exam at the rescreening is not necessary, if the subject meets all of the following 
criteria and the investigator judges it appropriate. 
• 
There were no findings that would suggest a repeat ophthalmology exam performed within the next 3 months at the latest screening ophthalmology exam.  
• 
Subjects had no new eye-related symptoms or complaints since the latest screening ophthalmology exam until rescreening.  
• 
The latest screening ophthalmology exam was performed within 3 months prior to anticipated Day 1. 
12. Exams should be conducted at least one week after ESA treatment. 
 
 
Table 7    Blood Sampling Schedule for Pharmacokinetics 
PK sample 
Week 12 2 
Week 24 2 
Blood sampling timing 1 
1, 2, 3, and 4 h after administration of GSK1278863 
Subjects must take the study medication in consideration of blood sampling time. Subjects will record the date and time of the last two study medication doses taken prior to blood sampling in the medication 
diary. Preferably, there should be an interval of at least 12 h between these two doses.  
1. 
Blood sampling should be completed within +/- 30 min of the planned collected time. 
2. 
Blood sampling not performed at this visit may be postponed until the following visits.  
 
 
 


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7.2. 
Screening and Critical Baseline Assessments 
CV medical history/risk factors will be assessed (documented in the eCRF) at Screening. 
In addition, the following demographic information will be collected: 
• 
Year of birth 
• 
Gender 
• 
Race and ethnic  
• 
Medical history/treatment history/family history will be assessed in relation to the 
inclusion/exclusion criteria (Sections 5.1. and 5.2.).  
 
Full details of baseline assessments are provided in Table 6.  
 
7.3. 
Efficacy 
Efficacy will be assessed according to the Time and Event Table (Table 6).  
Hgb concentrations measured by the central laboratory will be used for efficacy assessment (see 
Section 7.4.6.).  
GSK will supply a point-of-care Hgb analyzer (HemoCue) to each site for rapid and convenient 
measurement of Hgb and to ensure consistency of Hgb measurements across all sites participating in 
the study. Hgb concentrations meaused by HemoCue will be used for eligibility (Sections 5.1 and 5.2.), 
withdrawal (Section 5.4.), and dose adjustment criteria (Section 6.3.).  
In addition, assessments of iron metabolism parameters used for efficacy assessment are outlined with 
specific procedures in Section 7.4.6. 
 
7.4. 
Safety 
Planned time points for all safety assessments are listed in the Time and Events Table (Table 6).  
Additional time points for safety tests (such as vital signs, physical exams and laboratory safety tests) 
may be added during the course of the study based on newly available data to ensure appropriate 
safety monitoring 
 
7.4.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) 
The definitions of an AE or SAE can be found in Section 12.6. 
The investigator and 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 
• 
AEs and SAEs will be collected from the start of Study Treatment until the follow-up contact 
(see 7.4.1.3.), at the time points specified in the Time and Events Table (Table 6). 
• 
Medical occurrences that begin prior to the start of study treatment but after obtaining informed 
consent may be recorded on the Medical History/Current Medical Conditions section of the CRF. 
• 
Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a GSK product will be recorded from 
the time a subject consents to participate in the study up to and including any follow-up contact.  
• 
All SAEs will be recorded and reported to GSK within 24 hours, as indicated in Section 12.6. 


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• 
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify GSK. 
 
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs plus procedures 
for completing and transmitting SAE reports to GSK are provided in Section 12.6. 
 
7.4.1.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about AE occurrence.  
Appropriate questions include: 
• 
“How are you feeling?”  
• 
“Have you had any (other) medical problems since your last visit/contact?” 
• 
“Have you taken any new medicines, other than those provided in this study, since your last 
visit/contact?” 
 
7.4.1.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest (as defined in Section 
7.4.2.) will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up (as defined in Section 5.4.). Further information on 
follow-up procedures is given in Section 12.6.  
 
7.4.1.4. 
Cardiovascular and Death Events 
For any CV events detailed in Section 12.6. and all deaths, whether or not they are considered SAEs, 
specific CV and Death sections of the CRF will be required to be completed.  These sections include 
questions regarding CV (including sudden cardiac death) and non-CV death.  
The CV CRFs are presented as queries in response to reporting of certain CV Medical Dictionary for 
Regulatory Activities (MedDRA) terms.  The CV information should be recorded in the specific CV 
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. 
 
7.4.1.5. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to study 
treatment (even for non- interventional post-marketing studies) is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects and the safety of a product under clinical 
investigation are met.  
 
GSK has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a product under clinical investigation.  GSK will comply with country 


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specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) and investigators. 
 
Investigator safety reports are prepared for suspected unexpected serious adverse reactions according 
to local regulatory requirements and GSK policy and are forwarded to investigators as necessary. 
 
An investigator who receives an investigator safety report describing a SAE(s) or other specific safety 
information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements. 
 
7.4.2. 
Adverse Events of Special Interest 
The investigator (or subinvestigator) or designee will be responsible for detecting, documenting, and 
reporting any AEs of special interest listed below. These events have been identified based on the 
known safety profiles of ESAs, theoretical or potential risks based on the mechanism of action of 
GSK1278863, and findings from completed nonclinical studies of GSK1278863.  
 
• 
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 
• 
Death, myocardial infarction (MI), stroke, heart failure, thromboembolic events, thrombosis of 
vascular access 
• 
Cardiomyopathy   
• 
Pulmonary artery hypertension 
• 
Cancer-related mortality and tumor progression and recurrence  
• 
Esophageal and gastric erosions 
• 
Proliferative retinopathy, macular edema, choroidal neovascularization  
• 
Exacerbation of rheumatoid arthritis 
 
Any relevant AE should be recorded in the relevant section of the subject’s eCRF. 
 
7.4.3. 
Pregnancy 
• 
Details of all pregnancies in female subjects will be collected after the start of dosing and until 
the follow-up contact. 
• 
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of learning of 
the pregnancy and should follow the procedures outlined in Section 12.4. 
 
7.4.4. 
Vital Signs/Height/Weight 
Systolic and diastolic blood pressure and heart rate will be measured before and after dialysis, in 
sitting or semi-supine position (chair for dialysis is acceptable) after at least 5 minutes rest at each 
visit. When measuring before dialysis, it should be conducted prior to blood sampling for lab tests. 
One reading of blood pressure and heart rate will be taken and recorded in the source document and 
the CRF. Height and weight will be measured at screening visit only. Weight should be measured after 
dialysis. 
 


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7.4.5. 
Electrocardiogram (ECG) 
12-lead ECGs will be recorded in supine position. The heart rate, PR, QRS, and QT (pre-corrected) 
intervals will be measured. QTcB should be calculated by machine or manually by designated staff at 
each site. The investigator determines whether the ECG data is assessable or not. Measurement 
method and measurement timing (i.e., before or after dialysis) should be consistent as far as possible 
during the study period. 
At Screening visit when an ECG is performed, two additional ECGs are required if initial ECG 
indicates prolonged QTcB. The average QTcB value calculated from all three ECGs will be used to 
determine eligibility. 
QTc exclusion criteria can be found in Section 5.2. Refer to SRM for further details. 
 
7.4.6. 
Clinical Laboratory Assessments 
All study-required laboratory assessments will be performed by a central laboratory with the exception 
of HemoCue Hgb. The results of each HemoCue Hgb must be entered into the subject’s eCRF. Details 
are provided in the SRM.  
All laboratory assessments, as defined in Table 8, must be conducted in accordance with the 
Laboratory Manual and Protocol Time and Events Schedule (Table 6). Laboratory requisition forms 
must be completed and samples must be clearly labeled with the subject number, protocol number, 
site/center number, and sample collection date. Reference ranges for all parameters will be provided to 
the site by the central laboratory. Details of blood sampling (including the volume of blood to be 
collected) as well as procedures for processing, storage, and shipment of samples are provided in the 
SRM.  
PK assessment of GSK1278863 is outlined in Section 7.5. 
 
Table 8    Laboratory Assessments 
Laboratory 
assessment 
Parameter 
Hematology 
Platelet count 
RBC indices: 
WBC Differential 
RBC count 
Mean Corpuscular Volume 
(MCV) 
Neutrophils 
Reticulocyte count 
Mean Corpuscular Hemoglobin 
(MCH) 
Lymphocytes 
Hemoglobin 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
Monocytes 
Hematocrit 
Red Blood Cell Distribution 
Width (RDW) 
Eosinophils 
WBC count 
 
Basophils 
Clinical chemistry 
Sodium 
Aspartate Aminotransferase 
(AST) 
Bicarbonate 
Potassium 
ALT 
Inorganic phosphate 
Chloride 
Creatinine 
Glucose 
Calcium (total and albumin-
corrected) 
Total bilirubin 
Direct/indirect bilirubin  
Albumin 
Urea nitrogen 
 
Total cholesterol 
High Density Lipoprotein 
(HDL) cholesterol 
Low Density Lipoprotein (LDL) 
cholesterol 
Iron parameters 
Serum Iron 
Serum ferritin 
Serum transferrin 
TIBC 
UIBC 
TSAT 
Hepcidin 
 
 
Other laboratory FSH 1 
Estradiol 1 
iPTH 


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tests 
Serum hCG2 
 
 
1. 
Measured in female subjects only to determine the menopausal status (See Section 5.1.)  
2. 
Performed in females of childbearing potential ( See Section5.1.)  
 
If additional non-protocol specified laboratory assessments are performed at the institution’s local 
laboratory and result in a change in subject management or are considered clinically significant by the 
investigator (or subinvestigator) (e.g., SAE or AE or dose modification), the results must be recorded 
in the eCRF. 
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate and/or 
additional blood draws. 
 
All laboratory tests with values that are considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline. If such 
values do not return to normal within a period judged reasonable by the investigator (or 
subinvestigator), the etiology should be identified and the Sponsor notified. 
 
7.4.7. 
Ophthalmology 
The ophthalmologic examination will be performed by a study-designated ophthalmology specialist.  
Each assessment will include a comprehensive eye exam with at least the following components: 
measurement of best corrected visual acuity, intraocular pressure, an anterior segment exam, and a 
fundoscopic exam. These exams will be used for assessment of ocular adverse events. Assessment 
results will be captured on worksheets which will be transferred to the eCRF. Further details of the 
procedure are provided in the SRM.  
 
7.5. 
Pharmacokinetics 
Blood samples for PK analysis of GSK1278863 will be collected as outlined in Table 7, and the date 
and time of the last two study medication doses taken prior to blood sampling as well as the date and 
time of sampling must be recorded in the eCRF.  
Blood PK analysis will be performed under the control of GSK Platform Technologies and Science-
Drug Metabolism and Pharmacokinetics (PTS-DMPK)/Scinovo and GSK-Japan Bioanalysis, the 
details of which will be included in the SRM. Concentrations of parent GSK1278863 will be 
determined in blood samples using the currently approved analytical methodology. Raw data will be 
archived at the bioanalytical site. 
Procedures for processing, storage, and shipment of samples are provided in the SRM.  
 
7.6. 
Genetics 
A blood sample will be collected for genetic analysis from consenting subjects to genetics. This 
sample can be collected on Day 1 once written informed consent has been obtained. Information 
regarding genetic research is included in Section 12.7.  
 


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8. DATA MANAGEMENT 
• 
For this study subject data will be entered into GSK defined CRFs, transmitted electronically to 
GSK or designee and combined with data provided from other sources in a validated data system. 
• 
Management of clinical data will be performed in accordance with applicable GSK standards and 
data cleaning procedures to ensure the integrity of the data, e.g., removing errors and 
inconsistencies in the data. 
• 
Adverse events and concomitant medications terms will be coded using MedDRA and an internal 
validated medication dictionary, GSKDrug.   
• 
CRFs (including queries and audit trails) will be retained by GSK, and copies will be sent to the 
investigator to maintain as the investigator copy.  Subject initials will not be collected or 
transmitted to GSK according to GSK policy. 
 
 
9. STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A detailed description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP). Any deviations from the analyses described in the protocol will be documented in the RAP or 
the final study report.  
 
9.1. 
Hypotheses 
This single arm study is a study with an aim of an estimation. The primary objective of this study is to 
evaluate the initial anemia correction of GSK1278863  in HD patients not using ESAs. There will be 
no hypothesis testing performed in this study. Two-sided 95% confidence intervals will be used for 
efficacy estimation. 
 
9.2. 
Sample Size Considerations 
9.2.1. 
Sample Size Assumptions 
Since the number of HD patients not using ESAs in Japan are limited, the sample size of 22 as 
enrolled was determined based on feasibility. 
The precision of the mean change from baseline in Hgb at Week 4, which is the primary endpoint of 
this study, will be characterized by the half-width of the 95% confidence interval (distance from the 
mean to the confidence limit). If 20 subjects receive GSK1278863 up to Week 4 and the standard 
deviation is 1.5 g/dL, assuming t-distribution,, the half-width of the 95% confidence interval for the 
mean change from baseline in Hgb at Week 4 would be 0.702 g/dL. 
 
9.2.2. 
Sample Size Sensitivity 
Table 9 shows the precision with different sample sizes and different standard deviations. 
Table 9   Sample Size Sensitivity 
Sample size 
Half-width of the 95% confidence 
interval (SD=1.0) 
Half-width of the 95% confidence 
interval (SD=1.5) 
17 
0.514 
0.771 
20 
0.468 
0.702 
22 
0.443 
0.665 
SD = Standard Deviation 


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9.2.3. 
Sample Size Re-estimation or Adjustment  
No sample size re-estimation is planned in this study. 
 
9.3. 
Data Analysis Considerations 
9.3.1. 
Analysis Populations 
• 
All Screening Population 
The All Screening Population consists of all subjects who are given subject number and whose data 
are collected, including demographics at screening.  
 
• 
All Treated Subjects Population 
The All Treated Subjects Population will consist of all subjects who received at least one dose of 
GSK1278863. This population will be used for evaluation of the efficacy, safety and demographic 
data. 
 
• 
PK Population 
The PK Population will consist of all subjects who received GSK1278863 with the PK samples 
collected and analyzed. 
 
Additional populations may be defined in the RAP. 
 
9.3.2. 
Interim Analysis 
No interim analysis is planned. 
 
9.3.3. 
Final Analysis 
Once all subjects complete protocol-defined visits, final analysis will be performed after database lock. 
 
9.4. 
Key Elements of Analysis Plan 
9.4.1. 
Efficacy Analysis 
9.4.1.1. 
Primary Analysis 
The primary analysis is to assess modest increase in Hgb in initial response to GSK1278863 (i.e., Hgb 
increase by  2 g/dL after 4 weeks of treatment), on the basis of the mean change from baseline in 
Hgb at Week 4 as well as the number (%) of subjects by Hgb change from baseline category at 
Week 4 as the primary efficacy endpoints. 
For the change from baseline in Hgb at Week 4, the summary statistics will be calculated, along with 
the two-sided 95% confidence interval based on t-distribution. The change in Hgb at Week 4 will be 
classifieds into different categories (i.e.,-2, >-2 to -1, >-1 to 0, >0 to 1, >1 to 2, and >2 g/dL), and the 
number (%) of subjects in each category will be summarized. 
 
9.4.1.2. 
Secondary Analysis 
The secondary analysis is to assess appropriate control of Hgb within the target range, on the basis of 
the Hgb mean at Week 24 and the number (%) of subjects with Hgb within the target range as 
secondary endpoints. 


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For the Hgb at Week 24, the summary statistics will be calculated, along with the two-sided 95% 
confidence interval based on t-distribution. The percentage of subjects with Hgb within the target 
range will be calculated at Week 24, with calculation of exact two-sided 95% confidence interval 
based on binomial distribution. In addition, the time (in days) to reach the lower target Hgb level 
(10.0 g/dL) will be calculated in each subject, and summarized descriptively. 
Also for other secondary efficacy endpoints, such as iron use and iron metabolism, the data will be 
summarized descriptively. 
 
9.4.2. 
Safety Analysis 
9.4.2.1. 
Exposure 
Exposure information will be listed for all subjects. The duration of treatment (number of days), 
cumulative dose will be tabulated. In addition, distribution of the dose level at each assessment visit 
and final assessment visit will be tabulated. Frequency of dose adjustment and duration of treatment 
interruption due to Hgb >13 g/dL will be summarized. 
 
9.4.2.2. 
Adverse Events 
Adverse events will be classified by System Organ Class and Preferred Term of the MedDRA, and the 
number and percentage of subjects with each event will be summarized. All adverse events, serious 
adverse events, adverse events leading to discontinuation of study treatment, and adverse events of 
special interest will be summarized separately. Similar summary will be provided for adverse events 
related to GSK1278863. 
 
9.4.2.3. 
Other Safety Measures 
For laboratory tests, vital signs, and ECG, parameters and/or changes from baseline will be 
summarized using summary statistics at each assessment visit. The number and percentage of subjects 
with values of the potential clinical importance will be tabulated. The criteria for the potential clinical 
importance will be described in the RAP. For lipid parameters (total cholesterol, LDL cholesterol, and 
HDL cholesterol), percent changes will also be tabulated. 
 
9.4.3. 
Pharmacokinetic Analysis 
For plasma concentrations of GSK1278863 over time, individual data will be listed, and summary 
statistics at each time point will be calculated by each dose level. For PK parameters (AUC 0-4 and 
Cmax), summary statistics will be calculated by each dose level, and scatter plots against the dose 
level will be generated.  
 
 
 


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


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he/she may take the consent form home. The person who conducted the informed consent discussion 
and study collaborator giving supplementary explanation, where applicable, should sign and 
personally date the consent form. If an impartial witness is required, the witness should sign and 
personally date the consent form. The investigator (or subinvestigator) should retain this signed and 
dated form (and other written information) together with the source medical records, such as clinical 
charts (in accordance with the rules for records retention, if any, at each medical institution) and give a 
copy to the subject and the subject’s legally acceptable representative. 
 
10.3. Quality Control (Study Monitoring) 
In accordance with applicable regulations including GCP, and GSK procedures, GSK monitors will 
contact the site prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements.   
When reviewing data collection procedures, the discussion will also include identification, agreement 
and documentation of data items for which the CRF will serve as the source document. 
 
GSK will monitor the study and site activity to verify that the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol and any other study 
agreements, GCP, and all applicable regulatory requirements. 
 
The investigator and the head of the medical institution (where applicable) agrees to allow the monitor 
direct access to all relevant documents 
 
10.4. Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a 
quality assurance assessment and/or audit of the site records, and the regulatory agencies may conduct 
a regulatory inspection at any time during or after completion of the study.  
In the event of an assessment, audit or inspection, the investigator (and institution) must agree to grant 
the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to allocate their 
time and the time of their staff to discuss the conduct of the study, any findings/relevant issues and to 
implement any corrective and/or preventative actions to address any findings/issues identified. 
 
10.5. Study and Site Closure 
Upon completion or premature discontinuation of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff, as appropriate, in accordance with applicable regulations 
including GCP, and GSK Standard Operating Procedures. 
GSK reserves the right to temporarily suspend or prematurely discontinue this study at any time for 
reasons including, but not limited to, safety or ethical issues or severe non-compliance. For 
multicenter studies, this can occur at one or more or at all sites.   
If GSK determines such action is needed, GSK will discuss the reasons for taking such action with the 
investigator or the head of the medical institution (where applicable).  When feasible, GSK will 
provide advance notification to the investigator or the head of the medical institution, where 


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applicable, of the impending action. 
If the study is suspended or prematurely discontinued for safety reasons, GSK will promptly inform 
all investigators, heads of the medical institutions (where applicable) and/or institution(s) conducting 
the study. GSK will also promptly inform the relevant regulatory authorities of the suspension or 
premature discontinuation of the study and the reason(s) for the action.   
If required by applicable regulations, the investigator or the head of the medical institution (where 
applicable) must inform the IRB/IEC promptly and provide the reason for the suspension or premature 
discontinuation. 
 
10.6. Records Retention 
Following closure of the study, the investigator or the head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local regulations to be 
maintained elsewhere), in a safe and secure location.   
The records must be maintained to allow easy and timely retrieval, when needed (e.g., for a GSK audit 
or regulatory inspection) and must be available for review in conjunction with assessment of the 
facility, supporting systems, and relevant site staff.   
Where permitted by local laws/regulations or institutional policy, some or all of these records can be 
maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution 
needs to be exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and retrieval 
standards, including re-generating a hard copy, if required.  Furthermore, the investigator must 
ensure there is an acceptable back-up of these reproductions and that an acceptable quality control 
process exists for making these reproductions. 
GSK will inform the investigator of the time period for retaining these records to comply with all 
applicable regulatory requirements.  The minimum retention time will meet the strictest standard 
applicable to that site for the study, as dictated by any institutional requirements or local laws or 
regulations, GSK standards/procedures, and/or institutional requirements.   
The investigator must notify GSK of any changes in the archival arrangements, including, but not 
limited to, archival at an off-site facility or transfer of ownership of the records in the event the 
investigator is no longer associated with the site. 
 
10.7. Provision of Study Results to Investigators, Posting of Information on 
Publically Available Clinical Trials Registers and 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. 
 
The procedures and timing for public disclosure of the results summary and for development of a 
manuscript for publication will be in accordance with GSK Policy. 


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


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11. REFERENCES 
Akizawa Tadao, Makino Hirofumi, Matsuo Seiichi, et al. Management of anemia in chronic kidney 
disease patients: baseline findings from Chronic Kidney Disease Japan Cohort Study. Clin Exp 
Nephrol. 2011;15:248-57. 
Szczech Lynda A., Barnhart Huiman X., Inrig Jula K, et al. Secondary analysis of the CHOIR trial 
epoetin-alpha dose and achieved hemoglobin outcomes. Kidney International. 2008;74:791-8. 
Tsubakihara Yoshiharu, Nishi Shinichi, Akiba Takashi, et al. 2008 Japanese Society for Dialysis 
Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease. Therapeutic Apheresis and 
Dialysis. 2010;14(3):240-75. 
 
 


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12. APPENDICES 
12.1. Appendix 1: Abbreviations and Trademarks 
 
Abbreviations 
ALT 
Alanine Aminotransferase 
AMD 
Age-Related Macular Degeneration 
AST 
Aspartate Aminotransferase 
AUC 
Area Under Curve 
BCRP 
Breast Cancer Resistance Protein 
CKD 
Chronic Kidney Disease 
Cmax 
Maximum Concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine Phosphokinase 
CT 
Computed Tomography 
CYP 
Cytochrome P450 
CV 
Cardiovascular 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
EPO 
Erythropoietin 
ESA 
Erythropoiesis Stimulating Agent 
FDA 
Food and Drug Administration 
FRP 
Females of Reproductive Potential 
FSH 
Follicle Stimulating Hormone 
GSK 
GlaxoSmithKline 
hCG 
Human Chorionic Gonadotrophin 
HD 
Hemodialysis 
HDF 
Hemodiafiltration 
HDL 
High Density Lipoprotein 
HDPE 
High Density Polyethylene 
Hgb 
Hemoglobin 
HIF 
Hypoxia-Inducible Factor 
HRT 
Hormone Replacement Therapy 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IB 
Investigator's Brochure 
INR 
International Normalized Ratio 
iPTH 
Intact Parathyroid Hormone 
IWRS 
Interactive Web Recognition System 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein 
MAD 
Maximum Acceptable Dose 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
ND 
Non dialysis 
NYHA 
New York Heart Association 
OATP 
Organic Anion Transporting Polypeptide 
PAH 
Pulmonary Arterial Hypertension 


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PHI 
Prolyl Hydroxylase Inhibitor 
PK 
Pharmacokinetic 
QT 
Q-T Interval 
QTc 
Q-T Interval Corrected for Heart Rate 
QTcB 
Bazett’s Correction of QT Interval 
RAP 
Reporting and Analysis Plan 
RDW 
Red Blood Cell Distribution Width 
rhEPO 
Recombinant Human Erythropoietin 
RNA 
Ribonucleic Acid 
SD 
Standard Deviation 
SRM 
Study Reference Manual 
TIBC 
Total Iron Binding Capacity 
TSAT 
Transferrin Saturation 
UIBC 
Unsaturated iron Binding Capacity 
ULN 
Upper Limit of Normal 
VEGF 
Vascular Endothelial Growth Factor 
 
Trademark Information 
Trademarks of the GlaxoSmithKline group of 
companies 
 
Trademarks not owned by the GlaxoSmithKline 
group of companies 
None 
 
Hemocue 
 
 
 
 
 
 
 


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12.2. Appendix 2: Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
GSK1278863  
Excessive erythropoiesis (polycythemia) 
leading to thrombosis and/or tissue ischemia 
In animal studies, excessive erythropoiesis attributed to 
GSK1278863 was associated with vascular congestion, 
microthrombi, and tissue ischemia in a number of organs. 
Following review of clinical data received to date, this has not 
been identified as a safety concern for GSK1278863. 
Phase 2 dose-ranging studies, and associated statistical and 
exposure response modelling has informed Phase 3 dose 
rationale, starting doses, dose levels, and dose adjustment 
scheme to optimize Hgb management. 
• 
Specific eligibility criteria related to 
requirements for entry Hgb are detailed 
in Section 5.1. 
• 
Hgb will be closely monitored 
throughout the dosing period as 
outlined in the Time and Events Table 
Section 7.1. 
• 
Specific guidance for dose adjustment, 
dose interruption, or discontinuation of 
GSK1278863 based on achieved Hgb is 
provided in Section 5.4. 
• 
These risks have been identified as AEs 
of special interest and will be 
monitored instreamly by the internal 
safety review team throughout the 
study period. 
Risk of death, MI, stroke, heart failure, 
thromboembolic events, thrombosis of 
vascular access at Hgb levels which are within 
the normal range (i.e. not polycythemic 
conditions) 
Marketed recombinant human EPO (rhEPO)/ESAs have been 
associated with an increased risk for death and serious CV 
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 7.4.1.1.  
• 
Hgb will be closely monitored 
throughout the dosing period as 
outlined in the Time and Events Table 
Section 7.4.1.4. 
• 
These risks have been identified as AEs 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
of special interest and will be 
monitored instreamly by the internal 
safety review team throughout the 
study period. 
Esophageal and gastric erosions 
In animal studies, undesirable GI effects including emesis, 
abnormal feces and/or decreased food consumption/body 
weight loss and stomach erosions/ ulcers with hemorrhage were 
observed.   
In rodents stomach erosions observed with intravenous and oral 
administration of GSK1278863. 
Gender-averaged systemic exposure (AUC) at the no observed 
adverse effect levels are 3.3 -fold (monkeys) and 737 -fold 
(rats) above human exposure (25 mg). 
In clinical trials to date, mild-moderate GI signs and symptoms 
represent the most frequently reported adverse event, however 
causal association has not been established. 
Following review of clinical data received to date, GI erosions 
have not been identified as a safety concern for GSK1278863. 
• 
Suspected GI bleeding or significant 
symptoms consistent with erosion 
should be investigated diagnostically 
(i.e. endoscopic examination) as 
clinically warranted 
• 
These risks have been identified as AEs 
of special interest and will be 
monitored instreamly by the internal 
safety review team throughout the 
study period. 
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 60 mg/kg GSK1278863 to mice caused 
minimal increases in circulating VEGF while significant 
EPO increases were observed. 
In clinical studies up to 4 weeks duration, a dose-ordered 
increase in VEGF plasma concentrations, an angiogenic factor 
that has been implicated in tumor growth, was observed at 
doses ranging from 10 to 150 mg. In clinical studies up to 24 
weeks duration at doses up to 25 mg, changes in VEGF plasma 
concentrations were variable but similar relative to control. 
• 
Specific eligibility criteria related to 
personal history of malignancy are 
outlined in Section 5.2. 
• 
Stopping criteria for subjects with 
treatment emergent malignancy are 
outlined in Section 5.4. 
• 
These risks have been identified as AEs 
of special interest and will be 
monitored instreamly by the internal 
safety review team throughout the 
study period. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Following review of clinical data received to date, this has 
not been identified as a safety concern for 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 100 mg has no clinically 
significant effect on echocardiographically estimated 
pulmonary artery systolic pressure (PASP) under either 
normoxic or hypoxic conditions. 
ECHO assessments performed in Phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful 
changes in systolic pulmonary artery pressure (sPAP) in 
subjects not on dialysis. In hemodialysis subjects, mean 
absolute change from baseline in sPAP was similar for both 
treatment groups; however, there was a numeric imbalance 
(GSK Total: 8 [7%]; Control 0) in subjects reaching the sPAP 
potential clinical importance (PCI) (>20 mmHg increase from 
baseline). Regarding this imbalance, there were a number of 
confounding factors in the study, most notably a 4.5:1 
randomization scheme and inconsistency in timing of ECHOs 
• 
These risks have been identified as AEs 
of special interest and will be 
monitored instreamly by the internal 
safety review team throughout the 
study period. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
relative to dialysis day.  Additionally, 2 of 3 subjects with 
resolution of sPAP on safety follow-up ECHOs had 
confounding conditions that could contribute to resolution of 
sPAP other than discontinuation of study treatment; and there 
was no dose relationship for subjects meeting the sPAP PCI 
criterion. Overall, there is insufficient evidence to conclude a 
relationship to treatment with daprodustat. 
Following review of clinical data received to date, this has not 
been identified as a safety concern for GSK1278863.   
Cardiomyopathy 
Published data suggest that cardiac effects of HIF stabilization 
are likely a function of the mechanism, extent, and duration of 
the effects, and can range from protective to detrimental 
depending upon the specific model and experimental conditions 
utilized. 
Small increases in cardiac troponin in 6 month rat study were 
consistent with the background finding of spontaneous rodent 
cardiomyopathy.  There were no elevations observed in 
cardiac troponin in 9 month monkey study. 
Cardiomyopathy has not been associated with naturally 
occurring mutation in man which results in increased HIF 
stabilization. 
ECHO assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful 
changes in left ventricular ejection rate. 
Following review of clinical data received to date, this has not 
been identified as a safety concern for GSK1278863. 
• 
These risks have been identified as AEs 
of special interest and will be 
monitored instreamly by the internal 
safety review team throughout the 
study period. 
Proliferative retinopathy, macular edema, 
choroidal neovascularization 
Increases in local (ocular) Vascular Endothelial Growth Factor 
(VEGF) production with retinal neovascularization and macular 
edema observed in diabetic retinopathy and to choroidal 
leakage, edema and neovascularization seen in age-related 
macular degeneration [Campochiaro, 2006]. 
Administration of 60 mg/kg GSK1278863 to mice caused 
minimal increases in circulating VEGF while significant EPO 
increases were observed. 
• 
Ophthalmology exams (defined in 
Section 7.4.7.) will be performed 
during screening, at approximately 12 
weeks on-study, and at the end of 
treatment. 
• 
These risks have been identified as AEs 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
No ocular abnormalities were seen in non-clinical studies of up 
to 13 weeks duration in mice and dogs, 26 weeks in rats, and 
39-weeks in monkeys.   
In clinical studies up to 4 weeks duration, a dose-ordered 
increase in VEGF plasma concentrations was observed at doses 
ranging from 10 to 150 mg. In studies up to 24 weeks duration 
at doses up to 25 mg, changes in VEGF plasma concentrations 
were variable but similar relative to control. 
Ophthalmologic assessments performed in phase 2b studies (24 
weeks treatment duration) did not identify any clinically 
meaningful changes in proliferative retinopathy, macular 
edema, or choroidal neovascularization. 
Following review of clinical data received to date, this has not 
been identified as a safety concern for GSK1278863. 
of special interest and will be 
monitored instreamly by the internal 
safety review team throughout the 
study period. 
• 
Suspected proliferative retinopathy, 
macular edema, choroidal 
neovascularization or symptoms 
consistent with these events should be 
investigated by ophthalmologic 
consultation as clinically warranted. 
Exacerbation of rheumatoid arthritis 
In inflamed rheumatic joints, activation of HIF- related genes 
secondary to decreased oxygen and pro-inflammatory cytokines 
has been postulated to contribute to the neo-angiogenesis, 
proliferation and infiltration of rheumatoid synovial fibroblasts 
[Westra, 2010; Muz, 2009]. 
No abnormalities seen in non-clinical studies conducted to date. 
Following review of clinical data received to date, this has not 
been identified as a safety concern for GSK1278863. 
• 
These risks have been identified as AEs 
of special interest and will be 
monitored instreamly by the internal 
safety review team throughout the 
study period. 
Drug-drug interactions 
Co-administration of GSK1278863 with a strong CYP2C8 
inhibitor increased the Cmax and AUC of GSK1278863, 4- 
and 19-fold, respectively, while co-administration of a weak 
inhibitor increased the Cmax and AUC of GSK1278863 by 
1.3- and 1.5-fold, respectively. Population PK analysis from 
completed Phase 2 studies suggests that co-administration of 
GSK1278863 with a moderate CYP2C8 inhibitor, leads to a 
~ 2-fold increase in AUC, with no clinically-significant 
increase in the measured Hgb response. 
Co-administration of GSK1278863 with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 
inducers (e.g., rifampin/rifampicin) is not 
permitted as outlined in Section 6.10.2. 
Co-administration of GSK1278863 with 
moderate CYP2C8 inhibitors (i.e., clopidogrel, 
teriflunomide, deferasirox) should be 
performed with caution. If one of these 
medications is started, stopped or the dose is 
changed, Hgb should be monitored every 4 
weeks for 12 weeks as outlined in Section 
6.10.1. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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 Breast Cancer 
Resistance Protein (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 Organic Anion Transporting 
Polypeptide (OATP)1B1/1B3 in vitro, with IC50 values of 
6 µM and 11 µM, respectively. A clinical drug interaction study 
between 25 mg GSK1278863 with either a CYP2C8 substrate 
or an OATP1B1/1B3 substrate showed that there is no PK 
interaction at this dose of GSK1278863. 
Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in 
Section 6.10.. 
• 
Hgb will be closely monitored 
throughout the dosing period as 
outlined in the Time and Events Table 
Section 7.1. 
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of 
GSK1278863 based on achieved Hgb 
concentrations/changes is provided in Section 
6.3. 
Safety data will be monitored instreamly by 
the internal safety review team throughout the 
study period. 
 
References 
Campochiaro et al., Ocular versus Extraocular Neovascularization: Mirror Images or Vague Resemblances; Invest Ophthalmol & Vis Sci 2006. 47:462-474. 
 
Formenti et al., Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha 
gain-of-function mutation. FASEB J. 2011, 25(6): 2001-2011. 
 
Muz et al., The role of hypoxia and HIF-dependent signaling events in rheumatoid arthritis, Arthritis Research & Therapy 2009. 11:201-210. 
 
Smith et al., Mutation of von Hippel–Lindau. Tumour Suppressor and Human Cardiopulmonary Physiology PLOS 2006. 3:1176-1186. 
 


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


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12.3. Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in 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. 
1. 
Contraceptive subdermal implant that meets the product label effectiveness criteria including a 
<1% rate of failure per year, as stated in the product label  
2. 
Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a 
<1% rate of failure per year, as stated in the product label [Hatcher, 2011] 
3. 
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]  
4. 
Injectable progestogen [Hatcher, 2011] 
5. 
Contraceptive vaginal ring [Hatcher, 2011] 
6. 
Percutaneous contraceptive patches [Hatcher, 2011] 
7. 
Male partner sterilization with documentation of azoospermia prior to the female subject's entry 
into the study, and this male is the sole partner for that subject [Hatcher, 2011].   
 
These allowed methods of contraception are only effective when used consistently, correctly and in 
accordance with the product label. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception. 
 
References 
Trussell J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, Kowal D, and 
Policar M (editors). Contraceptive Technology: Twentieth Revised Edition. New York: Ardent Media, 
2011 


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


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


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liver event follow up assessments within 24 
hrs 
• 
Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• 
A specialist or hepatology consultation is 
recommended 
For All other criteria:  
• 
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  
24-72 hrs  
• 
Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
alcohol intake case report form 
 
For bilirubin or INR criteria: 
• 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins). 
• 
Serum acetaminophen protein adduct 
HPLC assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]). 
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
13. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT  3xULN and bilirubin  2xULN. 
Additionally, (for ND patients only) if serum bilirubin fractionation testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
14. All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, if 
INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold 
value stated will not apply to subjects receiving anticoagulants 
15. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)    
16. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody or Hepatitis E RNA 
17. PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the 
SRM.   
 
 
Phase III-IV liver chemistry increased monitoring criteria with continued therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
 
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
• 
Notify the GSK medical monitor within 24 hours 
of learning of the abnormality to discuss subject 


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be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks. 
OR 
ALT 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks. 
 
safety.  
• 
Subject can continue study treatment   
• 
Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline  
• 
If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above 
• 
If ALT decreases from ALT 5xULN and 
<8xULN to ≥3xULN but <5xULN, continue to 
monitor liver chemistries weekly.  
• 
If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to 
within baseline. 
 
  
Reference 
James LP, Letzig L, Simpson PM, et al. 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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12.6. Appendix 6: Definition of and Procedures for Recording, Evaluating, Follow-
Up and Reporting of Adverse Events 
12.6.1. 
Definition of Adverse Events 
Adverse Event Definition: 
• 
An AE is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a medicinal product. 
 
Events meeting AE definition include: 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those 
that worsen from baseline, and felt to be clinically significant in the medical and scientific 
judgement of the investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it may 
have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication (overdose per se will not be reported as an AE/SAE unless this is an 
intentional overdose taken with possible suicidal/self-harming intent.  This should be reported 
regardless of sequelae). 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE.  However, the signs and symptoms and/or clinical sequelae resulting from lack 
of efficacy will be reported if they fulfil the definition of an AE or SAE. 
 
Events NOT meeting definition of an AE include: 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the subject’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
 


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12.6.2. 
Definition of Serious Adverse Events 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of 
disease, etc). 
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
NOTE: 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at 
risk of death at the time of the event.  It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE: 
• 
In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or out-patient setting.  Complications that 
occur during hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious.  When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. 
Results in disability/incapacity 
NOTE: 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute 
a substantial disruption 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above definition.  These 
should also be considered serious. 
• 
Examples of such events are invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse 
g. 
Is associated with liver injury and impaired liver function defined as: 
• 
ALT  3xULN and total bilirubin*  2xULN (>35% direct), or 
• 
ALT  3xULN and INR** > 1.5. 
* Serum bilirubin fractionation should be performed if testing is available. If fractionation is 


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unavailable and ALT  3xULN and total bilirubin  2xULN, then the event is still to be reported as an 
SAE. 
** INR testing not required per protocol and the threshold value does not apply to subjects receiving 
anticoagulants.  If INR measurement is obtained, the value is to be recorded on the SAE form. 
 
 
12.6.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the following AEs 
and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
 
12.6.4. 
Recording of AEs and SAEs 
AEs and SAE Recording: 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event. 
• 
The investigator will then record all relevant information regarding an AE/SAE in the CRF 
• 
It is not acceptable for the investigator to send photocopies of the subject’s medical records to 
GSK in lieu of completion of the GSK, AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by GSK.  
In this instance, all subject identifiers, with the exception of the subject number, will be blinded 
on the copies of the medical records prior to submission of to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  In such cases, the diagnosis will be documented as the 
AE/SAE and not the individual signs/symptoms. 
• 
PRO questionnaires and the collection of AE data are independent components of the study. 
• 
Responses to each question in PRO questionnaire will be treated in accordance with standard 
scoring and statistical procedures detailed by the scale’s developer. 
• 
The use of a single question from a multidimensional health survey to designate a cause-effect 
relationship to an AE is inappropriate. 
 
12.6.5. 
Evaluating AEs and SAEs 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the study 


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and will assign it to one of the following categories: 
• 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
• 
Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities 
• 
Severe: An event that prevents normal everyday activities. - an AE that is assessed as severe will 
not be confused with an SAE. Severity is a category utilized for rating the intensity of an event; 
and both AEs and SAEs can be assessed as severe. 
• 
An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as 
described in the definition of an SAE. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE. 
• 
A "reasonable possibility" is meant to convey that there are facts/evidence or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other 
risk factors, and the temporal relationship of the event to the study treatment will be considered 
and investigated. 
• 
The investigator will also consult the Investigator Brochure (IB) and/or Product Information, for 
marketed products, in the determination of his/her assessment. 
• 
For each AE/SAE the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
• 
There may be situations when an SAE has occurred and the investigator has minimal information 
to include in the initial report to GSK.  However, it is very important that the investigator 
always make an assessment of causality for every event prior to the initial transmission of 
the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up information, 
amending the SAE data collection tool accordingly. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to elucidate as 
fully as possible the nature and/or causality of the AE or SAE. 
• 
The investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals. 
• 
If a subject dies during participation in the study or during a recognized follow-up period, the 
investigator will provide GSK with a copy of any post-mortem findings, including 
histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 


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• 
The investigator will submit any updated SAE data to GSK within the designated reporting time 
frames. 
 
12.6.6. 
Reporting of SAEs to GSK 
SAE reporting to GSK via electronic data collection tool 
• 
Primary mechanism for reporting SAEs to GSK will be the electronic data collection tool 
• 
If the electronic system is unavailable for greater than 24 hours, the site will use the paper SAE 
data collection tool and fax it to the SAE contact. 
• 
Site will enter the serious adverse event data into the electronic system as soon as it becomes 
available. 
• 
The investigator will confirm that causal relationship of SAE has been considered, by ticking the 
'reviewed' box at the bottom of eCRF page within 72 hours following the submission of SAE. 
• 
After the study is completed at a given site, the electronic data collection tool (e.g., InForm 
system) will be taken off-line to prevent the entry of new data or changes to existing data 
• 
If a site receives a report of a new SAE from a study subject or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, the site 
can report this information on a paper SAE form or to the SAE contact by telephone. 
• 
Contacts for SAE receipt can be found at the beginning of this protocol on the Sponsor/Medical 
Monitor Contact Information page. 


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


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• 
A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A Blood 
sample is collected at the baseline visit, after the subject has been randomized and provided 
informed consent for genetic research. Instructions for collection and shipping of the genetic 
sample are described in the laboratory manual. The DNA from the blood sample may undergo 
quality control analyses to confirm the integrity of the sample. If there are concerns regarding the 
quality of the sample, then the sample may be destroyed. The blood sample is taken on a single 
occasion unless a duplicate sample is required due to an inability to utilize the original sample.   
 
The genetic sample is labelled (or “coded”) with the same study specific number used to label other 
samples and data in the study. This number can be traced or linked back to the subject by the 
investigator or site staff. Coded samples do not carry personal identifiers (such as name or social 
security number).  
 
Samples will be stored securely and may be kept for up to 15 years after the last subject completes the 
study, or GSK may destroy the samples sooner. GSK or those working with GSK (for example, other 
researchers) will only use samples collected from the study for the purpose stated in this protocol and 
in the informed consent form. Samples may be used as part of the development of a companion 
diagnostic to support the GSK medicinal product. 
 
Subjects can request their sample to be destroyed at any time. 
 
Informed Consent 
Subjects who do not wish to participate in the genetic research may still participate in the study.  
Genetic informed consent must be obtained prior to any blood being taken. 
 
Subject Withdrawal from Study 
If a subject who has consented to participate in genetic research withdraws from the clinical study for 
any reason other than being lost to follow-up, the subject will be given a choice of one of the 
following options concerning the genetic sample, if already collected: 
 
• 
Continue to participate in the genetic research in which case the genetic DNA sample is retained 
• 
Discontinue participation in the genetic research and destroy the genetic DNA sample  
 
If a subject withdraws consent for genetic research or requests sample destruction for any reason, the 
investigator must complete the appropriate documentation to request sample destruction within the 
timeframe specified by GSK and maintain the documentation in the site study records.  
 
Genotype data may be generated during the study or after completion of the study and may be 
analyzed during the study or stored for future analysis.  
 
• 
If a subject withdraws consent for genetic research and genotype data has not been analyzed, it 
will not be analyzed or used for future research.   


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• 
Genetic data that has been analyzed at the time of withdrawn consent will continue to be stored 
and used, as appropriate. 
 
Screen and Baseline Failures 
If a sample for genetic research has been collected and it is determined that the subject does not meet 
the entry criteria for participation in the study, then the investigator should instruct the subject that 
their genetic sample will be destroyed. No forms are required to complete this process as it will be 
completed as part of the consent and sample reconciliation process. In this instance a sample 
destruction form will not be available to include in the site files. 
 
Provision of Study Results and Confidentiality of Subject’s Genetic Data 
GSK may summarize the genetic research results in the clinical study report, or separately and may 
publish the results in scientific journals.  
 
GSK may share genetic research data with other scientists to further scientific understanding in 
alignment with the informed consent. GSK does not inform the subject, family members, insurers, or 
employers of individual genotyping results that are not known to be relevant to the subject’s medical 
care at the time of the study, unless required by law. This is due to the fact that the information 
generated from genetic studies is generally preliminary in nature, and therefore the significance and 
scientific validity of the results are undetermined. Further, data generated in a research laboratory may 
not meet regulatory requirements for inclusion in clinical care. 
 
References 
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular Degeneration 
(AMD) Susceptibility Gene CFH and Treatment Response of AMD: A Meta-Analysis. PloS ONE 
2012; 7: e42464 
 
Gorin MB. Genetic insights into age-related macular degeneration: Controversies addressing risk, 
causality, and therapeutics. Mol. Asp. Med. 2012;33:467-486. 


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12.8. Appendix 8: Protocol Changes 
12.8.1. 
Amendment 1 － Summary of Changes and Rationale 
This is applicable to all study sites. 
 
List of Protocol Changes with Rationale for Each 
 
6.2. 
Treatment Assignment 
Original Text:  
This is an open-label, non-comparative study. All eligible subjects will take GSK1278863.  
 
Revised Text: 
This is an open-label, non-comparative study. All eligible subjects will take GSK1278863. Refer to 
Study Reference Manual (SRM) regarding details such as allocation of randomization number. 
 
Reason: 
To clarify procedure 
 
 
7.1. 
Time and Events Table: Footnote 4 
Original Text: 
4. 
Ophthalmology exams should be conducted at the following time points. 
• 
Screening: anytime after consenting and prior to first dose of study medication (Day 1) 
• 
Week 12: window from weeks 10-14 (inclusive) 
• 
End of study: window from weeks 20-24 (inclusive) 
• 
Early study medication discontinuation or study withdrawal: withdrawal eye exam as close 
to the last dose as possible 
 
Revised Text: 
4. 
Ophthalmology exams should be conducted at the following time points. 
• 
Screening: anytime after consenting and prior to first dose of study medication (Day 1) 
• 
Week 12: window from weeks 10-14 (inclusive) 
• 
End of study: window from weeks 20-24 (inclusive) 
• 
Early study medication discontinuation or study withdrawal: withdrawal eye exam as close 
to the last dose as possible.  Re-conduct is not required if the exam is conducted within 
two weeks prior to withdrawal visit. 
 
Reason: 
To clarify study procedure  
 
 


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7.1. 
Time and Events Table: Table 6 Time and Events Table, To add footnote 11 
Revised Text: 
To add footnote 11 to 'Hematology' at Screening Visit 
11. Exams should be conducted at least one week after ESA treatment. 
 
Reason: 
To clarify study procedure  
 
 
7.4.5. 
Electrocardiogram (ECG) 
Original Text: 
At the Day 1 visit when an ECG is performed, two additional ECGs are required if initial ECG 
indicates prolonged QTcB.  
 
Revised Text: 
At the Screening visit when an ECG is performed, two additional ECGs are required if initial ECG 
indicates prolonged QTcB.  
 
Reason: 
To correct an error  
 
 
12.2. 
Appendix 2: Risk Assessment: ‘Summary of Data/Rationale for Risk’ with regards to 
one of Potential Risk: Pulmonary artery hypertension (PAH) 
 
Original Text: 
• 
ECHO assessments performed in Phase 2b studies (24 weeks treatment duration) did not identify 
any clinically meaningful changes in systolic pulmonary artery pressure (sPAP) in subjects not 
on dialysis. Further interrogation of sPAP data in dialysis subjects is ongoing. 
 
Revised Text: 
• 
ECHO assessments performed in Phase 2b studies (24 weeks treatment duration) did not identify 
any clinically meaningful changes in systolic pulmonary artery pressure (sPAP) in subjects not 
on dialysis. In hemodialysis subjects, mean absolute change from baseline in sPAP was similar 
for both treatment groups; however, there was a numeric imbalance (GSK Total: 8 [7%]; Control 
0) in subjects reaching the sPAP potential clinical importance (PCI) (>20 mmHg increase from 
baseline). Regarding this imbalance, there were a number of confounding factors in the study, 
most notably a 4.5:1 randomization scheme and inconsistency in timing of ECHOs relative to 
dialysis day.  Additionally, 2 of 3 subjects with resolution of sPAP on safety follow-up ECHOs 
had confounding conditions that could contribute to resolution of sPAP other than 
discontinuation of study treatment; and there was no dose relationship for subjects meeting the 
sPAP PCI criterion. Overall, there is insufficient evidence to conclude a relationship to treatment 
with daprodustat. 
 


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Reason: 
To update ‘Summary of Data/Rationale for Risk’ to the latest information 
 
 
12.2. 
Appendix 2: Risk Assessment: ‘Mitigation Strategy’ with regards to one of Potential 
Risks: Proliferative retinopathy, macular edema, choroidal neovascularization 
 
Original Text: 
• 
Ophthalmology exams (defined in Section 7.4.7.) will be performed during screening, at 
approximately 12 weeks on-study, and at the end of treatment. 
• 
These risks have been identified as AEs of special interest and will be monitored instreamly by 
the internal safety review team throughout the study period. 
 
Revised Text: 
• 
Ophthalmology exams (defined in Section 7.4.7.) will be performed during screening, at 
approximately 12 weeks on-study, and at the end of treatment. 
• 
These risks have been identified as AEs of special interest and will be monitored instreamly by 
the internal safety review team throughout the study period. 
• 
Suspected proliferative retinopathy, macular edema, choroidal neovascularization or symptoms 
consistent with these events should be investigated by ophthalmologic consultation as clinically 
warranted. 
 
Reason: 
To clarify procedure to investigate and treat any eye related AESIs 
 
 
12.5. 
Appendix 5: Liver Safety Required Actions and Follow up Assessments: ‘Follow Up 
Assessments’ of ‘Required Actions and Follow up Assessments following ANY Liver Stopping 
Event’ 
 
Original Text: 
For bilirubin or INR criteria: 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin G (IgG or gamma globulins). 
 
Revised Text: 
For bilirubin or INR criteria: 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin G (IgG or gamma globulins). 
• 
Serum acetaminophen protein adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in the preceding 
week [James, 2009]). 
 


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Reference 
 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute 
Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
 
Reason: 
To clarify procedure of follow-up Assessment 
 


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12.8.2. 
Amendment 2 － Summary of Changes and Rationale 
This is applicable to all study sites. 
 
List of Protocol Changes with Rationale for Each 
 
5.1. 
Inclusion Criteria  
Original Text:  
3. Use of any erythropoiesis stimulating agent (ESA):  
• 
Newly started dialysis (Dialysis newly started < 12 weeks before screening): Patients not 
using ESAs after the start of dialysis 
• 
Maintenance dialysis (Dialysis started  12 weeks before screening): Patients not using 
ESAs within 8 weeks before screening (including interruption of ESA therapy) 
 
Revised Text: 
3. Use of any erythropoiesis stimulating agent (ESA):  
• 
Newly started dialysis (Dialysis newly started < 12 weeks before screening): Patients not 
using ESAs after the start of dialysis 
• 
Maintenance dialysis (Dialysis started  12 weeks before screening): Patients not using 
ESAs within 8 weeks before screening [including patients who are on treament/interruption 
of ESA theyapy and planned to intruppt ESA therapy for at least 8 weeks prior to Screening 
exam (at the time of informed consent)]  
 
Reason: 
To clarify that patients who plan to interrupt ESA therapy for ≥8 weeks will be included in the 
maintenance dialysis population 
 
 
5.3. 
Screening Failures 
Original Text: 
No text 
 
Revised Text: 
In the rescreening case, the re-exams of the ophthalmology at the rescreening are not required if the 
investigator judges it appropriate to use the previous screening result (see Table 6). 
 
Reason: 
To clarify the ophthalmology exam procedure at rescreening. 
 
 


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6.9. 
Treatment after the End of the Study 
Original Text: 
Since the target disease studied is not life-threatening or severely debilitating and there are alternative 
treatments for the target disease, subjects will not receive any additional treatment from GSK after 
completion of the study. The investigator (or subinvestigator) is responsible for ensuring that 
consideration has been given to post-study care of the subject’s medical condition. 
 
Revised Text: 
Since the target disease studied is not life-threatening or severely debilitating and there are alternative 
treatments for the target disease, subjects will not receive any additional treatment from GSK after 
completion of the study. Regardless of whether the sponsor provides specific treatments after the 
completion of the study, the investigator (or subinvestigator) is responsible for ensuring that 
consideration has been given to post-study care of the subject’s medical condition. 
 
Reason: 
To correct an error. 
 
 
7.1. 
Time and Events Table: Table 6    Time and Events Table, To add additional row 
for screening and move ‘informed consent’ to the left low 
 
Reason: 
To clarify the informed consent process.  
 
 
7.1. 
Time and Events Table: Table 6    Time and Events Table, To add footnote 11 
Revised Text: 
11. In the rescreening case, the previous result of ophthalmology exam at the screening may be used 
and the ophthalmology exam at the rescreening is not necessary, if the subject meets all of the 
following criteria and the investigator judges it appropriate. 
• 
There were no findings that would suggest a repeat ophthalmology exam performed within 
the next 3 months at the latest screening ophthalmology exam. 
• 
Subjects had no new eye-related symptoms or complaints since the latest screening 
ophthalmology exam until rescreening.  
• 
The latest screening ophthalmology exam was performed within 3 months prior to 
anticipated Day 1. 
 
Reason: 
To clarify the ophthalmology exam procedure at rescreening. 
 
 


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7.4.6. 
Clinical Laboratory Assessments 
Original Text: 
 
 
Revised Text: 
 
 
Reason: 
To correct an error. 
 
 
12.6.6. 
Reporting of SAEs to GSK 
Original Text: 
• 
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, 
 
 
Revised Text: 
• 
Site will enter the serious adverse event data into the electronic system as soon as it becomes 
available. 
• 
The investigator will confirm that causal relationship of SAE has been considered, by ticking the 
'reviewed' box at the bottom of eCRF page within 72 hours following the submission of SAE. 
• 
After the study is completed at a given site, 
 
Reason: 
To reflect amendment of procedure. 
 


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12.8.3. 
Amendment 3 － Summary of Changes and Rationale 
This is applicable to all study sites. 
 
List of Protocol Changes with Rationale for Each 
 
Sponsor Signatory: 
Original Text: 
Hiromu Nakajima 
Head, 
Medicines Development, 
Japan Development and Medical Affairs (JDMA), 
GlaxoSmithKline K. K. 
 
Revised Text: 
Kihito Takahashi 
Director 
Japan Development and Medical Affairs (JDMA), 
GlaxoSmithKline K. K. 
 
Reason: 
To reflect change of Sponsor Signatory. 
 
 
Emergency Contact 
Original Text: 
Emergency Contact at night and holiday (Mon to Fri 6pm to 10am, Sat, Sun, national holiday and 
year-end and New Year holidays) 
Bell Medical Solutions Inc. 
 
Revised Text: 
Emergency Contact at night and holiday (Mon to Fri 6pm to 10am, Sat, Sun, national holiday and 
year-end and New Year holidays) 
BI Medical Inc. 
 
Reason: 
To reflect change of company name. 
 
 


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5.2. 
Exclusion Criteria 
Original Text: 
8. 
Liver disease (if any of the following occurs): 
• 
ALT > 2 x upper limit of normal (ULN) 
• 
Bilirubin > 1.5 x ULN (If bilirubin fractions are measured and direct bilirubin is < 35%, 
isolated bilirubin > 1.5 x ULN will be acceptable.) 
 
Revised Text: 
8. 
Liver disease (if any of the following occurs): 
• 
(Screening verification only): ALT > 2 x upper limit of normal (ULN) 
• 
(Screening verification only): Bilirubin > 1.5 x ULN (If bilirubin fractions are measured and 
direct bilirubin is < 35%, isolated bilirubin > 1.5 x ULN will be acceptable.) 
 
Reason: 
To clarify the timing of eligibility assessment regarding exclusion criteria. 
 
 
6.10.2. 
Prohibited Medications and Non-Drug Therapies 
Original Text: 
None 
 
Revised Text: 
Use of the following drug; from HD induction until the end of the treatment period for newly started 
dialysis, from 8 weeks prior to screening until the end of the treatment period for maintenance HD: 
• 
Erythropoietin (e.g., epoetin/ darbepoetin alfa/ epoetin beta pegol) 
 
Reason: 
To clarify that there is a limitation to use erythropoietin. 
 
 
7.1. 
Time and Events Table 
Original Text: 
Unless otherwise specified, all assessments should occur before dialysis on the day. 
 
Revised Text: 
In any case, the study visit should occur on the first dialysis session day of the week. Unless otherwise 
specified, all assessments should occur before dialysis on the day. 
 
Reason: 
To clarify study proceduer. 
 
 


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7.4.2. 
Adverse Events of Special Interest 
Original Text: 
• 
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 
• 
Death, myocardial infarction (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  
• 
Exacerbation of inflammatory joint disease (e.g., rheumatoid arthritis) 
 
Revised Text: 
• 
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 
• 
Death, myocardial infarction (MI), stroke, congestive heart failure, venous thromboembolism, 
thrombosis of vascular access 
• 
Cardiomyopathy   
• 
Pulmonary artery hypertension 
• 
Cancer-related mortality and tumor progression and recurrence  
• 
Esophageal and gastric erosions 
• 
Proliferative retinopathy, macular edema, choroidal neovascularization  
• 
Exacerbation of rheumatoid arthritis 
 
Reason: 
To edit to correct text. 
 
 
12.2. 
Appendix 2: Risk Assessment: ‘Mitigation Strategy’ with regards to one of Potential 
Risks: Drug-drug interactions 
Original Text: 
These risks have been identified as AEs of special interest and will be monitored instreamly by the 
internal safety review team throughout the study period. 
 
Revised Text: 
Safety data will be monitored instreamly by the internal safety review team throughout the study 
period. 
 
Reason: 
To edit to correct text. 
 


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12.8.4. 
Amendment 4 － Summary of Changes and Rationale 
This is applicable to all study sites. 
 
List of Protocol Changes with Rationale for Each 
 
1. 
PROTOCOL SYNOPSIS FOR STUDY PHI204716 
Original Text:  
For the change from baseline in Hgb at Week 4, the summary statistics will be calculated, along with 
the two-sided 95% confidence interval based on t-distribution. The change in Hgb at Week 4 will be 
classified into different categories (i.e., <-2, -2 to -1, -1 to 0, 0 to 1, 1 to 2, and >2 g/dL), and the 
number (%) of subjects in each category will be summarized. 
 
Revised Text: 
For the change from baseline in Hgb at Week 4, the summary statistics will be calculated, along with 
the two-sided 95% confidence interval based on t-distribution. The change in Hgb at Week 4 will be 
classified into different categories (i.e., -2, >-2 to -1, >-1 to 0, >0 to 1, >1 to 2, and >2 g/dL), and the 
number (%) of subjects in each category will be summarized. 
 
Reason: 
To update of the category for Hgb change from baseline at Week 4. 
 
 
5.3. 
Screening Failures 
Original Text:  
Screen failures are defined as subjects who consent to participate in the clinical trial and are screened, 
but are not subsequently officially enrolled in the study. 
 
Revised Text: 
Screen failures are defined as subjects who consent to participate in the clinical trial, but are not 
subsequently officially enrolled in the study. 
 
Reason: 
To change for definition of screen failures. 
 
 
5.4. 
Withdrawal Criteria 
Original Text:  
• 
Need for chronic (more than 14 days) use of prohibited medication 
 
Revised Text: 
• 
Need for chronic (more than 14 days) use of prohibited medication (strong inhibitors/ inducers of 
CYP2C8 meet this criteria) 
 


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Reason: 
To clarify the withdrawal criteria for prohibited medication. 
 
6.8. 
Treatment of Study Treatment Overdose 
Original Text:  
No text 
 
Revised Text: 
In this study, an overdose of GSK1278863 is defined as any dose greater than the highest daily dose 
included in the protocol. 
 
Reason: 
To clarify the definition of overdose of GSK1278863. 
 
 
7.4.2. 
Adverse Events of Special Interest 
Original Text:  
• 
Death, myocardial infarction (MI), stroke, congestive heart failure, venous thromboembolism, 
thrombosis of vascular access 
 
Revised Text: 
• 
Death, myocardial infarction (MI), stroke, heart failure, thromboembolic events, thrombosis of 
vascular access 
 
Reason: 
To update AESI. 
 
 
9.3.2. 
Interim Analysis 
Original Text:  
No interim analysis is planned with the statistical aspects. However, since this study will be 
considered as Primary Completion Achieved when 4-week dosing is completed in all subjects, an 
analysis is will be performed based on all collected data. 
 
Revised Text: 
No interim analysis is planned 
 
Reason: 
To cancel the interim analysis. 
 
 


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9.4.1.1. Primary Analysis 
Original Text:  
For the change from baseline in Hgb at Week 4, the summary statistics will be calculated, along with 
the two-sided 95% confidence interval based on t-distribution. The change in Hgb at Week 4 will be 
classifieds into different categories (i.e., <-2, -2 to -1, -1 to 0, 0 to 1, 1 to 2, and >2 g/dL), and the 
number (%) of subjects in each category will be summarized. 
 
Revised Text: 
For the change from baseline in Hgb at Week 4, the summary statistics will be calculated, along with 
the two-sided 95% confidence interval based on t-distribution. The change in Hgb at Week 4 will be 
classifieds into different categories (i.e.,-2, >-2 to -1, >-1 to 0, >0 to 1, >1 to 2, and >2 g/dL), and the 
number (%) of subjects in each category will be summarized. 
 
Reason: 
To update of the category for Hgb change from baseline at Week 4. 
 
 
12.2. 
Appendix 2: Risk Assessment: Potential Risk of Clinical Significance 
Original Text:  
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) 
 
Revised Text: 
Risk of death, MI, stroke, heart failure, thromboembolic events, thrombosis of vascular access at Hgb 
levels which are within the normal range (i.e. not polycythemic conditions) 
 
Reason: 
To update AESI. 
 
 

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
204716 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for 204716  
A 24-week, Phase III, open-label, non-comparative, multi-
center study to evaluate efficacy and safety of GSK1278863 
in Japanese hemodialysis subjects with anemia associated 
with chronic kidney disease who are not taking erythropoiesis 
stimulating agents.  
Compound Number  : GSK1278863 
Effective Date  
: 29-Nov-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 204716. 
 
This RAP is intended to describe the 204716 analyses required for the study. 
 
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable. 
 
Author’s Name and Functional Area: 
 
29-Nov-2017 
Biostatistics Group 2, Biomedical Data Sciences Japan 
 
Approved by: 
 
29-Nov-2017 
Manager, Biostatistics Group 2, Biomedical Data Sciences Japan 
 
29-Nov-2017 
Manager, Statistical Programming & Reporting Group, Biomedical 
Data Sciences Japan 
 
Revision History (Appendix 16): 
Version 
Date 
Reporting and Analysis Plan_204716_Final_V1.0 
19-Jun-2017 
Reporting and Analysis Plan_204716_Amendment_Final_V1.1 
11-Oct-2017 
Reporting and Analysis Plan_204716_Amendment_Final_V1.2 
29-Nov-2017 
 
 
PPD
PPD
PPD


 
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The GlaxoSmithKline group of companies 
 
204716 
 
2 
 
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorized copying or use of this information is prohibited. 


 
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TABLE OF CONTENTS 
PAGE 
1. 
REPORTING & ANALYSIS PLAN SYNOPSIS ........................................................... 6 
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.................................................................................................. 10 
2.4. 
Statistical Hypotheses ................................................................................... 10 
3. 
PLANNED ANALYSES .............................................................................................. 11 
3.1. 
Interim Analyses ............................................................................................ 11 
3.2. 
Final Analyses ............................................................................................... 11 
4. 
ANALYSIS POPULATIONS ...................................................................................... 11 
4.1. 
Protocol Deviations ........................................................................................ 12 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ........................................................................................................ 13 
6. 
STUDY POPULATION ANALYSES .......................................................................... 14 
6.1. 
Overview of Planned Analyses ...................................................................... 14 
6.1.1. 
Planned Summary Display Details ................................................ 15 
7. 
PRIMARY STATISTICAL ANALYSES ...................................................................... 19 
7.1. 
Primary Efficacy Analyses ............................................................................. 19 
7.1.1. 
Overview of Planned Primary Efficacy Analyses .......................... 19 
7.1.2. 
Planned Efficacy Statistical Analyses ............................................ 19 
7.1.3. 
Planned Summary Display Details ................................................ 21 
8. 
SECONDARY STATISTICAL ANALYSES ............................................................... 22 
8.1. 
Secondary Efficacy Analyses ........................................................................ 22 
8.1.1. 
Overview of Planned Secondary Efficacy Analyses ...................... 22 
8.1.2. 
Planned Efficacy Table Displays ................................................... 24 
8.1.3. 
Planned Hgb Efficacy Statistical Analyses .................................... 27 
8.2. 
Safety Analyses ............................................................................................. 29 
8.2.1. 
Overview of Planned Adverse Events Analyses ........................... 29 
8.2.2. 
Overview of Planned Clinical Laboratory Analyses ....................... 32 
8.2.3. 
Overview of Planned Other Safety Analyses ................................ 34 
8.3. 
Pharmacokinetic Analyses ............................................................................ 36 
8.3.1. 
Overview of Planned Pharmacokinetic Analyses .......................... 36 
8.3.2. 
Drug Concentration Measures ....................................................... 36 
8.3.3. 
Pharmacokinetic Parameters ......................................................... 37 
8.3.4. 
Population Pharmacokinetic (PopPK) Analyses ........................... 37 
8.4. 
Pharmacodynamic Analyses ......................................................................... 38 
8.5. 
Pharmacokinetic / Pharmacodynamic Analyses ........................................... 38 
9. 
REFERENCES .......................................................................................................... 39 


 
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10.  APPENDICES ............................................................................................................ 40 
10.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population........................................................................................ 41 
10.2. 
Appendix 2: Time & Events ........................................................................... 42 
10.2.1. 
Protocol Defined Time & Events .................................................... 42 
10.3. 
Appendix 3: Assessment Windows ............................................................... 44 
10.3.1. 
Definitions of Analysis Time Point ................................................. 44 
10.4. 
Appendix 4: Treatment States and Phases .................................................. 45 
10.4.1. 
Treatment States ............................................................................ 45 
10.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 47 
10.5.1. 
Study Treatment & Sub-group Display Descriptors ...................... 47 
10.5.2. 
Baseline Definition & Derivations................................................... 47 
10.5.3. 
Reporting Process & Standards .................................................... 48 
10.6. 
Appendix 6: Derived and Transformed Data ................................................. 50 
10.6.1. 
General ........................................................................................... 50 
10.6.2. 
Study Population ............................................................................ 51 
10.6.3. 
Efficacy ........................................................................................... 52 
10.6.4. 
Safety ............................................................................................. 57 
10.6.5. 
Pharmacokinetic ............................................................................. 58 
10.7. 
Appendix 7: Premature Withdrawals & Handling of Missing Data ................ 60 
10.7.1. 
Premature Withdrawals .................................................................. 60 
10.7.2. 
Handling of Missing Data ............................................................... 60 
10.8. 
Appendix 8: Values of Potential Clinical Importance .................................... 61 
10.8.1. 
Laboratory Values .......................................................................... 61 
10.8.2. 
Vital Signs ...................................................................................... 61 
10.9. 
Appendix 9: Multicenter Studies .................................................................... 62 
10.10.  Appendix 10: Examination of Covariates, Subgroups & Other Strata .......... 63 
10.10.1.  Handling of Covariates, Subgroups & Other Strata ...................... 63 
10.11.  Appendix 11: Multiple Comparisons & Multiplicity ........................................ 64 
10.11.1.  Handling of Multiple Comparisons & Multiplicity............................ 64 
10.12.  Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses ........................................................................................................ 65 
10.13.  Appendix 13 – Abbreviations & Trade Marks ................................................ 66 
10.13.1.  Abbreviations ................................................................................. 66 
10.13.2.  Trademarks .................................................................................... 67 
10.14.  Appendix 14: List of Data Displays ............................................................... 68 
10.14.1.  Data Display Numbering ................................................................ 68 
10.14.2.  Mock Example Shell Referencing .................................................. 68 
10.14.3.  Study Population Tables ................................................................ 69 
10.14.4.  Efficacy Tables ............................................................................... 72 
10.14.5.  Efficacy Figures .............................................................................. 77 
10.14.6.  Safety Tables ................................................................................. 80 
10.14.7.  Safety Figures ................................................................................ 85 
10.14.8.  Pharmacokinetic Tables ................................................................. 86 
10.14.9.  Pharmacokinetic Figures ............................................................... 87 
10.14.10. ICH Listings .................................................................................... 89 
10.14.11. Non-ICH Listings ............................................................................ 93 
10.14.12. Patient Profile Listings ................................................................... 96 
10.15.  Appendix 15: Example Mock Shells for Data Displays ................................. 98 
10.16.  Appendix 16: RAP Amendment(s) ................................................................ 99 


 
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1. 
REPORTING & ANALYSIS PLAN SYNOPSIS 
Overview 
Key Elements of the RAP 
Purpose 
 
This RAP describes the planned analyses and outputs required for the final 
Clinical Study Report (CSR) for study 204716. 
Protocol 
 
This RAP is based on the protocol amendment v04 (Dated: 19/Jul/2017) of 
study 204716 (GSK Document No.2015N266250_04]. 
Primary 
Objective  
 
To characterize the appropriateness of the starting dose of GSK1278863 in HD 
patients not using ESAs 
Primary 
Endpoint 
 
Change from baseline in Hgb at Week 4 
 
Number (%) of subjects by Hgb change from baseline category at Week 4 
Study 
Design 
 
This is a 24-week, Phase III, open-label, non-comparative, multi-center study to 
evaluate efficacy and safety of GSK1278863 in approximately 22 Japanese 
hemodialysis subjects with anemia associated with chronic kidney disease who 
are not taking erythropoiesis stimulating agents. 
Planned 
Analyses 
 
No interim analysis is planned. 
 
Final analyses will be performed according to the steps described in Section 
3.2. 
 
All decisions regarding final analyses, as defined in this RAP document, will be 
made prior to Database Freeze of the study data. 
Analysis 
Populations 
 
All Screening Population will consist of all subjects who are given subject 
number and are collected data at screening. 
 
Enrolled Population will consist of subjects in ‘All Screening’ except for screen 
failures (who never passed screening even if rescreened). 
 
Assigned Population will consist of all randomized subjects regardless of study 
treatment actually received or not 
 
All Treated Subjects Population will consist of all subjects who receive at least 
one dose of GSK1278863. 
 
Pharmacokinetic (PK) Population will consist of all subjects who received 
GSK1278863 with the PK samples collected and analysed. 
Hypothesis 
 
This single arm study is a study with an aim of an estimation. The primary 
objective of this study is to evaluate the initial anemia correction of 
GSK1278863 in HD patients not using ESAs. There will be no hypothesis 
testing performed in this study. 
Primary 
Analyses 
 
For the change from baseline in Hgb at Week 4, the summary statistics will be 
calculated, along with the two-sided 95% confidence interval based on t-
distribution.  
 
The change in Hgb at Week 4 will be classified into different categories (i.e., -


 
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Overview 
Key Elements of the RAP 
2, >-2 to -1, >-1 to 0, >0 to 1, >1 to 2, and >2 g/dL), and the number (%) of 
subjects in each category will be summarized. 
 


 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
No changes from the originally planned statistical analysis specified in the protocol 
amendment v04 (Dated: 19/Jul/2017) are present. 
 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary 
 
To characterize the appropriateness of 
the starting dose of GSK1278863 in HD 
patients not using ESAs 
 
Change from baseline in Hgb at Week 4 
 
Number (%) of subjects by Hgb change from 
baseline category at Week 4 
Secondary 
 
To characterize overall Hgb control of 
GSK1278863 in HD patients not using 
ESAs 
 
 
Hgb and changes from baseline 
 
Number (%) of subjects who have a Hgb 
level within the target range (10.0–12.0 g/dL)  
 
Time (in days) to reach the lower target Hgb 
level (10.0 g/dL)  
 
Number (%) of subjects who have a Hgb 
level of less than < 7.5 g/dL 
 
Number (%) of subjects who have a Hgb 
increase of more than > 2-g/dL over any 4 
weeks 
 
Number (%) of subjects who have a Hgb 
level of more than > 13.0 g/dL and number of 
episodes 
 
To characterize the pharmacokinetics of 
GSK1278863 
 
AUC and Cmax of plasma GSK1278863 
 
To characterize the effect on iron use of 
GSK1278863 in HD patients not using 
ESAs 
 
Dose of intravenous iron 
 
Number (%) of subjects who used 
intravenous iron 
 
To characterize the effect on iron 
metabolism of GSK1278863 in HD 
patients not using ESAs 
 
Change from baseline in ferritin 
 
Change from baseline in transferrin 
saturation  


 
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Objectives 
Endpoints 
 
 
Changes from baseline in hepcidin, serum 
iron, and total iron binding capacity (TIBC) 
 
To characterize dose adjustment of 
GSK1278863 in HD patients not using 
ESAs 
 
Distribution of dose level 
 
Frequency of dose adjustments 
 
Duration of treatment interruption due to Hgb 
> 13 g/dL 
Safety 
 
To assess the safety and tolerability of 
GSK1278863 in HD patients not using 
ESAs 
 
Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
including adverse events of special interest 
(AESIs) 
 
Reasons for discontinuation of study 
medication 
 
Laboratory tests, electrocardiogram (ECG), 
vital signs, and ophthalmology assessments 
 
 


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
 
 
 
 
 
 
 
 
Screening period 
(4 weeks) 
 
Fixed-dose period 
Dose adjustment period  
(target Hgb 10-12 g/dL)  
(20 weeks) 
 
Follow-up period 
(2–4 weeks) 
 
(4 weeks) 
 
 
 
 
 
 
 
 
 
Patients on 
hemodialysis or 
hemodiafiltration 
not using ESAs 
 
GSK1278863(N=22) 
 
 
 
 
 
 
 
 
 
 
Week -4                Day 1              Week 4                    Week 24              Week 26-28
 
 
Design Features 
 This is a 24-week, Phase III, open-label, non-
comparative, multi-center study to evaluate the efficacy 
and safety of GSK1278863 in Japanese HD patients 
with renal anemia not using ESAs.  
 This study will consist of a 4-week screening period, a 
24-week treatment period (4-week fixed-dose period 
and a 20-week dose adjustment period), and a 2- to 4-
week follow-up period.  
Dosing 
 Subjects meeting the eligibility criteria will receive 
GSK1278863 orally once daily initially at 4 mg for 4 
weeks from Day 1. Subsequently, subjects will receive 
GSK1278863 orally once a day according to follow a 
pre-defined study treatment dose adjustment algorithm 
to achieve or maintain Hgb within the target range 
(10.0–12.0 g/dL). 
 Further details of administration schedule are provided 
protocol Section 6.3 
Treatment Assignment 
 This is an open-label, non-comparative study. All 
eligible subjects will take GSK1278863. 
Interim Analysis 
 No interim analysis is planned. 
 
2.4. 
Statistical Hypotheses 
This single arm study is a study with an aim of an estimation. The primary objective of 
this study is to evaluate the initial anemia correction of GSK1278863 in HD patients not 


 
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11 
 
 
using ESAs. There will be no hypothesis testing performed in this study. Two-sided 95% 
confidence intervals will be used for efficacy estimation. 
 
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 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 Data Management. 
3. All criteria for releasing the randomization codes have been met.  
4. Randomization codes have been distributed according to RandAll NG procedures. 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
All Screening 
 Consists of all subjects who are given subject 
number and are corrected data at screening. 
 Study Population 
Enrolled 
 Consist of subjects in 'All Screening' except for 
screen failure (who never passed screening 
even if rescreened). 
 Study Population 
(some displays for 
EudraCT) 
Assigned 
 Consist of all subjects who are given 
randomization number regardless of whether 
they actually receive GSK1278863. 
 Study Population 
All Treated 
Subjects 
 Consist of all subjects who received at least 
one dose of GSK1278863.  
 Study Population 
 Efficacy 

Safety 
PK 
 Consist of all subjects who received 
GSK1278863 with the PK samples collected 
and analyzed. 
 PK 
NOTES :  
 
Basically, enrolled population will be the same as assigned population because a subject is going to be given 
randomized number as soon as passed screening  
 
Please refer to Appendix 14: List of Data Displays which details the population to be used for each displays being 
generated. 
 


 
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4.1. 
Protocol Deviations 
 
Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed. 
 
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. 
 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan. 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorized on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions.  
Table 1 
Overview of Appendices 
Section Component 
10.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
10.2 
Appendix 2: Time & Events 
10.3 
Appendix 3: Assessment Windows 
10.4 
Appendix 4: Treatment States and Phases 
10.5 
Appendix 5: Data Display Standards & Handling Conventions 
10.6 
Appendix 6: Derived and Transformed Data 
10.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
10.8 
Appendix 8: Values of Potential Clinical Importance 
10.9 
Appendix 9: Multicenter Studies 
10.10 
Appendix 10: Examination of Covariates, Subgroups & Other Strata 
10.11 
Appendix 11: Multiple Comparisons & Multiplicity 
10.12 
Appendix 12: Model Checking and Diagnostics for Statistical Analyses. 
 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Analyses 
The study population analyses will be based on the All Treated Subjects population, 
unless otherwise specified. 
Table 2 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 2 
Overview of Planned Study Population Analyses 
Endpoint / Parameter / Display Type 
Population 
Data Displays Generated 
Table 
Figure 
Listing 
Subject Disposition 
Subject Status and Reason for Study Withdrawal 
Assigned 
Y 
 
 
Subject Status and Reason for Study Withdrawal 
  by Dialysis Status 
Assigned 
Y 
 
 
Reasons for Subject Withdrawal 
Assigned 
 
 
Y 
Treatment Status and Reasons for Discontinuation of 
Study Treatment 
All Treated 
Y 
 
Y 
Screening Status and Reasons for Screen Failure 
All Screening 
Y 
 
Y 
Subjects Enrolled by Country and Site ID 
Enrolled 
Y 
 
 
Protocol Deviations 
Important Protocol Deviations 
Assigned 
Y 
 
Y 
Subjects with Inclusion/Exclusion Criteria Deviations 
Assigned 
Y 
 
Y 
Populations Analyzed 
Study Populations 
All Screening 
Y 
 
 
Exclusions from Study Population 
Assigned 
Y 
 
 
Subjects Excluded from Any Population 
Assigned 
 
 
Y 
Demographic and Baseline Characteristics 
Demographic Characteristics 
All Treated 
Y 
 
Y 
Demographic Characteristics 
  by Dialysis Status 
All Treated 
Y 
 
 
Age Ranges 
Enrolled 
Y 
 
 
Race and Racial Combinations 
All Treated 
Y 
 
Y [1] 
Family History for CV Risk Factors 
All Treated 
Y 
 
Y 
Substance Use (History of Tobacco Use, Alcohol Intake) 
All Treated 
Y 
 
Y 
Prior and Concomitant Medications 
Current/Past Medical Conditions 
All Treated 
Y 
 
Y 
Current/Past Medical Conditions 
  by Dialysis Status 
All Treated 
Y 
 
 
Concomitant Medications [2] 
All Treated 
Y 
 
Y 
Other Concomitant Medications [3] 
All Treated 
Y 
 
Y 


 
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Endpoint / Parameter / Display Type 
Population 
Data Displays Generated 
Table 
Figure 
Listing 
Other Concomitant Medications [3] 
  by Dialysis Status 
All Treated 
Y 
 
 
Blood products and blood supportive care products [4] 
All Treated 
Y 
 
Y 
Blood products and blood supportive care products [4] 
  by Dialysis Status 
All Treated 
Y 
 
 
Dialysis 
Dialysis Status 
All Treated 
Y 
 
Y 
Baseline Mode of Dialysis 
All Treated 
Y 
 
Y 
Subjects with Change in Hemodialysis 
All Treated 
 
 
Y 
Baseline Vascular Access 
All Treated 
Y 
 
Y 
Subjects with Vascular Therapeutic Procedures during 
the study period 
All Treated 
 
 
Y 
Exposure and Treatment Compliance 
Exposure to Study Treatment 
All Treated 
Y 
 
Y 
Exposure to Study Treatment 
  by Dialysis Status 
All Treated 
Y 
 
 
Treatment Compliance 
All Treated 
Y 
 
Y 
NOTES : 
 
Y = Yes display generated. 
 
Some summaries will be generated as efficacy analyses. 
[1] Listing of race. 
[2] Concomitant medications in prior-therapy period, on-therapy period, and post-therapy period will be 
summarized separately. 
[3] On-therapy ESA and iron medication will be provided. 
[4] On-therapy blood products and blood supportive care products will be provided. 
 
6.1.1. 
Planned Summary Display Details 
A subject who has multiple subject numbers (i.e. rescreened subject) will be analyzed as 
a unique subject based on the latest screening result. 
The definition of subgroup is described in Appendix 10. 
 
Subject Disposition 
Subject Status and Reason for Study Withdrawal 
The number and percentage of subjects completing the study or withdrawing early from 
the study will be summarized overall and by reason for withdrawal. Reasons for 
withdrawal will be listed for subject. The subgroup analysis for dialysis status will be 
summarized as the same. 
Treatment Status and Reasons for Discontinuation of Study Treatment 


 
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The number and percentage of subjects completing the treatment or discontinuing the 
treatment during the study will be summarized overall and by reason. 
Screening Status and Reasons for Screen Failure 
The number and percentage of subjects who failed screening and were therefore not 
randomized into the study, overall and by reason, will be summarized for all screening 
population. Note that the reasons for rescreen subjects who initially failed but 
subsequently enrolled are not included in the display (see Section 10.6.2). 
Subjects Enrolled by Country and Site ID 
The number and percentage of subjects by region, country and center will be 
summarized. 
 
Protocol Deviations 
Important Protocol Deviations 
The number and percentage of subjects who had important protocol deviations defined in 
PDMP will be summarized. 
Subjects with Inclusion/Exclusion Criteria Deviations 
The number and percentage of subjects with any Inclusion/Exclusion Criteria Deviations 
will be summarized, further classifying inclusion/exclusion deviations. 
 
Population Analyzed 
Study Populations 
The number of subjects in each analysis population (defined in Section 4) will be 
summarized.  
Exclusions from Study Population 
The number of subjects excluded from All Treated Subjects population will be 
summarized for the assigned population. 
 
Demographic and Baseline Characteristics 
Demographic Characteristics 
The number and percentage of subjects or summary statistics will be provided for the 
demographic and baseline characteristics: Sex, Age (years), Age Group (years), Ethnicity, 
Race detail, Height, Weight, and Body Mass Index.  Age Group (years) will be 
categorized into 3 ('<=18', '19-64', '>=65'). The subgroup analysis for dialysis status will 
be summarized as the same. 


 
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Age Ranges 
The number and percentage of subjects within each age range category will be provided. 
Age range will be categorized into: Adult (18-64 years), >=65-84 years, >=85 years. 
Race and Racial Combinations 
Summaries of race and racial combinations will be provided. 
Family History for CV Risk Factors 
A summary of family (first degree relatives) history for CV risk factors will be provided. 
Substance Use (History of Tobacco Use, Alcohol Intake) 
A summary of substance use will be provided. 
 
Prior and Concomitant Medications 
Current/Past Medical Conditions 
The number and percentage of subjects with current and past medical conditions recorded 
in eCRF will be provided. The subgroup analysis for dialysis status will be summarized 
as the same. 
Concomitant Medications 
The number and percentage of subjects reporting the use of each concomitant medication 
will be summarized by anatomical therapeutic chemical (ATC) Level 1, and Ingredient. 
Summaries of pre-therapy, on-therapy, and post-therapy medication will be provided 
separately. See Section 10.4.1.3 for treatment states for concomitant medications. 
Other concomitant medications 
The similar summary as above will be provided focusing on on-therapy ESA and iron 
medication. See Section 10.4.1.3 for treatment states. The subgroup analysis for dialysis 
status will be summarized as the same. 
Blood products and blood supportive care products 
The number and percentage of subjects who use blood products and/or blood supportive 
care products will be provided. The details for the use will also be provided. The 
subgroup analysis for dialysis status will be summarized as the same. 
 
Dialysis 
Dialysis Status 


 
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The number and percentage of subjects with dialysis status of newly started dialysis and 
maintenance dialysis will be provided. Definitions of dialysis status are described in the 
protocol section 5.3. 
Baseline Mode of Dialysis 
The number and percentage of subjects with each baseline mode of dialysis (i.e. 
haemodialysis, haemofiltration, or haemodiafiltration) will be provided. 
Baseline Vascular Access 
The number and percentage of subjects with each baseline vascular access will be 
provided. Previous vascular access will be summarized as the same. 
 
Exposure and Treatment Compliance 
Exposure to Study Treatment 
Full details of exposure definition are presented in Appendix 6. 
Daily dose, cumulative dose, and days on study drug will be summarized using mean, 
standard deviation, median, minimum, and maximum. Regarding days on study drug, the 
number and percentage of subjects within each category (i.e. 1-28, 29-56, 57-84, 85-112, 
113-140, 141-168, >168 (days)) will also be provided. The subgroup analysis for dialysis 
status will be summarized as the same. 
Treatment Compliance 
Full details of treatment compliance definition are presented in Appendix 6. 
The number and percentage of subjects within each category of treatment compliance 
will be provided and the categories will be classified into <80%, 80% to 120%, and 
>120%. 


 
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7. 
PRIMARY STATISTICAL ANALYSES 
7.1. 
Primary Efficacy Analyses 
7.1.1. 
Overview of Planned Primary Efficacy Analyses 
The primary efficacy analyses will be based on the All Treated Subjects population, 
unless otherwise specified. 
Table 3 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays. 
Table 3 
Overview of Planned Primary Efficacy Analyses 
Endpoint / Parameter/ Display Type 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Change from baseline in Hgb at Week 4 
 
 
 
Y 
 
 
 
Number (%) of subjects by Hgb change from baseline 
category at Week 4 [1] 
 
 
 
Y 
 
 
 
Change from baseline in Hgb at Week 4 
  by Dialysis Status 
 
 
 
Y 
 
 
 
Number (%) of subjects by Hgb change from baseline 
category at Week 4 [1] 
  by Dialysis Status 
 
 
 
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] -2, -2 to -1, -1 to 0, 0 to 1, 1 to 2, and >2 g/dL. In addition, within 1 g/dL and over 2 g/dL. 
 
7.1.2. 
Planned Efficacy Statistical Analyses 
Primary Analyses 
Endpoint(s) 
 Change from baseline in Hgb at Week 4 
 Number (%) of subjects by Hgb change from baseline category at Week 4
Model Specification 
 Hgb values from central laboratory will be used, unless otherwise specified. However, if a 
central laboratory Hgb value is missing, a corresponding non-missing HemoCue Hgb value will 
be used (See Section 10.6.3). 
 The primary analysis is to assess modest increase in Hgb in initial response to GSK1278863 
(i.e., Hgb increase by  2 g/dL after 4 weeks of treatment), on the basis of the mean change 
from baseline in Hgb at Week 4 as well as the number (%) of subjects by Hgb change from 
baseline category at Week 4 as the primary efficacy endpoints. 
 For the change from baseline in Hgb at Week 4, the summary statistics will be calculated, 


 
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along with the two-sided 95% confidence interval based on t-distribution.  
 The change in Hgb at Week 4 will be classifieds into different categories (i.e., -2, >-2 to -
1, >-1 to 0, >0 to 1, >1 to 2, and >2 g/dL), and the number (%) of subjects in each category 
will be summarized. In addition, ‘within  1 g/dL (i.e., -1 and 1 g/dL)’ and ‘over  2 g/dL 
(i.e., <-2 and >2 g/dL)’ categories will be provided. 


 
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7.1.3. 
Planned Summary Display Details 
The definition of subgroup is described in Appendix 10. 
Change from baseline in Hgb at Week 4 
This summary will be included within a summary of change from baseline in Hgb at each 
assessment visit (See Section 8.1.2). The values will be summarized using mean, standard 
deviation, 95%CI, minimum, P25, median, P75, and maximum at Week 4 visit. The 
subgroup analysis will be summarized as the same.  
Number (%) of subjects by Hgb change from baseline category at Week 4 
The number and percentage of subjects within each category will be provided and the 
categories will be classified into -2, >-2 to -1, >-1 to 0, >0 to 1, >1 to 2, and >2 g/dL). In 
addition, ‘within  1 g/dL (i.e., -1 and 1)’ and ‘over  2 g/dL (i.e., <-2 and >2)’ 
categories will be provided. The subgroup analysis will be summarized as the same. 


 
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8. 
SECONDARY STATISTICAL ANALYSES 
8.1. 
Secondary Efficacy Analyses 
8.1.1. 
Overview of Planned Secondary Efficacy Analyses 
The secondary efficacy analyses will be based on the All Treated Subjects population, 
unless otherwise specified.  
Table 4 provides an overview of the planned secondary efficacy analyses, with further 
details of data displays being presented in Appendix 14: List of Data Displays. 
Table 4 
Overview of Planned Efficacy Analyses 
Endpoint / Parameter/ Display Type 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
T 
F 
F 
L 
Hgb 
Hgb at each assessment visit 
 
 
Y 
Y 
 
Y 
Hgb at each assessment visit 
  by Dialysis Status 
 
 
Y 
Y 
 
 
Change from baseline at each assessment visit 
 
 
Y 
Y 
 
Y 
Change from baseline at each assessment visit 
  by Dialysis Status 
 
 
Y 
Y 
 
 
Number (%) of subjects with Hgb within the target range 
at each assessment visit [1] 
 
 
Y 
Y 
 
 
Number (%) of subjects with Hgb within the target range 
at each assessment visit [1] 
  by Dialysis Status 
 
 
Y 
Y 
 
 
Time (in days) to reach the lower target Hgb level 
(10.0 g/dL) [2] [3] 
Y 
Y 
 
 
 
 
Time (in days) to reach the lower target Hgb level 
(10.0 g/dL) [2] [3] 
  by Dialysis Status 
Y 
Y 
 
 
 
 
Number (%) of subjects who have an Hgb level of less 
than 7.5 g/dL [3] 
 
 
Y 
 
 
Y 
Number (%) of subjects who have an Hgb level of less 
than 7.5 g/dL [3] 
  by Dialysis Status 
 
 
Y 
 
 
 
Number (%) of subjects who have an Hgb increase of 
more than 2.0 g/dL over any 4 weeks [3] 
 
 
Y 
 
 
Y 
Number (%) of subjects who have an Hgb increase of 
more than 2.0 g/dL over any 4 weeks [3] 
  by Dialysis Status 
 
 
Y 
 
 
 
Number (%) of subjects who have an Hgb level of more 
than 13.0 g/dL and number of episodes [3] 
 
 
Y 
 
 
Y 
Number (%) of subjects who have an Hgb level of more 
than 13.0 g/dL and number of episodes [3] 
  by Dialysis Status 
 
 
Y 
 
 
 
Hemocue Hgb 
 
 
 
 
 
Y 


 
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Endpoint / Parameter/ Display Type 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
T 
F 
F 
L 
Scatter plot of Hgb assessments: Central Laboratory vs. 
HemoCue 
 
Y 
 
 
 
 
Iron use 
Dose of i.v. iron during the treatment period 
 
 
Y 
 
 
Y 
Dose of i.v. iron during the treatment period 
  by Dialysis Status 
 
 
Y 
 
 
 
Number (%) of subjects who use iron during the treatment 
period 
 
 
Y 
 
 
 
Number (%) of subjects who use iron during the treatment 
period 
  by Dialysis Status 
 
 
Y 
 
 
 
Iron Parameters (ferritin, TSAT [4], hepcidin [4], serum iron, and TIBC) 
Raw observed value at each assessment visit 
 
 
Y 
 
 
Y 
Raw observed value at each assessment visit 
  by Dialysis Status 
 
 
Y 
 
 
 
Change from baseline at each assessment visit 
 
 
Y 
Y 
 
 
Change from baseline at each assessment visit 
  by Dialysis Status 
 
 
Y 
 
 
 
Dose adjustment [5] 
Dose level (mg) at each assessment visit 
 
 
Y 
Y 
 
Y 
Dose level (mg) at each assessment visit 
  by Dialysis Status 
 
 
Y 
Y 
 
 
Duration (days) of treatment interruption due to Hgb 
>13.0 g/dL [3] 
 
 
Y 
 
 
 
Duration (days) of treatment interruption due to Hgb 
>13.0 g/dL [3] 
  by Dialysis Status 
 
 
Y 
 
 
 
Dose adjustment 
 
 
Y 
 
 
 
Dose adjustment 
  by Dialysis Status 
 
 
Y 
 
 
 
Number (%) of subjects with each dose level at each 
assessment visit 
 
 
Y 
 
 
 
Number (%) of subjects with each dose level at each 
assessment visit 
  by Dialysis Status 
 
 
Y 
 
 
 
Number of dose adjustment to reach the lower Hgb target 
Hgb level (10.0 g/dL) 
 
 
Y 
 
 
 
Number of dose adjustment to reach the lower Hgb target 
Hgb level (10.0 g/dL) 
  by Dialysis Status 
 
 
Y 
 
 
 
Other 
Scatter plot of change from baseline in Hgb at Week 4 vs. 
candidate covariates [6] 
 
 
 
Y 
 
 
Scatter plot of mean dose vs. candidate covariates [6] 
 
 
 
Y 
 
 
NOTES : 
[1] Not only within the target range, but also subjects with above and below target range will be assessed. 
[2] Time to first reach the lower target Hgb level will be estimated by Kaplan-Meier method using P25, median and 
P75. Subjects who could not reach lower target will be regarded as censored. 


 
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Endpoint / Parameter/ Display Type 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
T 
F 
F 
L 
[3] On-therapy Hgb values observed in scheduled visits will be included. On-therapy Hgb values observed in 
unscheduled visits will be included if specified (see Section 8.1.2) 
[4] Based on literature review the distributions of TSAT and hepcidin are skewed and require a log-transformation. 
[5] Summaries for dose adjustment will be based on HemoCue Hgb values including those of unscheduled visits. 
[6] Figures will include the candidate covariates of body weight and baseline Hgb, and will be produced for overall 
and dialysis status groups. 
 
8.1.2. 
Planned Efficacy Table Displays 
 
Hgb 
Hgb at each assessment visit 
The values will be summarized using mean, standard deviation, 95%CI, minimum, P25, 
median, P75, and maximum at each assessment visit. Graphical summaries will be 
provided using mean and 95% CI over time. The subgroup analysis for dialysis status 
will be summarized as the same.  
Change from baseline at each assessment visit 
The values will be summarized using mean, standard deviation, 95%CI, minimum, P25, 
median, P75, and maximum at each assessment visit. Graphical summaries will be 
provided using mean and 95% CI over time. This will be also summarized by baseline 
dialysis status.  
Number (%) of subjects with Hgb within the target range at each assessment visit 
The number and percentage of subjects with Hgb within, above and below the target 
range at each assessment visit will be summarized. This will be also summarized by 
baseline dialysis status. 
Time (in days) to reach the lower target Hgb level (10.0 g/dL) 
The time (in days) will be summarized using P25, median, and P75 by Kaplan-Meier 
method. Kaplan-Meier plot of time to event will be provided using on-therapy Hgb 
values. Subjects who could not reach lower target will be regarded as censored. This will 
be also summarized by baseline dialysis status. 
Number (%) of subjects who have an Hgb level of less than 7.5 g/dL 
The number and percentage of subjects who have an Hgb level of less than 7.5 g/dL will 
be summarized. On-therapy Hgb values observed in both scheduled and unscheduled 
visits will be included in the summary. This will be also summarized by baseline dialysis 
status.  


 
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Number (%) of subjects who have an Hgb increase of more than 2.0 g/dL over any 4 
weeks 
The number and percentage of subjects who have an Hgb increase of more than 2.0 g/dL 
over any 4 weeks will be summarized. On-therapy Hgb values will be used for the 
summary. This will be also summarized by baseline dialysis status. See Section 10.6.3 for 
detailed derivation. 
Number (%) of subjects who have an Hgb level of more than 13.0 g/dL and number of 
episodes 
The number and percentage of subjects who have an Hgb level of more than 13.0 g/dL 
and number of episodes will be summarized. On-therapy Hgb values observed in both 
scheduled and unscheduled visits will be included in the summary. This will be also 
summarized by baseline dialysis status. 
Scatter plot of Hgb assessments: Central Laboratory vs. HemoCue 
A scatter plot of Hgb values measured by Central Laboratory versus Hgb values 
measured by Hemocue will be produced along with Pearson’s correlation coefficient. All 
available pairs of Hgb (i.e. non-missing values in both from central laboratory and from 
the corresponding HemoCue measurement) will be used. 
 
Iron Use 
Dose of i.v. iron during the treatment period 
Average quarterly i.v. iron dose (See Section 10.6.3) will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum. Quarter 1 (Day 1 to 
Week 12) and Quarter 2 (Week 12 to Week 24) will be used. This will be also 
summarized by baseline dialysis status. 
Number (%) of subjects who use iron during the treatment period 
The number and percentage of subjects who use iron (both i.v. and oral iron) during the 
treatment period will be summarized. This will be also summarized by baseline dialysis 
status. 
 
Iron Parameter (ferritin, TSAT, hepcidin, serum iron, and TIBC) 
Based on literature review the distributions of TSAT and hepcidin are skewed and require 
a log-transformation (See Section 10.6.3).  
Raw observed value at each assessment visit 
Ferritin, serum iron, and TIBC values will be summarized using mean, standard deviation, 
95%CI, minimum, P25, median, P75, and maximum at each assessment visit. TSAT and 
hepcidin values will be summarized using geometric mean, standard error, coefficient of 


 
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variation, and 95%CI based on log-transformed parameters, and median, minimum, and 
maximum based on original scale at each assessment visit. This will be also summarized 
by baseline dialysis status. 
Change from baseline at each assessment visit 
Change from baseline in Ferritin, serum iron, and TIBC values will be summarized using 
mean, standard deviation, 95%CI, minimum, P25, median, P75, and maximum at each 
assessment visit. Percent Change from baseline in TSAT and hepcidin values will be 
summarized using geometric mean and 95%CI based on log-transformed parameters, and 
median, minimum, and maximum based on original scale at each assessment visit. 
Graphical summaries will be provided using mean and 95% CI over time. This will be 
also summarized by baseline dialysis status. 
 
Dose adjustment 
The dose adjustment algorithm is described in Section 10.6.3, based on HemoCue Hgb 
values including those in both scheduled and unscheduled visits 
Dose level (mg) at each assessment visit 
The values will be summarized using mean, standard deviation, minimum, P25, median, 
P75, mode, and maximum at each assessment visit. The mean dose during Week 12 to 24 
will also be summarized. This will be also summarized by baseline dialysis status. 
Duration (days) of treatment interruption due to Hgb >13.0 g/dL 
The number and percentage of subjects who have a period of treatment interruption due 
to Hgb >13.0 g/dL will be summarized. On subjects who have a period of treatment 
interruption due to Hgb >13.0 g/dL, the duration (in days) of treatment interruption due 
to Hgb >13.0 g/dL per subject will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum. Hgb values observed in both scheduled and 
unscheduled visits will be counted in the summary. This will be also summarized by 
baseline dialysis status. 
Dose adjustment 
The number and percentage of subjects with dose adjustments will be provided. Number 
of dose adjustments will be summarized using mean, standard deviation, minimum, 
median, mode, and maximum. For dose adjustments frequency, the number and 
percentage of subjects will be provided by the number of dose adjustments (i.e. zero, one, 
two, three, four, and five or more). For timing of dose adjustments, the number and 
percentage of subjects with dose adjustments by each assessment visit will be provided. 
This will be also summarized by baseline dialysis status. 
Number (%) of subjects with each dose level at each assessment visit 


 
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The number and percentage of subjects with each dose level adjustments will be provided. 
Graphical summaries will be provided with the number of subjects in each dose level. 
Dose level categories will be classified into 10; W/d (early withdrawal), 0 mg (treatment 
interruption), 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 12 mg, 18 mg, and 24 mg). This will be also 
summarized by baseline dialysis status. 
Number of dose adjustment to reach the lower Hgb target (10.0 g/dL) 
The number and percentage of subjects with dose adjustments to reach the lower Hgb 
target will be provided on the basis of on-therapy Hgb. Number of dose adjustment to 
reach the lower Hgb target will be summarized using mean, standard deviation, minimum, 
median, mode, and maximum. For dose adjustments frequency, the number and 
percentage of subjects will be provided by the number of dose adjustments (i.e., zero, one, 
two, three, four, five or more). Subjects who does not reach the lower Hgb target during 
treatment period will be excluded from the summary. This will be also summarized by 
baseline dialysis status. 
 
Other 
The following two sorts of scatter plots of interest will be produced for overall and 
dialysis status groups:  
 
Change from baseline in Hgb at Week 4 versus the candidate covariates 
 
Mean dose during Week 12 to 24 versus the candidate covariates 
See Appendix 10 for the candidate covariates and Section 10.6.3 for the detailed 
derivations.  
 
8.1.3. 
Planned Hgb Efficacy Statistical Analyses 
Secondary Hgb Analyses 
Endpoint(s) 
 Hgb and changes from baseline 
 Number (%) of subjects who have a Hgb level within the target range (10.0–12.0 g/dL)   
 Time (in days) to reach the lower target Hgb level (10.0 g/dL)  
 Number (%) of subjects who have a Hgb level of less than 7.5 g/dL 
 Number (%) of subjects who have a Hgb increase of more than 2.0 g/dL over any 4 weeks 
 Number (%) of subjects who have a Hgb level of more than 13.0 g/dL and number of episodes 
Model Specification 
 Hgb values from central laboratory will be used, unless otherwise specified. However, if a 
central laboratory Hgb value is missing, a corresponding non-missing HemoCue Hgb value will 
be used (See Section 10.6.3). 
 The secondary analysis is to assess appropriate control of Hgb within the target range, on the 
basis of the Hgb mean at Week 24 and the number (%) of subjects with Hgb within the target 


 
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Secondary Hgb Analyses 
range as secondary endpoints. 
 For the Hgb, the summary statistics will be calculated, along with the two-sided 95% 
confidence interval based on t-distribution. 
 The percentage of subjects with Hgb within the target range will be calculated at Week 24, with 
calculation of exact two-sided 95% confidence interval based on binomial distribution.  
 The time (in days) to reach first the lower target Hgb level (10.0 g/dL) will be calculated in each 
subject, and summarized descriptively by Kaplan-Meier method using P25, median, and P75. 
Subjects who could not reach lower target will be regarded as censored at Study Treatment 
Stop Date (See Section 10.6.1). 
 


 
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8.2. 
Safety Analyses 
The safety analyses will be based on the All Treated Subjects population, unless 
otherwise specified. 
Table 5, Table 6, and Table 7 provide overviews of the planned analyses, with further 
details of data displays being presented in Appendix 14: List of Data Displays. 
8.2.1. 
Overview of Planned Adverse Events Analyses 
All AEs will be categorized by the MedDRA (version 20.0 or higher if available) system 
organ class and preferred term to tabulate the number and incidence.  
AEs of special interest will be manually-selected at patient-level (i.e. following case-by-
case review by members of the SRT including representatives from the local Japan team) 
and not at preferred term level. 
Table 5 
Overview of Planned AEs Analyses 
Endpoint / Parameter/ Display Type 
Absolute 
Summary 
Individual 
T 
F 
L 
Adverse Events (AEs) 
On-therapy AEs by SOC and PT 
Y 
 
Y 
On-therapy AEs by SOC and PT 
  by Dialysis Status 
Y 
 
 
On-therapy AEs by SOC and PT and Maximum Intensity 
Y 
 
 
On-therapy AEs up to Week 4 by SOC and PT 
Y 
 
 
On-therapy AEs up to Week 4 by SOC and PT 
  by Dialysis Status 
Y 
 
 
On-therapy AEs up to Week 4 by SOC and PT and Maximum Intensity 
Y 
 
 
Post-therapy AEs by SOC and PT 
Y 
 
Y 
Post-therapy AEs by SOC and PT and Maximum Intensity 
Y 
 
 
On-therapy Drug-Related AEs by SOC and PT 
Y 
 
 
On-therapy Drug-Related AEs by SOC and PT 
  by Dialysis Status 
Y 
 
 
On-therapy Drug-Related AEs by SOC and PT and Maximum Intensity 
Y 
 
 
On-therapy Drug-Related AEs up to Week 4 by SOC and PT 
Y 
 
 
On-therapy Drug-Related AEs up to Week 4 by SOC and PT 
  by Dialysis Status 
Y 
 
 
On-therapy Drug-Related AEs up to Week 4 by SOC and PT and Maximum 
Intensity 
Y 
 
 
Post-therapy Drug-Related AEs by SOC and PT 
Y 
 
 
Post-therapy Drug-Related AEs by SOC and PT and Maximum Intensity 
Y 
 
 
On-therapy Common (>= 5 %) Non-Serious AEs by SOC and PT (Subjects & 
No. of Occurrences) 
Y 
 
 


 
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Endpoint / Parameter/ Display Type 
Absolute 
Summary 
Individual 
T 
F 
L 
Subject Numbers for Individual AEs 
 
 
Y 
Relationship Between AE SOCs, PT & Verbatim Text 
 
 
Y 
Serious and Other Significant AEs 
Fatal Serious AEs 
 
 
Y 
Non-Fatal Serious AEs 
 
 
Y 
On-therapy Serious AEs 
Y 
 
 
Post-therapy Serious AEs 
Y 
 
 
Serious AEs in Screening Period [1] 
 
 
Y 
Reasons for Considering as a Serious AE 
 
 
Y 
Serious AEs by SOC and PT (Subjects & No. of Occurrences) 
Y 
 
 
AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study 
Treatment by SOC and PT 
Y 
 
Y 
CV Events 
 
 
Y 
AEs of special interest [2] 
On-therapy AEs of special interest 
Y 
 
Y 
On-therapy AEs of special interest 
  by Dialysis Status 
Y 
 
 
Post-therapy AEs of special interest 
Y 
 
Y 
Other Safety Summary for Plain Language Summary 
On-therapy Serious Drug-Related AEs 
Y 
 
 
On-therapy Non-Serious Drug-Related AEs 
Y 
 
 
NOTES: 
 
T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term. 
 
Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data. 
 
Individual = Represents FL related to any displays of individual subject observed raw data.  
[1] Listing will be based on All Screening Population. 
[2] See Section 10.6.4. 
 
8.2.1.1. 
Planed AE Analyses Displays 
 
Adverse Events 
AEs by SOC and PT 
The number and percentage of subjects reporting at least one AE will be provided. These 
events will be summarized by primary system organ class and preferred term. On-therapy, 
on-therapy up to week 4, and post-therapy AEs will be summarized separately. On-
therapy AE will be also summarized by baseline dialysis status. 
AEs by SOC and PT and Maximum Intensity 


 
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AEs will be summarized by Maximum Intensity (not applicable, mild, moderate, or 
severe) by primary system organ class and preferred term. Subjects who experience the 
same event several times with different intensities will only be counted with the 
maximum intensity in the order of (not applicable < mild < moderate < severe). On-
therapy, on-therapy up to week 4, and post-therapy AEs will be summarized separately. 
Drug-Related AEs by SOC and PT 
The number and percentage of subjects reporting at least one drug-related AE will be 
provided. These events will be summarized by primary system organ class and preferred 
term. On-therapy, on-therapy up to week 4, and post-therapy AEs will be summarized 
separately. On-therapy AE will be also summarized by baseline dialysis status. 
Drug-Related AEs by SOC and PT and Maximum Intensity 
Drug-related AEs will be summarized by Maximum Intensity (not applicable, mild, 
moderate, or severe) by primary system organ class and preferred term. Subjects who 
experience the same event several times with different intensities will only be counted 
with the maximum intensity in the order of (not applicable < mild < moderate < severe). 
On-therapy, on-therapy up to week 4, and post-therapy AEs will be summarized 
separately. 
On-therapy Common (>= 5 %) Non-Serious AEs by SOC and PT (Subjects & No. of 
Occurrences) 
The number and percentage of subjects reporting at least one on-therapy common ( 5 %) 
non-serious AE will be provided. The number of on-therapy non-serious AE occurrences 
will also be provided. These events will be summarized by primary system organ class 
and preferred term. 
 
Serious and Other Significant AEs 
Serious AEs 
The number and percentage of subjects reporting at least one Serious AE will be provided. 
These events will be summarized by primary system organ class and preferred term. On- 
and post-therapy serious AEs will be summarized separately. 
On-therapy Serious AEs by SOC and PT (Subjects & No. of Occurrences) 
The number and percentage of subjects reporting at least one on-therapy serious AE will 
be provided. The number of on-therapy serious AE occurrences will also be provided. 
These events will be summarized by preferred term. 
AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study Treatment 
by SOC and PT 


 
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The number and percentage of subjects reporting each on-therapy AE leading to 
discontinuation of study treatment will be summarized. These events will be summarized 
by preferred term. 
 
AEs of Special Interest (AESIs) 
How to identify the AESIs is described in Section 10.6.4. 
AEs of Special Interest 
The number and percentage of subjects reporting at least one AESI will be provided. 
These events will be summarized by each AESI term (See Section 10.6.4). On-therapy 
and post-therapy AESIs will be summarized separately. On-therapy AE will be also 
summarized by baseline dialysis status. 
 
Other Safety Summary for Plain Language Summary 
Serious/Non-serious Drug-Related AEs 
The number and percentage of subjects with on-therapy serious or non-serious drug-
related AEs will be summarized by preferred term. The serious AEs and the non-serious 
AEs will be summarized separately. 
 
8.2.2. 
Overview of Planned Clinical Laboratory Analyses 
Table 6 
Overview of Planned Clinical Laboratory Analyses 
Endpoint / Parameter/ Display Type 
Absolute 
Change from BL 
Summary 
Individual 
Summary 
Individual 
T 
F 
L 
T 
F 
L 
Chemistry 
Chemistry Values by Visit  
Y 
 
Y 
Y 
 
 
Percent change from Baseline in Lipid Parameters [1] 
(total cholesterol, LDL cholesterol, and HDL cholesterol) 
 
 
Y 
Y 
Y 
 
Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline  
Y 
 
 
 
 
 
Worst Case Chemistry Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline  
Y 
 
 
 
 
 
Hematology 
Hematology Values by Visit 
Y 
 
Y 
Y 
 
 
Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline  
Y 
 
 
 
 
 
Worst Case Hematology Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline  
Y 
 
 
 
 
 
Other Laboratory Tests [2] 


 
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Endpoint / Parameter/ Display Type 
Absolute 
Change from BL 
Summary 
Individual 
Summary 
Individual 
T 
F 
L 
T 
F 
L 
Other Laboratory Values by Visit [2] 
Y 
 
Y 
Y 
 
 
Worst Case Other Laboratory Results Relative to Normal 
Range Post-Baseline Relative to Baseline  [2] 
Y 
 
 
 
 
 
Worst Case Other Laboratory Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline  [2] 
Y 
 
 
 
 
 
Hepatobiliary (Liver) 
Liver Monitoring/Stopping Event Reporting 
Y 
 
 
 
 
 
Hepatobiliary Laboratory Abnormalities 
Y 
 
 
 
 
 
Medical Conditions for Subjects with Liver Stopping 
Events 
 
 
Y 
 
 
 
Substance Use for Subjects with Liver Stopping Events 
 
 
Y 
 
 
 
Scatter Plot of Maximum vs. Baseline for ALT 
 
Y[3] 
 
 
 
 
Scatter Plot of Maximum ALT vs Maximum Total Bilirubin 
 
Y[3] 
 
 
 
 
All Laboratory 
All Laboratory Data for Subjects with any Value of 
Potential Clinical Concern/PCI 
 
 
Y 
 
 
 
Laboratory Values of PCI 
 
 
Y 
 
 
 
NOTES: 
 
T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance 
 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
 
Individual = Represents FL related to any displays of individual subject observed raw data.  
[1] Lipid parameters will be log-transformed and the percent change from baseline will be reported. 
[2] Only iPTH will be collected as other laboratory tests. 
[3] This figure may not be provided in this study because this is required for 'larger study' by the GSK Core RAP 
requirements in the RAP Template. 
 
 
8.2.2.1. 
Planned Clinical Laboratory Analyses Displays 
 
Chemistry/Hematology/Other Laboratory Tests 
Clinical Laboratory Values by Visit 
The values will be summarized using mean, standard deviation, median, minimum, and 
maximum at each assessment visit and baseline. Chemistry values, hematology values, 
and other laboratory values will be summarized separately. 
Percent change from Baseline in Lipid Parameters 
Lipid parameters will be log-transformed and the percent change from baseline will be 
reported. The percent change from baseline in each lipid parameter, including baseline 
values, will be summarized using geometric mean, 95% CI, minimum, median, and 
maximum at each assessment visit. In baseline values, the coefficient of variation will 
also be provided. 


 
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Clinical Laboratory Changes from Baseline by Visit 
The values will be summarized using mean, standard deviation, median, minimum, and 
maximum at each assessment visit. Change from baseline in chemistry, hematology, and 
other laboratory will be summarized separately. 
Worst Case Laboratory Results Relative to Normal Range/PCI Criteria Post-Baseline 
Relative to Baseline  
The number of subjects with worst laboratory results relative to normal range/potential 
clinical importance (PCI) criteria which are post-baseline relative to baseline, including 
unscheduled assessments, will be summarized by test and category. Summaries for 
normal range and PCI will be provided separately. The categories for normal range are: 
To Low, To Normal or No Change, To High; the categories for PCI criteria are: To Low, 
To w/in Range or No Change, To High. The categorization is determined by comparing 
the baseline category to the worst case post-baseline category.  
 
Hepatobiliary (Liver) 
Details of liver chemistry stopping criteria are described in the protocol. 
Liver monitoring/stopping events will be summarized.  
Hepatobiliary laboratory abnormalities will be summarized.  
A scatter plot of maximum on-therapy ALT values versus baseline ALT values will be 
produced if larger data permit. 
A scatter plot of maximum total bilirubin (xULN) versus maximum ALT (xULN) values 
on-therapy will be produced if larger data permit. 
 
8.2.3. 
Overview of Planned Other Safety Analyses 
Table 7 
Overview of Planned Other Safety Analyses 
Endpoint / Parameter/ Display Type 
Absolute 
Change from BL 
Summary 
Individual 
Summary 
Individual 
T 
F 
L 
T 
F 
L 
ECG 
ECG Findings by Visit 
Y 
 
Y 
 
 
 
ECG Values by Visit 
 
 
Y 
Y 
 
 
Abnormal ECG Findings 
 
 
Y 
 
 
 
Vital Signs 
Vital Signs by Visit 
Y 
 
Y 
Y 
 
 
Worst Case Vital Sign Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline  
Y 
 
 
 
 
 


 
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Endpoint / Parameter/ Display Type 
Absolute 
Change from BL 
Summary 
Individual 
Summary 
Individual 
T 
F 
L 
T 
F 
L 
All Vital Signs for Subjects with Values of PCI 
 
 
Y 
 
 
 
Ophthalmology 
Ophthalmologic Exams at Screening 
Y 
 
Y 
 
 
 
On-Therapy Ophthalmologic Exams 
Y 
 
Y 
 
 
 
NOTES: 
 
T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance 
 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
 
Individual = Represents FL related to any displays of individual subject observed raw data.  
 
8.2.3.1. 
Planned Other Safety Analyses Displays 
 
ECG 
ECG findings ('normal', 'abnormal, not clinically significant', 'abnormal, clinically 
significant') will be summarized by each assessment visit.  Findings without regard to 
visits (labelled “Worst Case Post-Baseline”, only the worst case finding for each subject, 
will also be provided.  All ECG measures (heart rate, PR interval, QRS duration, QT 
(uncorrected) interval and QTcB (calculated), result of ECG) will be included in a subject 
listing. 
 
Vital Signs 
Vital sign values will be summarized using mean, standard deviation, minimum, median, 
and maximum for each assessment visit. Separate summary statistics of pre- and post-
dialysis vital signs will be provided for raw values and change from baseline. In a 
summary of change from baseline, each baseline value (i.e. pre- and post-dialysis 
baseline) will be used for calculation (Section 10.5.2). 
The number of subjects with worst case vital sign results relative to PCI criteria which 
are post-baseline relative to baseline, including unscheduled assessments, will also be 
summarized by test and category.  The categories for PCI criteria are: To Low, To w/in 
Range or No Change, To High. The categorization is determined by comparing the 
baseline category to the worst case post-baseline category. 
 
Ophthalmology Exams 
The responses to each question will be summarized using number and percentage at each 
assessment visit. The response will be classified into 'Yes' and 'No'. Ophthalmology exam 
at screening and at on-therapy will be summarized separately. The number of subjects 
with worst case after-screening ophthalmology exams (i.e., the response is ‘Yes’ at least 
once during whole treatment period, including unscheduled visits) will also be 
summarized by each question. 


 
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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 PK 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. Summaries will be produced for week 12, week 24, 
and pooled. 
Table 8 
Overview of Planned Pharmacokinetic Analyses 
Endpoints 
Untransformed 
Log-Transformed 
Summary 
Individual 
Summary 
Individual 
F 
T 
F 
L 
F 
T 
F 
L 
Plasma Concentrations of 
GSK1278863 
Y [1] [2] 
Y 
Y [1] 
Y 
 
 
 
 
Derived PK Parameters 
Y [3] 
Y [3] 
Y[3] 
Y 
 
Y[3] 
 
 
Dose Normalized PK 
Parameters 
Y [3] 
Y [3] 
Y[3] 
Y 
 
Y[3] 
 
 
NOTES : 
 
T = Table, F = Figures, L = Listings, Y = Yes display generated. 
 
Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data. 
 
Individual = Represents FL related to any displays of individual subject observed raw data. 
1. 
Linear and Semi-Log plots will be created on the same display. 
2. 
Separate Mean (± SD) and Median plots will be generated. 
3. 
Individual PK parameters calculated less than 4 time point concentration or any time deviated concentration will 
be omitted from summaries and figures. 
 
8.3.2. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3 
Reporting Process & Standards). 
Concentrations of GSK1278863 in plasma will be listed and summarized by dose group 
and nominal time. Individual plasma concentration-time profiles and median/mean 
profiles by dose group will be plotted. Each of figures will contain one plot on the 
untransformed scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. a 
log-linear plot). 


 
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8.3.3. 
Pharmacokinetic Parameters 
8.3.3.1. 
Deriving Pharmacokinetic Parameters 
 Derivation of pharmacokinetic parameters will be performed by, or under the direct 
auspices of, Clinical Pharmacology & Science Promotion Office, GlaxoSmithKline 
K.K. 
 Refer to Appendix 5: Data Display Standards & Handling Conventions 
(Section 10.5.3 Reporting Process & Standards). 
 The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using Win Nonlin (version 6.3 or 
higher). 
 All calculations of non-compartmental parameters will be based on actual sampling 
times. 
 Pharmacokinetic parameters described in Table 9 will be determined from the Plasma 
GSK1278863 concentration-time data, as data permits. 
Table 9 
Derived Pharmacokinetic Parameters 
Parameter 
Parameter Description 
AUC(0-4) 
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(last)) will be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the linear trapezoidal for each decremental trapezoid. 
The concentration at 0 hr will be set to 0. 
AUC(0-7) 
Area under the concentration-time curve from time zero to seven will be calculated using the 
linear trapezoidal rule for each incremental trapezoid and the linear trapezoidal for each 
decremental trapezoid. 
The concentration at 0 hr and 7 hr will be set to 0. 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
Tmax 
Time to first occurrence of Cmax will be obtained directly from the concentration-time data. 
NOTES: 
 
Additional parameters may be included as required. 
 
C(last) is expected to be the concentration observed at 4hours after the most recent dose. 
 
8.3.4. 
Population Pharmacokinetic (PopPK) Analyses 
No population pharmacokinetic analysis is planned. 


 
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8.4. 
Pharmacodynamic Analyses 
No pharmacodynamic analysis is planned. 
8.5. 
Pharmacokinetic / Pharmacodynamic Analyses 
No pharmacokinetic / pharmacodynamic analysis is planned. 
 


 
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9. 
REFERENCES 
N/A 


 
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10. 
APPENDICES 
Section 
Appendix 
RAP Section 4 : Analysis Populations 
Section 10.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions 
Section 10.2 
Appendix 2: Time and Events 
Section 10.3 
Appendix 3: Assessment Windows 
Section 10.4 
Appendix 4: Treatment States & Phases 
Section 10.5 
Appendix 5: Data Display Standards & Handling Conventions 
 Study Treatment & Sub-group Display Descriptors 
 Baseline Definitions & Derivations 
 Reporting Process & Standards 
Section 10.6 
Appendix 6: Derived and Transformed Data 
 General, Study Population & Safety 
 Efficacy 
 Pharmacokinetic 
Section 10.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
 Premature Withdrawals 
 Handling of Missing Data 
Section 10.8 
Appendix 8: Values of Potential Clinical Importance 
Section 10.9 
Appendix 9: Multicenter Studies 
 Laboratory Values 
 ECG 
 Vital Signs 
Section 10.10 
Appendix 10: Examination of Covariates and Subgroups 
Section 10.11 
Appendix 11: Multiple Comparisons and Multiplicity 
Section 10.12 
Appendix 12: Model Checking and Diagnostics for Statistical Analyses 
Other RAP Appendices 
Section 10.13 
Appendix 13: Abbreviations & Trade Marks 
Section 10.14 
Appendix 14: List of Data Displays 
Section 10.15 
Appendix 15: Example Mock Shells for Data Displays 
 


 
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10.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
 
Per Protocol Population will not be defined in this study. 
 


 
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10.2. 
Appendix 2: Time & Events 
10.2.1. 
Protocol Defined Time & Events 
Period 
Screening 
Treatment 
Follow-up 
Visits 
All assessments pre-dialysis, unless 
noted. 
 
Week  
-4 
Day 1 
Week  
4 
Week  
8 
Week  
12 
Week  
16 
Week  
20 
Week  
24 
Early 
withdraw
al 10 
2–4 weeks 
after Week 24 
or early 
withdrawal  
Allowable window (days) 
 
7 
- 
3 
3 
3 
3 
3 
3 
- 
3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
 
X 
X 
 
 
 
 
 
 
 
 
Medical history, demography, height, 
body weight 1 
 
X 
 
 
 
 
 
 
 
 
 
IWRS call 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study medication dispensing 2 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Study medication compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs (before and after dialysis) 3 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Ophthalmology examination 4 
 
X 11 
 
 
 
 
 
 
 
 
 
ECG 
 
X 
 
 
 
X 
 
 
X 
 
 
HemoCue Hgb 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology 
 
X 12 
X 
X 
Hgb 
only 
X 
Hgb 
only 
Hgb 
only 
X 
X 
X 
Clinical chemistry 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Ferritin, TSAT 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
Serum iron, TIBC, UIBC, serum 
transferrin, hepcidin 
 
 
X 
X 
 
X 
 
 
X 
X 
 
Serum pregnancy test 5 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Estradiol 5, FSH 6 
 
X 
 
 
 
 
 
 
 
 
 
Pharmacokinetics 7 
 
 
 
 
 
X 
 
 
X 
 
 
iPTH 
 
 
X 
X 
 
X 
 
 
X 
 
 
Genetics sample 8 
 
 
X 
 
 
 
 
 
 
 
 
Adverse event assessment 9 
 
 
 
Concomitant medication assessment  
 
 
 


 
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1. 
Body weight is measured after dialysis. 
2. 
If a subject visit the study site only to receive study medication, only the IWRS call, study medication dispensing, and study medication compliance will be required 
3. 
At visits without dialysis, only one measurement of each parameter will be obtained. 
4. 
Ophthalmology exams should be conducted at the following time points. 
• 
Screening: anytime after consenting and prior to first dose of study medication (Day 1) 
• 
Week 12: window from weeks 10-14 (inclusive) 
• 
End of study: window from weeks 20-24 (inclusive) 
• 
Early study medication discontinuation or study withdrawal: withdrawal eye exam as close to the last dose as possible.  Re-conduct is not required if the exam is conducted within two weeks prior 
to withdrawal visit. 
5. 
Only for females of reproductive potential. 
6. 
Only at determination of menopausal status in female subjects (Section 5.1). 
7. 
See Table 7 
8. 
For optional genetic research, informed consent should be obtained before the specimen collection. 
9. 
See Section 7.4.1. 
10. For examination at early withdrawal, the specified assessments should be performed as far as possible 
11. The previous result of ophthalmology exam at the screening may be used if the subject meets all of the following criteria and the investigator judges it appropriate. 
• 
There were no findings that would suggest a repeat ophthalmology exam performed within the next 3 months at the latest screening ophthalmology exam.  
• 
Subjects had no new eye-related symptoms or complaints since the latest screening ophthalmology exam.  
• 
The latest screening ophthalmology exam was performed within 3 months prior to anticipated Day 1. 
12. Exam should be conducted at least one week after ESA treatment. 
 
 
Blood Sampling Schedule for Pharmacokinetics 
PK sample 
Week 12 2 
Week 24 2 
Blood sampling timing 1 
1, 2, 3, and 4 h after administration of GSK1278863 
Subjects must take the study medication in consideration of blood sampling time. Subjects will record the date and time of the last two study medication doses taken prior to blood sampling in the medication 
diary. Preferably, there should be an interval of at least 12 h between these two doses.  
1. 
Blood sampling should be completed within +/- 30 min of the planned collected time. 
2. 
Blood sampling not performed at this visit may be postponed until the following visits.  
 


 
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10.3. 
Appendix 3: Assessment Windows 
 
All data will be reported according to the nominal visit date for which it was reported 
(that is, no visit windows will be applied during dataset creation). Permissible range at 
each visit was specified in time & event table (See Appendix 2). Records in the eCRF 
unscheduled visit will not be slotted to a particular time point, but remain as unscheduled 
if they are either summarized or listed unless otherwise specified. 
 
10.3.1. 
Definitions of Analysis Time Point 
Analysis Time Point 
Definitions 
Screening [1] 
Data collected in Screening visit 
Day 1 [1] 
Data collected in Day 1 visit 
Week 4 
Data collected in Week 4 visit 
Week 8 
Data collected in Week 8 visit 
Week 12 
Data collected in Week 12 visit 
Week 16 
Data collected in Week 16 visit 
Week 20 
Data collected in Week 20 visit 
Week 24 
Data collected in Week 24 visit 
Follow-up 
Data collected in Follow-up visit 
Note: Any unscheduled visit will not be slotted to a particular time point. 
[1] For rescreened subjects, data collected in screening-pass visit will be used for analysis. They may have multiple 
records at Screening and/or Day 1 visit, which associates with a screening-pass visit and screening failure visit(s) 
 


 
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10.4. 
Appendix 4: Treatment States and Phases 
10.4.1. 
Treatment States 
Assessments and events will be classified according to time of occurrence relative to the 
randomization date and study treatment stop date. 
10.4.1.1. 
Treatment States for Hgb Data 
Treatment State 
Definition 
Pre-therapy 
Date ≤ Randomization Date 
On-therapy 
Randomization Date < Date ≤ Study Treatment Stop Date + 1 day 
Post-therapy 
Date > Study Treatment Stop Date + 1 day 
NOTES:  
 
If Randomization date is missing then the assessment will be consider to be Pre-therapy 
 
If study treatment stop date is missing then the assessment will be considered to be On-therapy 
 
10.4.1.2. 
Treatment States for AE Data 
Treatment State 
Definition 
Pre-therapy 
AE Start Date < Randomization Date 
On-therapy 
If AE onset date is on or after randomization date & on or before Study Treatment Stop 
Date + 1 day 
Randomization Date ≤ AE Start Date ≤ Study Treatment Stop Date + 1 day 
Post-therapy 
If AE onset date is after Study Treatment Stop Date + 1 day 
AE Start Date > Study Treatment Stop Date + 1 day 
Duration (Days)  
AE Resolution Date – AE Onset Date + 1 day 
Drug-related 
If relationship is marked ‘YES’ on eCRF or value is missing. 
NOTES:  
 
If Randomization date is missing then the assessment will be consider to be Pre-therapy 
 
If study treatment stop date is missing then the AE will be considered to be On-therapy. 
 
10.4.1.3. 
Treatment States for Concomitant Medications Data 
Treatment State 
Definition 
Pre-therapy 
Concomitant Medication Start Date ≤ Randomization Date 
On-therapy 
Define as (A) or (B) 
(A): If concomitant medication start date is on or after randomization date & on or 
before Study Treatment Stop Date 
 
Randomization Date ≤ Concomitant Medication Start Date ≤ Study Treatment 
Stop Date 
If Study Treatment Stop Date is missing, just check if the start date is on or after 
randomization date. (B): If concomitant medication start date is before randomization 
date & concomitant medication stop date is on or after randomization date 
 
Concomitant Medication Start Date < Randomization Date 


 
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Treatment State 
Definition 
 
Randomization Date ≤ Concomitant Medication Stop Date  
Post-therapy 
Concomitant Medication Stop Date > Study Treatment Stop Date 
If Study Treatment Stop Date is missing: 
 
post-therapy = blank 
where Concomitant Medication Stop Date  Randomization Date 
 
post-therapy = Y 
where concomitant medication stop date are missing 
 
post-therapy = N 
where Concomitant Medication Stop Date < Randomization Date 
NOTES:  
 
If Randomization date is missing then the assessment will be consider to be Pre-therapy 
 
Data of concomitant medication includes ESA, iron, and blood products and blood supportive care products. 
 
 
Illustrations of the pre-therapy, on-therapy, and post-therapy treatment states for 
concomitant medications are included below: 
 
Pre-
therapy 
On-therapy 
Post-therapy 
Pre-therapy 
medication 
On-therapy 
medication 
Post-therapy 
medication 
(a) 
xx 
Randomization Date 
 
Study Treatment Stop Date 
Study Treatment Stop Date + 1 Days 
 
Y 
N 
N 
(b) 
x 
x 
 
Y 
Y 
N 
(c) 
x 
 
x 
Y 
Y 
Y 
(d) 
 
xx 
 
N 
Y 
N 
(e) 
 
x 
x 
N 
Y 
Y 
(f) 
 
 
xx 
N 
N 
Y 
(g) 
? x 
 
 
Y 
N 
N 
(h) 
? 
x 
 
Y* 
Y 
N 
(i) 
? 
 
x 
Y* 
Y* 
Y 
(j) 
x 
 
? 
Y 
Y** 
Y** 
(k) 
 
x 
? 
N 
Y 
Y** 
(l) 
 
 
x? 
N 
N 
Y 
(m) 
?  
 
 
 
 
? 
Y*** 
Y*** 
Y*** 
(n) 
x 
x 
 
 
 
 
Y 
Y 
N 
(o) 
?  
x 
 
 
 
 
Y* 
Y 
N 
(p) 
 
x 
x 
 
 
 
N 
Y 
N 
(q) 
 
x 
 
x 
 
 
N 
Y 
N 
(r) 
 
 
 
x 
 
x 
N 
Y 
Y 
(s) 
 
 
 
x 
 
? 
N 
Y 
Y** 
(t) 
 
 
 
 
x 
x 
N 
N 
Y 
(u) 
 
 
 
 
x 
? 
N 
N 
Y 
(v) 
 
 
x 
 
x 
 
N 
Y 
Y 
x = start/stop date of medication 
? = missing start/stop date of medication 
* If a medication is stopped On-therapy or Post-therapy and no start date is recorded it will be assumed that the 
medication was ongoing from the Pre-therapy phase 
** If a medication is started Pre-therapy or On-therapy and no stop date is recorded then usage will be assumed 
to be ongoing for the remainder of the study 
*** If a medication has no start or stop date it will be assumed that the medication was ongoing from the Pre-
therapy phase to the Post-therapy phase 
 


 
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10.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
10.5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description 
Order 
D1 
GSK1278863 
GSK1278863 
1 
 
10.5.2. 
Baseline Definition & Derivations 
10.5.2.1. 
Baseline Definitions 
The baseline value will be the latest pre-dose assessment. This is generally expected to be 
the pre-dose value from the Day 1 visit, except for ECG. For ECG, screening assessment 
will be used as a baseline. 
For vital signs, the baseline value at pre- and post-dialysis will be defined differently. 
10.5.2.2. 
Derivations and Handling of Missing Baseline Data 
Definition 
Reporting Details 
Change from Baseline 
= Post-Dose Visit Value – Baseline 
Change from Baseline 
For Vital Signs 
 Pre-dialysis: 
= Post-Dose Visit Value from Pre-Dialysis Assessment – 
Baseline from Pre-Dialysis Assessment 
 Post-dialysis: 
= Post-Dose Visit Value from Post-Dialysis Assessment – 
Baseline from Post-Dialysis Assessment 
% Change from Baseline 
For TSAT, Hepcidin, and Lipid 
Parameters 
1. Log-transform the data at both the baseline and the 
specified timepoint 
2. Calculate a change from baseline using the log-
transformed data for each subject 
3. Calculate the mean, and 95%CI and standard error (SE) of 
the log-transformed data 
4. Exponentially back-transform to the original scale  
5. Subtract 1, then multiply everything by 100% 
 
So, geometric mean for percent change from baseline  
= { exp(Mean [ln(Post-Dose Visit Value) – ln(Baseline)]) – 1 }x 
100 
 


 
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Definition 
Reporting Details 
Coefficient of variation will be calculated as 
CV%=[exp(Var in log scale)-1 ]1/2 x 100 
where 'Var in log scale' represents variance of percent change 
from baseline in log scale. 
NOTES : 
 
Unless otherwise specified, the baseline definitions specified in Section 10.5.2.1 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. 
 
10.5.3. 
Reporting Process & Standards 
Reporting Process 
Software 
 The currently supported versions of SAS software and S-Plus will be used. 
Reporting Area 
HARP Server 
: uk1salx00175 
HARP Area 
: /arenv/arprod/gsk1278863/mid204716/final_01 
QC Spreadsheet 
: /arenv/arprod/gsk1278863/mid204716/final_01/documents 
Analysis Datasets  
 Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.1.3 & 
ADaM IG Version 1.0. 
 For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM. 
Generation of RTF Files 
 Not 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 
 All data will be reported according to the actual treatment the subject received unless 
otherwise stated. 
 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. 
Planned and Actual Time 


 
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Reporting Standards 
 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. 
 For Individual PK figures, the plot will use actual relative time. 
 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.  
 Scheduled visits outside the protocol defined time-windows (i.e. recorded as protocol 
deviations) will be included in listings, figures, summaries and statistical analyses. 
Unscheduled Visits 
 Unscheduled visits will not be included in summary tables, unless otherwise specified. 
 If unscheduled visits are included in a summary, it will be provided how a summary will be 
produced as appropriate. 
 Unscheduled visits will not be included in figures, unless otherwise specified. 
 All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1: This does not apply to the output of 
statistical models or when the standard list is inappropriate. 
 Hgb and iron summary statistics will include 95%CI and percentiles (P25 
and P75). 
 Dose level and dose adjustment frequency summary statistics will 
include mode. 
Categorical Data 
N, n, frequency, % 
Reporting of Pharmacokinetic Concentration Data 
Descriptive 
Summary Statistics 
Refer to IDSL Statistical Principle 6.06.1 
Assign zero to NQ values (Refer to GUI_51487 for further details) 
Reporting of Pharmacokinetic Parameters 
Descriptive 
Summary Statistics 
(Log Transformed) 
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) 
of log-transformed data and between geometric coefficient of variation (CVb 
(%)) will be reported. 
[1] CVb (%) = √ (exp(SD2) - 1) * 100 
(SD = SD of log transformed data)  
Graphical Displays 
 Refer to IDSL Statistical Principals 7.01 to 7.13. 
 


 
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10.6. 
Appendix 6: Derived and Transformed Data 
10.6.1. 
General 
Multiple Measurements at One Time Point 
 Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented. 
 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. 
 For multiple measurements at Screening and Day 1 visit, the screening-pass visit record will be 
used for analysis (See Appendix 3). 
Study Day 
 Calculated as the number of days from randomization date: 
 Ref Date = Missing            → Study Day = Missing 
 Ref Date < Randomization Date   → Study Day = Ref Date – Randomization Date 
 Ref Date ≥ Randomization Date   → Study Day = Ref Date – (Randomization Date) +1 
Unique Subject ID 
 All subjects have unique subject ID for analyses even if a subject was enrolled after 
rescreened. Tables/figures/listings will be produced based on unique subject ID. 
 For a rescreened subject, the unique subject ID will be derived from the first-assigned subject 
number though he or she seems to have multiple subject numbers in eCRF records by 
screening assessment. The other subject numbers, which are to be recorded within a 
supplemental domain, will be associated with the unique subject ID. 
Rescreening Subjects 
 For rescreened subjects, data collected in screening-pass visit will be used for analysis. They 
may have multiple records at Screening and/or Day 1 visit, which associates with a screening-
pass visit and screening failure visit(s) 
 Regarding a listing of SAEs in screening period, all pre-therapy SAEs captured in eCRF will be 
provided including screen failure records of rescreened subjects. 
Study Treatment Start Date 
 First randomized treatment start date 
Study Treatment Stop Date 
 Latest end date of treatment 
 Note that the end date of treatment will be captured as the end date when subjects were 
intended to end the treatment, rather than when subjects have actually ended the treatment.  
Time Definitions (per GSK standard principles) 
 1 week = 7 days 
 1 month = 30.4375 days 
 1 year = 365.25 days 


 
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10.6.2. 
Study Population 
Subject Disposition and Study Population 
 Screening status and reason for screening failure for a subject who has multiple subject 
numbers will be unique in the unique subject ID. 
o The screening status of a subject who failed screening but passed rescreening will be 
‘enrolled’, and the reason for failure will not be counted. 
o The screening status of a subject who failed more than one screening and never passed 
will be ‘failed’, and the reason for failure will be derived from the latest failure record. 
 Study population of subjects will be derived from the above unique screening status. 
Demographics and Baseline Characteristics 
Age 
 GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows: 
o A date and month will be imputed as ‘30th June’ as it will not be captured. 
 Randomization date will be used as reference date of calculation. 
o If randomization date is missing, screening date will be used. 
Body Mass Index (BMI) 
 Calculated as Weight (kg) / [Height (m)]2 
 
Exposure 
Prescribed Dose and Actual Dose 
 
Prescribed dose will be derived from a dose record captured in eCRF. 
 
In principle, actual dose will be the same as prescribed dose except for a case in which 
inconsistency between a prescribed dose and prescribed bottle(s) occurs. If such an 
inconsistency case (e.g. wrong treatment) is detected by study team, the actual dose may be 
replaced with a plausible value by case-by-case review. 
Extent of Exposure 
 Number of days of exposure to study drug will be calculated based on the formula: 
Duration of Exposure in Days = Sum of [Exposure Duration at Each Visit] 
where Exposure Duration at Each Visit = Treatment Stop date - Treatment Start date + 1 
If dose is interrupted in a visit according to dose adjustment algorithm, duration in the 
period will be included in duration of exposure. 
 Cumulative dose will be based on the formula using prescribed dose: 
Cumulative Dose = Sum of (Exposure Duration x Dose) at Each Visit 
 
Daily Dose 
Cumulative Dose / Duration of Exposure in Days 
Treatment Compliance 
 
Listing will include treatment compliance up to Week 4 and overall. 
Overall Compliance(%) = [(Total # of tablets actual taken)/(Total # of tablets planned 


 
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Exposure 
taken)]*100 
Compliance (%) up to Week 4 = [(# of tablets actual taken up to Week 4)/(# of tablets planned 
taken up to Week 4)]*100 
where 
Total # of tablets actual taken = Sum of (Numbers of Tablets Taken at Each Visit) 
Total # of tablets planned taken = Sum of [(Treatment Stop Date – Treatment Start Date + 1) x 
Planned # of tablet/day in the Visit] 
# of tablets actual taken up to Week 4 = Numbers of Tablets Taken of Day 1 record 
# of tablets planned taken up to Week 4= (Treatment Stop date of Day 1 record – Treatment 
Start Date of Day 1 record + 1) 
Planned # of tablet/day is defined as follows according to the protocol: 
o 0 mg  0 tablet/day 
o 1 mg  1 tablet/day 
o 2 mg  1 tablet/day 
o 4 mg  1 tablet/day 
o 6 mg  1 tablet/day 
o 8 mg  2 tablets/day 
o 12 mg  2 tablets/day 
o 18 mg  3 tablets/day 
o 24 mg  4 tablets/day 
where dose records are derived from prescribed doses. 
 
 
10.6.3. 
Efficacy 
Hgb Values for Efficacy Analyses 
Central laboratory and HemoCue Hgb Values 
 For reporting purposes, central laboratory Hgb values will be used, unless otherwise specified. 
However, if a central laboratory Hgb value is missing, a corresponding non-missing HemoCue 
Hgb value, which is associated with the identical subject number and visit, will be used.  
Evaluable Hgb Values 
 Note that this will not be applicable for reporting summaries and figures, but applicable for 
reporting listings. 
 Evaluable Hgb values will be based on on-therapy central laboratory and/or HemoCue Hgb 
values that are not taken within the 8 weeks following a transfusion or within the 8 weeks 
following a non-randomized ESA medication (except protocol-specified ESA treatment in 
screening period). 
If an Hgb record meets at least one following criteria, the Hgb record will have a flag of 
evaluable Hgb = 'N'. 
o Blood Product Administration Date < Date of Hgb data ≤ Blood Product 
Administration Date + 56 (days) 


 
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Hgb Values for Efficacy Analyses 
o ESA Start Date < Date of Hgb data ≤ ESA Stop Date + 56 (days) 
Flowchart for Hgb efficacy analyses 
 
 
 
Basically, scheduled visits between Day 1 and Week 24 will be applicable to this flowchart, but 
analyses including by-visit summaries may include other schedued visits (ie. screening and 
follow-up visit). 
[1] Regarding partially evaluated Hgb values, the following summaries of Hgb will include a 
unscheduled visit: 
 Summary of Number (%) of subjects who have an Hgb level of less than 7.5 g/dL 
 Summary of Number (%) of subjects who have an Hgb level of more than 13.0 g/dL and 
number of episodes 
 
Hgb increase of more than 2 g/dL over any 4 weeks 
 For this reporting purpose, Hgb values from central laboratory will be used as previously 
described. 
 A subject who has at least one record with Hgb increase of more than 2 g/dL over any 4 weeks 
will be counted. 
 Hgb increase will be calculated for scheduled visits between Day 1 and Week 24 if available 
(i.e. Week 4 Hgb - Day 1 Hgb, Week 8 Hgb - Week 4 Hgb, ...) 
 
Illustration of calculation (example in case of Week 12 missing) 
Hgb 
(g/dL) 
Lab Date 
Study 
Day 
Visit 
Hgb increase 
9.1 
01FEB2017 
1 
Day 1 
Not calculated 
9.8 
02MAR2017 
30 
Week 4 
0.7 
11.9 
02APR2017 
61 
Week 8 
2.1 
12.6 
07JUN2017 
127 
Week 16 
Not calculated 
12.7 
08JUL2017 
158 
Week 20 
0.1 
12.3 
02AUG2017 
183 
Week 24 
-0.4 
 
 
Scatter plot of Hgb assessments: Central Laboratory vs. HemoCue 
 All available pairs of Hgb (i.e. non-missing values in both from central laboratory and from the 
corresponding HemoCue measurement) will be used. The figure will include Pearson’s 


 
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Hgb Values for Efficacy Analyses 
correlation coefficient. 
Scatter plot of Change from Baseline in Hgb at Week 4 vs. Candidate Covariates 
 The following scatter plot figures will be produced for overall and dialysis status groups:  
 Change from baseline in Hgb at Week 4 vs. Body Weight at Screening 
 Change from baseline in Hgb at Week 4 vs. Baseline Hgb 
 Vertical axis will indicate the change from baseline in Hgb (g/dL) at Week 4, horizontal axis will 
indicate the candidate covariates; body weight (kg) at screening or baseline Hgb (g/dL). 
Scatter plot of Mean Dose during Week 12 to 24 vs. Candidate Covariates 
 The following scatter plot figures will be produced for overall and dialysis status groups:  
 Mean Dose during Week 12 to 24 vs. Body Weight at Screening 
 Mean Dose during Week 12 to 24 vs. Baseline Hgb 
 Vertical axis will indicate the mean dose (mg), horizontal axis will indicate the candidate 
covariates; body weight (kg) at screening or baseline Hgb (g/dL). 
 Mean dose will be calculated from the arithmetic mean using the latest 3 exposure records (i.e., 
for completers Week 12, 16, and 20), which are based on the prescribed doses and the 
scheduled visits. 
 Subjects who has less than 3 dosing records will be excluded from the figures. 
 Mean dose during Week 12 to 24 will also be summarized and listed.  
 
Dose Adjustment 
Dose adjustment algorithm 
 
Dose Adjustment algorithm will be based on HemoCue Hgb values at scheduled visits. No Hgb 
values measured at unscheduled visits will be included. 
 
Dose will be derived from prescribed dose recorded in eCRF, not actual dose associated with 
container numbers. 
 
The following table illustrates the algorithm using analysis flags as below: 
o 
(FL_A): Adjustment flags will be counted if prescribed dose recorded in eCRF is 
changed from that of the previous visit. 
o 
(FL_B): Over 13 g/dL flags will be counted if HemoCue Hgb >13 g/dL is observed. 
o 
(FL_C): Interruption flags will be counted if prescribed dose recorded in eCRF is zero. 
Treatment durations will be calculated based on the following formula: 
o 
Duration (days) = Treatment Stop Date – Treatment Start Date + 1 
 
Illustration of dose adjustment algorithm 
 
Visit 
(Example) 
Treatment 
Start date/ 
Stop date 
Duration 
HemoCue 
Hgb 
(g/dL) 
Dose 
(mg) 
(FL_A) 
(FL_B) 
(FL_C) 
Adjust-
ment 
Over 
13 g/dL 
Inter- 
ruption 
Day 1 
01FEB2017/ 
01MAR2017 
29 
11.1 
4 
N 
N 
N 
Week 4 
02MAR2017/ 
14 
11.4 
4 
N 
N 
N 


 
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Dose Adjustment 
15MAR2017 
Week 8 
02APR2017/ 
01MAY2017 
30 
11.8 
2 
Y 
N 
N 
Week 12 
02MAY2017/ 
01JUN2017 
31 
13.4 
0 
Y 
Y 
Y 
Week 16 
02JUN2017/ 
01JUL2017 
30 
11.6 
1 
Y 
N 
N 
Week 20 
02JUL2017/ 
01AUG2017 
31 
12.7 
0 
Y 
N 
Y 
Week 24 
- 
- 
12.3 
- 
- 
N 
- 
 
For summary tables, how to use flags is described within the next items; 
 'Duration (days) of treatment interruption due to Hgb >13 g/dL' 
 'Dose adjustment' 
Duration (days) of treatment interruption due to Hgb >13 g/dL 
Calculation of duration of treatment interruption due to Hgb >13 g/dL will be based on the above 
algorithm and the below formula. 
 Duration (days) = Sum of [Duration]n 
where 
[Duration]n represents exposure duration at visit n. 
If over 13 g/dL flag (FL_B) = 'Y' and interruption flag (FL_C) = 'Y': 
o Duration (days) = Treatment Stop Date - Treatment Start Date + 1 
If else: 
o Duration (days) = 0 
Frequency of dose adjustment 
Calculation of frequency of dose adjustment will be based on the above algorithm. 
 
Number of dose adjustment will be counted for each subject as follows: 
o Counts of adjustment flag = 'Y' 
Number of dose adjustment to reach the lower Hgb target (10.0 g/dL) 
Number of dose adjustment to reach the lower Hgb target will be counted for each subject as 
follows 
 
Counts of adjustment flag =’Y’ at visits before Date to reach the lower Hgb target, including a 
record which firstly achieved the lower Hgb target. 
 
Iron Endpoints 
Subjects who used i.v. and oraliron 
 Number of subjects who used i.v. and/or oral iron will be summarized 
 Subjects who used i.v. and oral iron will be defined as follows: 
 Subjects with on-therapy i.v. and/or oral iron medication collected in a specific eCRF form 
(CONMEDS-IRON). 


 
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Quarterly IV Iron Dose 
 Records of on-therapy iron medication will be used for the following calculations 
 Monthly average i.v. iron by quarter = Total i.v. iron dose during each quarter (mg) / (duration in 
a quarter (days) / 30.4375 days). 
 Total i.v. iron dose during each quarter (mg) will be carried with the following formula using each 
record. Duration will be derived from iron medication start/stop date: 
o Total i.v. iron dose in each quarter (mg) = (iron dose1*frequency1*duration1) + ... + 
(iron dosen*frequencyn*durationn) 
o Duration (days) =  (stop date1 - start date1 + 1) + ... + (stop daten - start daten + 1) 
Frequency is defined as follows: 
o If subject receives iron dose with once daily  frequency = 1 
o If subject receives iron dose with BID  frequency = 2 
o If subject receives iron dose with TID  frequency = 3 
o If subject receives iron dose with QID  frequency = 4 
 Quarters will be defined as follows: 
o Quarter 1:start date = Randomization Date 
end date = Treatment Start Date at Week 12 - 1 (day) 
o Quarter 2:start date = Treatment Start Date at Week 12 
end date = Study Treatment Stop Date 
o If treatment start date at Week 12 is missing (i.e. early withdrawal before Week 12), 
the end date of Quarter 1 will be replaced with Study Treatment Stop Date. 
Quarter 2 will not be generated. 
o Iron medication start/stop date will be defined newly for the analyses in addition to 
Quarter start/end date to derive amount of iron dose within a specified quarter 
(analysis flags may be used to judge which quarters the iron records should belong 
to). 
 If iron medication start date < randomization date, the iron medication start date will be replaced 
with randomization date for the analyses. 
 If iron medication end date > Study Treatment Stop Date, the iron medication stop date will be 
replaced with Study Treatment Stop Date for the analyses. 
 If iron medication start date and stop date step over quarters, the iron medication record will 
be divided; the end date in the former record and the start date in the latter record will be 
replaced with the quarter end date and the next quarter start date, respectively. 
 
Quarter State of Iron Medication 
Definition 
Quarter 1 
Iron Medication End Date ≤ Quarter 1 End Date 
Quarter 2 
Quarter 2 Start Date ≤ Iron Medication Start Date 
Quarter 1 & 2 (will be divided as 
described above) 
Iron Medication Start Date ≤ Quarter 1 End Date 
and 
Quarter 2 Start Date ≤ Iron Medication Stop Date 


 
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10.6.4. 
Safety 
Adverse Events 
AE up to Week 4 
Cut-off date of Week 4 for individuals will be based on Week 4 visit date which is associated with 
the earliest date throughout Week 4 records (i.e., SDTM.SVSTDTC).  
AE of Special Interest 
AEs of special interest are manually-selected at patient-level (i.e. following case-by-case review by 
members of the SRT including representatives from the local Japan team) and not at preferred term 
level. 
 
Adverse events of special interest are classified as follows: 
 Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis  
 Death, MI, stroke, heart failure, thromboembolic events, thrombosis of vascular access 
 Cardiomyopathy   
 Pulmonary artery hypertension 
 Cancer-related mortality and tumor progression and recurrence  
 Esophageal and gastric erosions 
 Proliferative retinopathy, macular edema, choroidal neovascularization  
 Exacerbation of rheumatoid arthritis 
 
NOTES:  
 
Only on-therapy iron medication will be evaluated. 
 
If no start or stop date is recorded on iron medication, the date will be replaced with Randomization 
Date or Study Treatment Stop Date, respectively. 
 
 
TIBC 
 TIBC will be calculated automatically by the central laboratory using: 
o TIBC = UIBC + total iron 
TSAT 
 Based on literature review the distribution of TSAT is skewed and requires a log-transformation. 
Calculation of statistics on log-transformed data are described in Section 10.5.2.2. 
 TSAT will be calculated automatically by the central laboratory using: 
o TSAT = 100 * (Serum Iron/TIBC) 
Hepcidin 
 Based on literature review the distribution of hepcidin is skewed and requires a log-
transformation. Calculation of statistics on log-transformed data are described in Section 
10.5.2.2. 


 
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CV Events 
Basically, patient profiles of CV events will be provided according to records captured in eCRF, 
except for Peripheral Arterial Thrombosis Embolism (PAT) form. 
 
CV events in PAT form will be provided only when a related AE sequence number is not present. 
This is because several records in PAT form are captured just for AESI information, instead of CV 
events.  
 
 
 
Laboratory Parameters 
Imputation 
 If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01  
o Example 2: 1 Significant Digit  =  ‘> x’ becomes x + 0.1   
o Example 3: 0 Significant Digits =  ‘< x’ becomes x – 1     
 The following laboratory values will not be applicable for this imputation: 
o Hgb, serum iron, serum ferritin, serum transferrin, TIBC, UIBC, TSAT, and Hepcidin 
 The default convention for reporting of clinical laboratory units will be the international system of 
units (SI units). 
Log-transformation 
 Lipid parameters will be log-transformed and the percent change from baseline will be reported. 
Based on literature review the distributions of hepcidin and TSAT are skewed and require a log-
transformation. Other endpoints may also be log-transformed if deemed appropriate (See 
Section 10.5.2.2). 
Others 
Just for summaries of PCI cutoffs, the absolute neutrophils and lymphocytes count will be calculated 
by multiplying the percentages given for each subject by the absolute white blood count. 
 
10.6.5. 
Pharmacokinetic 
Dose level 
 Summaries by dose level and used tablet strength will be based on an actual dose associated 
with a container number. (See Section 10.6.2). Tablet strength is defined as follows: 
o Actual dose = 0 mg  0 mg tablet strength 
o Actual dose = 1 mg  1 mg tablet strength 
o Actual dose = 2 mg  2 mg tablet strength 
o Actual dose = 4 mg  4 mg tablet strength 


 
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o Actual dose = 6 mg  6 mg tablet strength 
o Actual dose = 8 mg  4 mg tablet strength 
o Actual dose = 12 mg  6 mg tablet strength 
o Actual dose = 18 mg  6 mg tablet strength 
o Actual dose = 24 mg  6 mg tablet strength 
 Dose level will be derived from an actual dose of the visit (including unscheduled visits) which 
meets the following: 
o Treatment Start Date  Date of last dose taken prior to PK sampling  Treatment Stop Date 
Others 
 Dose normalized PK parameters will be derived from [PK parameters/actual dose (mg)]. 
 In pooled analyses, data collected in Week 12 and Week 24 will be aggregated. 
 For the PK parameters calculation, the concentration at 0 hr and 7 hr will be set to 0. 
 Individual’s PK parameters calculated less than 4 time point concentration or any time deviated 
(beyond  30 min of scheduled timepoints) concentration will be omitted from summaries and 
figures. 
 


 
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10.7. 
Appendix 7: Premature Withdrawals & Handling of Missing 
Data 
 
10.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
 Subject study completion (i.e. as specified in the protocol) was defined as 
completing all periods of the study including the follow-up visit.  
 The study will be completed with the last subject’s last study 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. 
 
10.7.2. 
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.  
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. 
10.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
Partial dates will be displayed as captured in subject listing displays. 
Concomitant 
Medications 
/Dialysis 
 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 day and 'Jan' will 
be used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
The recorded partial date will be displayed in listings. 
 
10.7.2.2. 
Handling of Missing Data for Statistical Analysis 
If a central laboratory Hgb value is missing, a corresponding non-missing HemoCue Hgb 
value will be used. Any other imputation will not be conducted for Hgb. 


 
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10.8. 
Appendix 8: Values of Potential Clinical Importance 
 
10.8.1. 
Laboratory Values 
Laboratory Parameter 
Units 
Clinical Concern Range 
Low Flag 
High Flag 
Albumin (serum) 
g/L 
< 30 g/L 
>55 g/L 
Aspartate Aminotransferase 
IU/L 
N/A 
 3x ULRR 
Alanine Aminotransferase 
IU/L 
N/A 
 3x ULRR 
Bilirubin (total) 
mol/L 
N/A 
 2x ULRR 
Calcium (albumin-adjusted) 
mmol/L 
< 1.87 mmol/L 
> 2.56 mmolL 
Bicarbonate (total) 
mmol/L 
< 20 mmol/L 
> 32 mmol/L 
Inorganic phosphate 
mmol/L 
< 0.81 mmol/L 
> 1.77 mmol/L 
Potassium (serum) 
mmol/L 
< 0.5 mmol/L below  
LLRR 
> 1.0 mmol/L above 
ULRR 
Sodium (serum) 
mmol/L 
< 130 mmol/L 
> 150 mmol/L 
 
Laboratory Parameter 
 
Units 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Platelet Count  
GI/L 
< 80 GI/L 
> 500 GI/L 
WBC Count 
GI/L 
< 1x LLRR 
>5x ULRR 
   Neutrophils 
GI/L 
< 1.0 GI/L 
N/A 
   Lymphocytes 
GI/L 
< 0.5 GI/L 
N/A 
 
Laboratory Parameter 
Units 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Ferritin 
g/L 
< 100 g/L  
> 1200 g/L 
TSAT 
% 
<15 % 
>40 % 
iPTH 
ng/L 
N/A 
> 9x ULRR 
 
10.8.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 mmHg 
> 180 mmHg 
Diastolic Blood Pressure 
mmHg 
< 45 mmHg 
> 110 mmHg 
Heart Rate 
beats/min 
< 40 beats/min 
> 110 beats/min 
 


 
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10.9. 
Appendix 9: Multicenter Studies 
 
It is anticipated that subject accrual will be spread thinly across centers and summaries of 
data by center would be unlikely to be informative. Therefore, data from all participating 
centers will be just pooled prior to analysis. 


 
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10.10. 
Appendix 10: Examination of Covariates, Subgroups & 
Other Strata 
10.10.1. 
Handling of Covariates, Subgroups & Other Strata 
 
The following is a list of covariates that may be used in descriptive summaries by 
subgroups.  
 
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 database freezing. 
 
Category 
Covariates and / or Subgroups 
Covariates[1] 
Body Weight (kg) at Screening 
Baseline Hgb (g/dL) 
Subgroup 
Dialysis Status 
• Newly started dialysis (Dialysis newly started < 12 weeks 
before screening): Patients not using ESAs after the start 
of dialysis 
• Maintenance dialysis (Dialysis started >= 12 weeks before 
screening): Patients not using ESAs within 8 weeks before 
screening (including interruption of ESA therapy) 
[1] This category will be used only to produce exploratory figures of scatter plot. 
 


 
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10.11. 
Appendix 11: Multiple Comparisons & Multiplicity 
10.11.1. 
Handling of Multiple Comparisons & Multiplicity 
There is no hypothesis to be tested.  


 
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10.12. 
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses 
 
There is no statistical analysis assumption. 


 
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10.13. 
Appendix 13 – Abbreviations & Trade Marks 
10.13.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
A&R 
Analysis and Reporting  
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
Hgb 
Hemoglobin 
ICH 
International Conference on Harmonisation 
IDSL 
Integrated Data Standards Library 
IP 
Investigational Product 
IV 
Intravenous 
GUI 
Guidance 
PCI 
Potential Clinical Importance 
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
SAC 
Statistical Analysis Complete 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
TIBC 
Total Iron Binding Capacity 
TSAT 
Transferrin Saturation 
UIBC 
Unsaturated Iron Binding Capacity 
GSK 
GlaxoSmithKline 
 


 
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10.13.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
N/A 
 
WinNonlin 
 
 
SAS 
 
 
HemoCue 
 


 
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10.14. 
Appendix 14: List of Data Displays 
10.14.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.32 
N/A 
Efficacy 
2.1 to 2.48 
2.1 to 2.16 
Safety 
3.1 to 3.46 
3.1 
Pharmacokinetic 
4.1 to 4.8 
4.1 to 4.15 
Section 
Listings 
ICH Listings 
1 to 28 
Other Listings 
29 to 69 
 
10.14.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in 10.15: Example Mock Shells for Data Displays. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
NOTES:  
 
Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’ 
 
 
 


 
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10.14.3. 
Study Population Tables 
Study Population Tables 
No. 
Populatio
n 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
SAC 
Subject Disposition 
1.1.  
Assigned 
ES8 
Summary of Subject Status and Reason for Study Withdrawal 
ICH E3, GSK CTR, FDAAA, EudraCT 
Y 
1.2.  
Assigned 
ES8 
Summary of Subject Status and Reason for Study Withdrawal by 
Dialysis Status 
 
Y 
1.3.  
All Treated 
Subjects 
SD1 
Summary of Treatment Status and Reasons for Discontinuation of Study 
Treatment 
ICH E3 
Y 
1.4.  
All 
Screening 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements 
Y 
1.5.  
Enrolled 
NS1 
Summary of Subjects Enrolled by Country and Site ID 
EudraCT/clinical operations 
Y 
Protocol Deviations 
1.6.  
Assigned 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
Y 
1.7.  
Assigned 
IE1 
Summary of Inclusion/Exclusion Criteria Deviations 
ICH E3 
Y 
Populations Analysed 
1.8.  
All 
Screening 
SP1 
Summary of Study Populations 
IDSL 
Y 
1.9.  
Assigned 
SP2A 
Summary of Exclusions from All Treated Subjects Population 
IDSL 
Y 
Demographic and Baseline Characteristics 
1.10. 
All Treated 
Subjects 
DM1 
Summary of Demographic Characteristics 
ICH E3, GSK CTR, FDAAA, EudraCT 
Y 
1.11. 
All Treated 
Subjects 
DM1 
Summary of Demographic Characteristics by Dialysis Status 
 
Y 


 
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Study Population Tables 
No. 
Populatio
n 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
SAC 
1.12. 
Enrolled 
DM11 
Summary of Age Ranges 
EudraCT 
Y 
1.13. 
All Treated 
Subjects 
DM5 
Summary of Race and Racial Combinations 
ICH E3, GSK CTR, FDAAA, EudraCT 
Y 
1.14. 
All Treated 
Subjects 
FH1 
Summary of Family History for CV Risk Factors 
IDSL 
Y 
1.15. 
All Treated 
Subjects 
SU1 
Summary of Substance Use (History of Tobacco Use, Alcohol Intake) 
IDSL 
Y 
Prior and Concomitant Medications 
1.16. 
All Treated 
Subjects 
MH4 
Summary of Current Medical Conditions 
ICH E3 
Y 
1.17. 
All Treated 
Subjects 
MH4 
Summary of Current Medical Conditions by Dialysis Status 
 
Y 
1.18. 
All Treated 
Subjects 
MH4 
Summary of Past Medical Conditions 
ICH E3 
Y 
1.19. 
All Treated 
Subjects 
MH4 
Summary of Past Medical Conditions by Dialysis Status 
 
Y 
1.20. 
All Treated 
Subjects 
CM1 
Summary of Concomitant Medications (Prior-Treatment) 
ICH E3 
Y 
1.21. 
All Treated 
Subjects 
CM1 
Summary of Concomitant Medications (On-therapy) 
ICH E3 
Y 
1.22. 
All Treated 
Subjects 
CM1 
Summary of Concomitant Medications (Post-therapy) 
ICH E3 
Y 
1.23. 
All Treated 
Subjects 
CM1 
Summary of Other Concomitant Medication (On-therapy) 
 
Y 


 
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Study Population Tables 
No. 
Populatio
n 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
SAC 
1.24. 
All Treated 
Subjects 
CM1 
Summary of Other Concomitant Medication by Dialysis Status (On-
therapy) 
 
Y 
1.25. 
All Treated 
Subjects 
POP_T1 
Summary of Blood Products and Blood Supportive Care Products (On-
therapy) 
 
Y 
1.26. 
All Treated 
Subjects 
POP_T1 
Summary of Blood Products and Blood Supportive Care Products by 
Dialysis Status (On-therapy) 
 
Y 
Dialysis 
1.27. 
All Treated 
Subjects 
POP_T2 
Summary of Dialysis Status 
 
Y 
1.28. 
All Treated 
Subjects 
POP_T3 
Summary of Baseline Hemodialysis 
 
Y 
1.29. 
All Treated 
Subjects 
POP_T4 
Summary of Baseline Vascular Access 
 
Y 
Exposure and Treatment Compliance 
1.30. 
All Treated 
Subjects 
POP_T5 
Summary of Exposure to Study Treatment 
ICH E3 
Y 
1.31. 
All Treated 
Subjects 
POP_T5 
Summary of Exposure to Study Treatment by Dialysis Status 
 
Y 
1.32. 
All Treated 
Subjects 
POP_T6 
Summary of Treatment Compliance 
 
Y 
 


 
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10.14.4. 
Efficacy Tables 
Efficacy: Tables 
No. 
Populatio
n 
IDSL / TST 
ID / Example 
Shell 
Title 
Programming Notes 
SAC 
Hgb 
2.1.  
All Treated 
Subjects 
EFF_T1 
Summary of Change from Baseline in Hgb by Visit 
 
Y 
2.2.  
All Treated 
Subjects 
EFF_T1 
Summary of Change from Baseline in Hgb by Visit by Dialysis Status 
 
Y 
2.3.  
All Treated 
Subjects 
EFF_T2 
Summary of Number (%) of subjects by Hgb change from baseline 
category at Week 4 
 
Y 
2.4.  
All Treated 
Subjects 
EFF_T2 
Summary of Number (%) of subjects by Hgb change from baseline 
category at Week 4 by Dialysis Status 
 
Y 
2.5.  
All Treated 
Subjects 
EFF_T1 
Summary of Hgb by Visit 
 
Y 
2.6.  
All Treated 
Subjects 
EFF_T1 
Summary of Hgb by Visit by Dialysis Status 
 
Y 
2.7.  
All Treated 
Subjects 
EFF_T3 
Summary of Number (%) of subjects with Hgb within the target range by 
Visit 
 
Y 
2.8.  
All Treated 
Subjects 
EFF_T3 
Summary of Number (%) of subjects with Hgb within the target range by 
Visit by Dialysis Status 
 
Y 
2.9.  
All Treated 
Subjects 
EFF_T4 
Summary of Time (in days) to reach the lower target Hgb level 
(10.0 g/dL) 
 
Y 
2.10. 
All Treated 
Subjects 
EFF_T4 
Summary of Time (in days) to reach the lower target Hgb level 
(10.0 g/dL) by Dialysis Status 
 
Y 
2.11. 
All Treated 
Subjects 
EFF_T5 
Summary of Number (%) of subjects who have an Hgb level of less than 
7.5 g/dL 
 
Y 


 
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Efficacy: Tables 
No. 
Populatio
n 
IDSL / TST 
ID / Example 
Shell 
Title 
Programming Notes 
SAC 
2.12. 
All Treated 
Subjects 
EFF_T5 
Summary of Number (%) of subjects who have an Hgb level of less than 
7.5 g/dL by Dialysis Status 
 
Y 
2.13. 
All Treated 
Subjects 
EFF_T5 
Summary of Number (%) of subjects who have an Hgb increase of more 
than 2.0 g/dL over any 4 weeks 
 
Y 
2.14. 
All Treated 
Subjects 
EFF_T5 
Summary of Number (%) of subjects who have an Hgb increase of more 
than 2.0 g/dL over any 4 weeks 
 
Y 
2.15. 
All Treated 
Subjects 
EFF_T6 
Summary of Number (%) of subjects who have an Hgb level of more 
than 13.0 g/dL and number of episodes by Dialysis Status 
 
Y 
2.16. 
All Treated 
Subjects 
EFF_T6 
Summary of Number (%) of subjects who have an Hgb level of more 
than 13.0 g/dL and number of episodes by Dialysis Status 
 
Y 
Iron Use 
2.17. 
All Treated 
Subjects 
EFF_T7 
Summary of Dose of i.v. iron during the treatment period 
 
Y 
2.18. 
All Treated 
Subjects 
EFF_T7 
Summary of Dose of i.v. iron during the treatment period by Dialysis 
Status 
 
Y 
2.19. 
All Treated 
Subjects 
EFF_T8 
Summary of Number (%) of subjects who use iron during the treatment 
period 
 
Y 
2.20. 
All Treated 
Subjects 
EFF_T8 
Summary of Number (%) of subjects who use iron during the treatment 
period by Dialysis Status 
 
Y 
Iron Parameters (ferritin, TSAT, hepcidin, serum iron, and TIBC) 
2.21. 
All Treated 
Subjects 
LB1 
Summary of Ferritin (ug/L) by Visit 
Includes Baseline values 
Y 
2.22. 
All Treated 
Subjects 
LB1 
Summary of Ferritin (ug/L) by Visit by Dialysis Status 
Includes Baseline values 
Y 


 
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Efficacy: Tables 
No. 
Populatio
n 
IDSL / TST 
ID / Example 
Shell 
Title 
Programming Notes 
SAC 
2.23. 
All Treated 
Subjects 
LB1 
Summary of Ferritin (ug/L) Change from Baseline by Visit 
 
Y 
2.24. 
All Treated 
Subjects 
LB1 
Summary of Ferritin (ug/L) Change from Baseline by Visit by Dialysis 
Status 
 
Y 
2.25. 
All Treated 
Subjects 
EFF_T9 
Summary of Transferrin Saturation (%) by Visit 
Includes Baseline values 
Y 
2.26. 
All Treated 
Subjects 
EFF_T9 
Summary of Transferrin Saturation (%) by Visit by Dialysis Status 
Includes Baseline values 
Y 
2.27. 
All Treated 
Subjects 
EFF_T10 
Summary of Transferrin Saturation (%) Percent Change from Baseline 
by Visit 
 
Y 
2.28. 
All Treated 
Subjects 
EFF_T10 
Summary of Transferrin Saturation (%) Percent Change from Baseline 
by Visit by Dialysis Status 
 
Y 
2.29. 
All Treated 
Subjects 
EFF_T9 
Summary of Hepcidin (nmol/L) by Visit 
Includes Baseline values 
Y 
2.30. 
All Treated 
Subjects 
EFF_T9 
Summary of Hepcidin (nmol/L) by Visit by Dialysis Status 
Includes Baseline values 
Y 
2.31. 
All Treated 
Subjects 
EFF_T10 
Summary of Hepcidin (nmol/L) Percent Change from Baseline by Visit 
 
Y 
2.32. 
All Treated 
Subjects 
EFF_T10 
Summary of Hepcidin (nmol/L) Percent Change from Baseline by Visit 
by Dialysis Status 
 
Y 
2.33. 
All Treated 
Subjects 
LB1 
Summary of Serum Iron (umol/L) by Visit 
Includes Baseline values 
Y 
2.34. 
All Treated 
Subjects 
LB1 
Summary of Serum Iron (umol/L) by Visit by Dialysis Status 
Includes Baseline values 
Y 


 
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Efficacy: Tables 
No. 
Populatio
n 
IDSL / TST 
ID / Example 
Shell 
Title 
Programming Notes 
SAC 
2.35. 
All Treated 
Subjects 
LB1 
Summary of Serum Iron (umol/L) Change from Baseline by Visit 
 
Y 
2.36. 
All Treated 
Subjects 
LB1 
Summary of Serum Iron (umol/L) Change from Baseline by Visit by 
Dialysis Status 
 
Y 
2.37. 
All Treated 
Subjects 
LB1 
Summary of Total Iron Binding Capacity (umol/L) by Visit 
Includes Baseline values 
Y 
2.38. 
All Treated 
Subjects 
LB1 
Summary of Total Iron Binding Capacity (umol/L) by Visit by Dialysis 
Status 
Includes Baseline values 
Y 
2.39. 
All Treated 
Subjects 
LB1 
Summary of Total Iron Binding Capacity (umol/L) Change from Baseline 
by Visit 
 
Y 
2.40. 
All Treated 
Subjects 
LB1 
Summary of Total Iron Binding Capacity (umol/L) Change from Baseline 
by Visit by Dialysis Status 
 
Y 
Dose adjustment 
2.41. 
All Treated 
Subjects 
EFF_T11 
Summary of Dose level (mg) by Visit 
Includes mean dose (mg) during Week 12 
to 24 
Y 
2.42. 
All Treated 
Subjects 
EFF_T11 
Summary of Dose level (mg) by Visit by Dialysis Status 
Includes mean dose (mg) during Week 12 
to 24 
Y 
2.43. 
All Treated 
Subjects 
EFF_T12 
Summary of Duration (days) of treatment interruption due to Hgb 
>13.0 g/dL 
 
Y 
2.44. 
All Treated 
Subjects 
EFF_T12 
Summary of Duration (days) of treatment interruption due to Hgb 
>13.0 g/dL by Dialysis Status 
 
Y 
2.45. 
All Treated 
Subjects 
EFF_T13 
Summary of Dose Adjustment 
 
Y 
2.46. 
All Treated 
EFF_T13 
Summary of Dose Adjustment by Dialysis Status 
 
Y 


 
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Efficacy: Tables 
No. 
Populatio
n 
IDSL / TST 
ID / Example 
Shell 
Title 
Programming Notes 
SAC 
Subjects 
2.47. 
All Treated 
Subjects 
EFF_T14 
Summary of Number (%) of Subjects with Each Dose Level by Visit 
 
Y 
2.48. 
All Treated 
Subjects 
EFF_T14 
Summary of Number (%) of Subjects with Each Dose Level by Visit by 
Dialysis Status 
 
Y 
 


 
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10.14.5. 
Efficacy Figures 
Efficacy: Figures 
No. 
Populatio
n 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
SAC 
Hgb 
2.1.  
All Treated 
Subjects 
EFF_F1 
Plot of Mean Hgb (g/dL) and 95% CI for Change from Baseline over 
Time 
 
Y 
2.2.  
All Treated 
Subjects 
EFF_F1 
Plot of Mean Hgb (g/dL) and 95% CI for Change from Baseline over 
Time by Dialysis Status 
 
Y 
2.3.  
All Treated 
Subjects 
EFF_F1 
Plot of Mean Hgb (g/dL) and 95% CI over Time 
 
Y 
2.4.  
All Treated 
Subjects 
EFF_F1 
Plot of Mean Hgb (g/dL) and 95% CI over Time by Dialysis Status 
 
Y 
2.5.  
All Treated 
Subjects 
EFF_F2 
Figure of Number (%) of subjects with Hgb within the target range over 
time 
Like Fig. 2.7.6.2.3.1-2 in NESP CTD 2.7.6 
Y 
2.6.  
All Treated 
Subjects 
EFF_F2 
Figure of Number (%) of subjects with Hgb within the target range over 
time by Dialysis Status 
 
Y 
2.7.  
All Treated 
Subjects 
EFF_F3 
Kaplan-Meier plot of Time (in days) to reach the lower target Hgb level 
(10.0 g/dL) 
 
Y 
2.8.  
All Treated 
Subjects 
EFF_F3 
Kaplan-Meier plot of Time (in days) to reach the lower target Hgb level 
(10.0 g/dL) by Dialysis Status 
 
Y 
2.9.  
All Treated 
Subjects 
EFF_F4 
Scatter plot of Hgb assessments: Central Laboratory vs. HemoCue 
 
Y 
Dose Adjustment 
2.10. 
All Treated 
Subjects 
EFF_F5 
Histogram of GSK1278863 Dose by Visit 
 
Y 


 
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Efficacy: Figures 
No. 
Populatio
n 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
SAC 
2.11. 
All Treated 
Subjects 
EFF_F6 
Subject Profiles of Hgb and Dose over Time 
 
Y 
Iron Parameters 
2.12. 
All Treated 
Subjects 
EFF_F1 
Plot of Mean and 95% CI for Ferritin Change from Baseline over time 
 
Y 
2.13. 
All Treated 
Subjects 
EFF_F1 
Plot of Geometric Mean and 95% CI for Transferrin Saturation Percent 
Change from Baseline over time 
 
Y 
2.14. 
All Treated 
Subjects 
EFF_F1 
Plot of Geometric Mean and 95% CI for Hepcidin Percent Change from 
Baseline over time 
 
Y 
2.15. 
All Treated 
Subjects 
EFF_F1 
Plot of Mean and 95% CI for Serum Iron Change from Baseline over 
time 
 
Y 
2.16. 
All Treated 
Subjects 
EFF_F1 
Plot of Mean and 95% CI for Total Iron Binding Capacity Change from 
Baseline over time 
 
Y 
Other 
2.17. 
All Treated 
Subjects 
EFF_F7 
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. Body Weight 
 
Y 
2.18. 
All Treated 
Subjects 
EFF_F7 
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. Body Weight 
by Dialysis Status 
 
Y 
2.19. 
All Treated 
Subjects 
EFF_F7 
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. Baseline Hgb 
 
Y 
2.20. 
All Treated 
Subjects 
EFF_F7 
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. Baseline Hgb 
by Dialysis Status 
 
Y 
2.21. 
All Treated 
Subjects 
EFF_F7 
Scatter Plot of Mean Dose during Week 12 to 24 vs. Body Weight 
 
Y 


 
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Efficacy: Figures 
No. 
Populatio
n 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
SAC 
2.22. 
All Treated 
Subjects 
EFF_F7 
Scatter Plot of Mean Dose during Week 12 to 24 vs. Body Weight by 
Dialysis Status 
 
Y 
2.23. 
All Treated 
Subjects 
EFF_F7 
Scatter Plot of Mean Dose during Week 12 to 24 vs. Baseline Hgb 
 
Y 
2.24. 
All Treated 
Subjects 
EFF_F7 
Scatter Plot of Mean Dose during Week 12 to 24 vs. Baseline Hgb by 
Dialysis Status 
 
Y 
 


 
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10.14.6. 
Safety Tables 
Safety : Tables 
No. 
Populatio
n 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
SAC 
Adverse Events (AEs) 
3.1.  
All Treated 
Subjects 
AE1 
Summary of On-Therapy AEs by SOC and PT 
ICH E3 
Y 
3.2.  
All Treated 
Subjects 
AE1 
Summary of On-Therapy AEs by SOC and PT by Dialysis Status 
 
Y 
3.3.  
All Treated 
Subjects 
AE5 
Summary of On-Therapy AEs by SOC and PT and Maximum Intensity 
ICH E3 
Y 
3.4.  
All Treated 
Subjects 
AE1 
Summary of On-Therapy AEs up to Week 4 by SOC and PT 
ICH E3 
Y 
3.5.  
All Treated 
Subjects 
AE1 
Summary of On-Therapy AEs up to Week 4 by SOC and PT by 
Dialysis Status 
 
Y 
3.6.  
All Treated 
Subjects 
AE5 
Summary of On-Therapy AEs up to Week 4 by SOC and PT and 
Maximum Intensity 
ICH E3 
Y 
3.7.  
All Treated 
Subjects 
AE1 
Summary of Post-Therapy AEs by SOC and PT 
ICH E3 
Y 
3.8.  
All Treated 
Subjects 
AE5 
Summary of Post-Therapy AEs by SOC and PT and Maximum 
Intensity 
ICH E3 
Y 
3.9.  
All Treated 
Subjects 
AE1 
Summary of On-Therapy Drug-Related AEs by SOC and PT 
ICH E3 
Y 
3.10. 
All Treated 
Subjects 
AE1 
Summary of On-Therapy Drug-Related AEs by SOC and PT by 
Dialysis Status 
 
Y 
3.11. 
All Treated 
Subjects 
AE5 
Summary of On-Therapy Drug-Related AEs by SOC and PT and 
Maximum Intensity 
ICH E3 
Y 


 
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Safety : Tables 
No. 
Populatio
n 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
SAC 
3.12. 
All Treated 
Subjects 
AE1 
Summary of On-Therapy Drug-Related AEs up to Week 4 by SOC 
and PT 
ICH E3 
Y 
3.13. 
All Treated 
Subjects 
AE1 
Summary of On-Therapy Drug-Related AEs up to Week 4 by SOC 
and PT by Dialysis Status 
 
Y 
3.14. 
All Treated 
Subjects 
AE5 
Summary of On-Therapy Drug-Related AEs up to Week 4 by SOC 
and PT and Maximum Intensity 
ICH E3 
Y 
3.15. 
All Treated 
Subjects 
AE1 
Summary of Post-Therapy Drug-Related AEs by SOC and PT 
ICH E3 
Y 
3.16. 
All Treated 
Subjects 
AE5 
Summary of Post-Therapy Drug-Related AEs by SOC and PT and 
Maximum Intensity 
ICH E3 
Y 
3.17. 
All Treated 
Subjects 
AE15 
Summary of On-Therapy Common (>=5%) Non-Serious AEs by SOC 
and PT (Subjects & No. of Occurrences) 
FDAAA, EudraCT 
Y 
Serious and Other Significant AEs 
3.18. 
All Treated 
Subjects 
AE1 
Summary of On-Therapy Serious AEs 
GSK CTR 
Y 
3.19. 
All Treated 
Subjects 
AE1 
Summary of Post-Therapy Serious AEs 
GSK CTR 
Y 
3.20. 
All Treated 
Subjects 
AE16 
Summary of Serious AEs by SOC and PT (Subjects & No. of 
Occurrences) 
FDAAA, EudraCT 
Y 
3.21. 
All Treated 
Subjects 
AE1 
Summary of AEs Leading to Withdrawal from Study / Permanent 
Discontinuation of Study Treatment by SOC and PT 
IDSL 
Y 
AEs of Special Interest 
3.22. 
All Treated 
Subjects 
SAFE_T1 
Summary of On-Therapy AEs of special interest 
 
Y 
3.23. 
All Treated 
SAFE_T1 
Summary of On-Therapy AEs of special interest by Dialysis Status 
 
Y 


 
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Safety : Tables 
No. 
Populatio
n 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
SAC 
Subjects 
3.24. 
All Treated 
Subjects 
SAFE_T1 
Summary of Post-Therapy AEs of special interest 
 
Y 
Laboratory Chemistry 
3.25. 
All Treated 
Subjects 
LB1 
Summary of Chemistry Values by Visit 
ICH E3 
Includes Baseline values 
Y 
3.26. 
All Treated 
Subjects 
LB1 
Summary of Chemistry Changes from Baseline by Visit 
ICH E3 
Y 
3.27. 
All Treated 
Subjects 
SAFE_T2 
Summary of Percent change from Baseline in Lipid Parameters (total 
cholesterol, LDL cholesterol and HDL cholesterol) by Visit 
 
Y 
3.28. 
All Treated 
Subjects 
LB15 
Summary of Worst Case Chemistry Results Relative to Normal Range 
Post-Baseline Relative to Baseline 
ICH E3 
Y 
3.29. 
All Treated 
Subjects 
LB17 
Summary of Worst Case Chemistry Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline 
ICH E3 
Y 
Hematology 
3.30. 
All Treated 
Subjects 
LB1 
Summary of Hematology Values by Visit 
ICH E3 
Includes Baseline values 
Y 
3.31. 
All Treated 
Subjects 
LB1 
Summary of Hematology Changes from Baseline by Visit 
ICH E3 
Y 
3.32. 
All Treated 
Subjects 
LB15 
Summary of Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline 
ICH E3 
Y 
3.33. 
All Treated 
Subjects 
LB17 
Summary of Worst Case Hematology Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline 
ICH E3 
Y 
Other Laboratory Tests 
3.34. 
All Treated 
LB1 
Summary of Other Laboratory Values by Visit 
ICH E3 
Y 


 
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Safety : Tables 
No. 
Populatio
n 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
SAC 
Subjects 
Includes Baseline values 
3.35. 
All Treated 
Subjects 
LB1 
Summary of Other Laboratory Changes from Baseline by Visit 
ICH E3 
Y 
3.36. 
All Treated 
Subjects 
LB15 
Summary of Worst Case Other Laboratory Results Relative to Normal 
Range Post-Baseline Relative to Baselinet 
ICH E3 
Y 
3.37. 
All Treated 
Subjects 
LB17 
Summary of Worst Case Other Laboratory Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline 
ICH E3 
Y 
Hepatobiliary (Liver) 
3.38. 
All Treated 
Subjects 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
IDSL 
Y 
3.39. 
All Treated 
Subjects 
LIVER10 
Summary of Subjects Meeting Emergent Hepatobiliary Laboratory 
Abnormality Criteria 
IDSL 
Listing may be sufficient if few events. 
Y 
ECG 
3.40. 
All Treated 
Subjects 
EG1 
Summary of ECG Findings 
IDSL 
Y 
3.41. 
All Treated 
Subjects 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
IDSL 
Y 
Vital Signs 
3.42. 
All Treated 
Subjects 
SAFE_T3 
based on VS1 
Summary of Vital Signs by Visit 
Summarized by each assessment status 
(i.e. pre-dialysis and post-dialysis) 
Y 
3.43. 
All Treated 
Subjects 
SAFE_T3 
based on VS1 
Summary Change from Baseline in Vital Signs by Visit 
Summarized by each assessment status 
(i.e. pre-dialysis and post-dialysis) 
Y 
3.44. 
All Treated 
Subjects 
SAFE_T4 
based on VS7 
Summary of Worst Case Vital Sign Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline  
Summarized by each assessment status 
(i.e. pre-dialysis and post-dialysis) 
Y 
Ophthalmology 


 
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Safety : Tables 
No. 
Populatio
n 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
SAC 
3.45. 
All Treated 
Subjects 
SAFE_T5 
Summary of Ophthalmologic Exams at Screening 
 
Y 
3.46. 
All Treated 
Subjects 
SAFE_T6 
Summary of On-Therapy Ophthalmologic Exams 
 
Y 
Safety Summaries for a Plain Language Summary 
3.47. 
All Treated 
Subjects 
AE3 
Summary of On-Therapy Serious Drug-Related AEs 
 
Y 
3.48. 
All Treated 
Subjects 
AE3 
Summary of On-Therapy Non-Serious Drug-Related AEs 
 
Y 
 


 
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10.14.7. 
Safety Figures 
Safety : Figures 
No. 
Populatio
n 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
SAC 
Clinical Laboratory Analyses 
3.1.  
All Treated 
Subjects 
SAFE_F1 
Plot of Percent change from Baseline in Lipid Parameters 
(total cholesterol, LDL cholesterol, and HDL cholesterol) over time 
 
Y 
 


 
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10.14.8. 
Pharmacokinetic Tables 
Pharmacokinetic : Tables 
No. 
Populatio
n 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
SAC 
Plasma GSK1278863 Concentrations 
4.1.  
PK 
PK01 
Summary of GSK1278863 Plasma Concentration by Dose level 
(non-transformed) 
 
Y 
4.2.  
PK 
PK_T1 
based on PK05 
Summary of GSK1278863 Plasma Concentration by Dose level 
(loge-transformed) 
 
Y 
PK parameters 
4.3.  
PK 
PK03 
Summary of GSK1278863 Pharmacokinetic Parameters by Dose 
level (non-transformed) 
 
Y 
4.4.  
PK 
PK05 
Summary of GSK1278863 Pharmacokinetic Parameters by Dose 
level (loge-transformed) 
 
Y 
4.5.  
PK 
PK03 
Summary of Dose Normalized GSK1278863 Pharmacokinetic 
Parameters by Dose level (non-transformed) 
 
Y 
4.6.  
PK 
PK05 
Summary of Dose Normalized GSK1278863 Pharmacokinetic 
Parameters by Dose level (loge-transformed) 
 
Y 
4.7.  
PK 
PK03 
Summary of Dose Normalized GSK1278863 Pharmacokinetic 
Parameters by Used Tablet Strength (non-transformed) 
 
Y 
4.8.  
PK 
PK05 
Summary of Dose Normalized GSK1278863 Pharmacokinetic 
Parameters by Used Tablet Strength (loge-transformed) 
 
Y 
 


 
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10.14.9. 
Pharmacokinetic Figures 
Pharmacokinetic : Figures 
No. 
Populati
on 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
SAC 
Plasma GSK1278863 Concentrations 
4.1.  
PK 
PK24 
Individual GSK1278863 Plasma Concentration-Time Plots  
(Linear and Semi-Log) (by Dose) 
Y 
4.2.  
PK 
PK17 
Mean GSK1278863 Plasma Concentration-Time Plots 
(Linear and Semi-Log) (by Dose) 
Y 
4.3.  
PK 
PK19 
Mean (+SD) GSK1278863 Plasma Concentration-Time Plots 
(Linear and Semi-Log) (by Dose) 
Y 
4.4.  
PK 
PK20 
Median GSK1278863 Plasma Concentration-Time Plots 
(Linear and Semi-Log) (by Dose) 
Y 
PK Parameters 
4.5.  
PK 
PK_F1 
Individual Plot of GSK1278863 Dose level and PK Parameters 
(AUC (0-4), AUC (0-7), Cmax) 
will provide only pooled data  
Y 
4.6.  
PK 
PK_F2 
Mean (+SD) Plot of GSK1278863 Dose level and PK Parameters 
(AUC (0-4), AUC (0-7), Cmax) 
will provide only pooled data 
Y 
4.7.  
PK 
PK_F3 
Median Plot of GSK1278863 Dose level and PK Parameters (AUC 
(0-4), AUC (0-7), Cmax) 
will provide only pooled data 
Y 
4.8.  
PK 
PK_F1 
Individual Plot of GSK1278863 Dose level and Dose Normalized PK 
Parameters (AUC (0-4), AUC (0-7), Cmax) 
will provide only pooled data 
Y 
4.9.  
PK 
PK_F2 
Mean (+SD) Plot of GSK1278863 Dose level and Dose Normalized 
PK Parameters (AUC (0-4), AUC (0-7), Cmax) 
will provide only pooled data 
Y 
4.10. 
PK 
PK_F3 
Median Plot of GSK1278863 Dose level and Dose Normalized PK 
Parameters (AUC (0-4), AUC (0-7), Cmax) 
will provide only pooled data 
Y 
4.11. 
PK 
PK_F4 
Box Plot of GSK1278863 Dose level and Dose Normalized PK 
Parameters (AUC (0-4), AUC (0-7), Cmax) 
will provide only pooled data 
Y 
4.12. 
PK 
PK_F1 
Individual Plot of GSK1278863 Used Tablet Strength and Dose 
Normalized PK Parameters (AUC (0-4), AUC (0-7), Cmax) 
will provide only pooled data 
Y 


 
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Pharmacokinetic : Figures 
No. 
Populati
on 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
SAC 
4.13. 
PK 
PK_F2 
Mean (+SD) Plot of GSK1278863 Used Tablet Strength and Dose 
Normalized PK Parameters (AUC (0-4), AUC (0-7), Cmax) 
will provide only pooled data 
Y 
4.14. 
PK 
PK_F3 
Median Plot of GSK1278863 Used Tablet Strength and Dose 
Normalized PK Parameters (AUC (0-4), AUC (0-7), Cmax) 
will provide only pooled data 
Y 
4.15. 
PK 
PK_F4 
Box Plot of GSK1278863 Used Tablet Strength and Dose 
Normalized PK Parameters (AUC (0-4), AUC (0-7), Cmax) 
will provide only pooled data 
Y 
 


 
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10.14.10. ICH Listings 
ICH : Listings 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title 
Programming Notes 
SAC 
Study Populations 
Subject Disposition 
1.  
Assigned 
ES2 
Listing of Reasons for Study Withdrawal 
ICH E3 
Y 
2.  
All Treated 
Subjects 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
Y 
3.  
All Screening 
ES7 
Listing of Reasons for Screen Failure 
Journal Guidelines 
Y 
Protocol Deviations 
4.  
Assigned 
DV2 
Listing of Important Protocol Deviations 
ICH E3 
Y 
5.  
Assigned 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
ICH E3 
Y 
Populations Analysed 
6.  
Assigned 
SP3 
Listing of Subjects Excluded from All Treated Subjects Population 
ICH E3 
Note: IDSL shell for SP3a in development. 
e.g., subjects screened but not randomized, 
subjects randomized but not treated, 
subjects with deviations leading to 
exclusion from per protocol population (can 
be separate listing per population). 
Y 
Demographic and Baseline Characteristics 
7.  
All Treated 
Subjects 
DM2 
Listing of Demographic Characteristics 
ICH E3 
Y 
8.  
All Treated 
Subjects 
DM9 
Listing of Race 
ICH E3 
Y 


 
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ICH : Listings 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title 
Programming Notes 
SAC 
Dialysis 
9.  
All Treated 
Subjects 
POP_L1 
Listing of Dialysis Status 
 
Y 
Exposure and Treatment Compliance 
10.  
All Treated 
Subjects 
POP_L2 
based on 
EX3 
Listing of Exposure Data 
ICH E3 
Y 
11.  
All Treated 
Subjects 
POP_L3 
Listing of Treatment Compliance 
ICH E3 
Up to Week 4 and overall compliance will 
be provided. 
Y 
Efficacy 
Hgb 
12.  
All Treated 
Subjects 
EFF_L1 
Listing of Hgb Data 
 
Y 
13.  
All Treated 
Subjects 
EFF_L2 
Listing of Subjects who have an Hgb level of less than 7.5 g/dL 
 
Y 
14.  
All Treated 
Subjects 
EFF_L2 
Listing of Subjects who have an Hgb increase of more than 2.0 g/dL over 
any 4 weeks 
 
Y 
15.  
All Treated 
Subjects 
EFF_L2 
Listing of Subjects who have an Hgb increase of more than 13.0 g/dL 
 
Y 
16.  
All Treated 
Subjects 
LB5 
Listing of Iron Parameter Data 
Ferritin, TSAT, hepcidin, serum iron, and 
TIBC will be included. 
Y 
Safety 


 
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ICH : Listings 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title 
Programming Notes 
SAC 
Adverse Events 
17.  
All Treated 
Subjects 
AE8 
Listing of All Adverse Events 
ICH E3 
Y 
18.  
All Treated 
Subjects 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3 
Y 
19.  
All Treated 
Subjects 
AE2 
Listing of Relationship Between Adverse Event System Organ Classes, 
Preferred Terms, and Verbatim Text 
IDSL 
Y 
Serious and Other Significant Adverse Events 
20.  
All Treated 
Subjects 
AE8 
Listing of Fatal Serious Adverse Events 
ICH E3 
Fatal and Non-Fatal SAEs are combined 
into a single listing for ClinPharm studies 
(i.e., “Listing of Serious Adverse Events”). 
Y 
21.  
All Treated 
Subjects 
AE8 
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
Fatal and Non-Fatal SAEs are combined 
into a single listing for ClinPharm studies 
(i.e., “Listing of Serious Adverse Events”). 
Y 
22.  
All Screening 
AE8 
Listing of Serious AEs in Screening Period 
All pre-therapy SAEs captured in eCRF will 
be provided including screen failure records 
of rescreened subjects. 
Y 
23.  
All Treated 
Subjects 
AE8 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment 
ICH E3 
Y 
24.  
All Treated 
Subjects 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3 
Y 


 
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ICH : Listings 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title 
Programming Notes 
SAC 
25.  
All Treated 
Subjects 
SAFE_L1 
Listing of Adverse Events of Special Interest 
ICH E3 
Displays will be produced with AESI 
category in addition of AE8 template. 
Y 
All Laboratory 
26.  
All Treated 
Subjects 
LB5 
Listing of All Chemistry Data for Subjects with Any Value Outside of 
Normal Range/of PCI 
ICH E3 
May be split into separate listings by 
chemistry, hematology, urinalysis, etc. 
Display ALL labs for a subject who 
experienced a value of potential clinical 
concern/importance. 
Y 
27.  
All Treated 
Subjects 
LB5 
Listing of All Hematology Data for Subjects with Any Value Outside of 
Normal Range/of PCI 
ICH E3 
Y 
28.  
All Treated 
Subjects 
LB5 
Listing of All Other Laboratory Data for Subjects with Any Value Outside 
of Normal Range/of PCI 
ICH E3 
Y 
29.  
All Treated 
Subjects 
LB14 
Listing of Laboratory Data with Character Results 
IDSL 
Rationale: This listing is required to ensure 
character laboratory results are presented. 
Y 
 
 
 


 
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10.14.11. Non-ICH Listings 
Non-ICH : Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
SAC 
Study Population 
Demographic and Baseline Characteristics 
30.  
All Treated 
Subjects 
FH4 
Listing of Family Members with History of Cardiovascular Risk Factors 
 
Y 
31.  
All Treated 
Subjects 
SU2 
Listing of Substance Use History 
 
Y 
Prior and Concomitant Medications 
32.  
All Treated 
Subjects 
MH2 
Listing of Medical Conditions 
 
Y 
33.  
All Treated 
Subjects 
CM2 
Listing of Concomitant Medications 
 
Y 
34.  
All Treated 
Subjects 
POP_L4 
Listing of ESA Concomitant Medications 
 
Y 
35.  
All Treated 
Subjects 
POP_L5 
Listing of Iron Concomitant Medications 
 
Y 
36.  
All Treated 
Subjects 
POP_L6 
Listing of Blood Products and Blood Supportive Care Products 
 
Y 
Dialysis 
37.  
All Treated 
Subjects 
POP_L7 
Listing of Baseline Hemodialysis and Changes in Hemodialysis 
 
Y 
38.  
All Treated 
Subjects 
POP_L8 
Listing of Baseline Vascular Access 
 
Y 


 
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Non-ICH : Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
SAC 
39.  
All Treated 
Subjects 
POP_L9 
Listing of Subjects with Vascular Therapeutic Procedures during the 
Study Period 
 
Y 
Efficacy 
Safety 
Suicidality-Related Adverse Event 
40.  
All Treated 
Subjects 
IDSL standard 
Listing of Possible Suicidality-Related Adverse Event Data: Event and 
Description (Sections 1-2) 
 
Y 
41.  
All Treated 
Subjects 
IDSL standard 
Listing of Possible Suicidality-Related Adverse Event Data: Possible 
Cause(s) (Section 3) 
 
Y 
42.  
All Treated 
Subjects 
IDSL standard 
Listing of Possible Suicidality-Related Adverse Event Data: (Section 
4) 
 
Y 
43.  
All Treated 
Subjects 
IDSL standard 
Listing of Possible Suicidality-Related Adverse Event Data: (Section 
5-8) 
 
Y 
Clinical Laboratory, ECG, Vital Sign, and Ophthalmology Exam 
44.  
All Treated 
Subjects 
LB5 
Listing of Chemistry Data 
 
Y 
45.  
All Treated 
Subjects 
LB5 
Listing of Hematology Data 
 
Y 
46.  
All Treated 
Subjects 
LB5 
Listing of Other Laboratory Data 
 
Y 
47.  
All Treated 
Subjects 
MH2 
Listing of Medical Conditions for Subjects with Liver Stopping Events 
This listing is required for medical review of 
subjects with liver stopping events. 
Y 
48.  
All Treated 
Subjects 
SU2 
Listing of Substance Use for Subjects with Liver Stopping Events 
This listing is required for medical review of 
subjects with liver stopping events. 
Y 


 
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Non-ICH : Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
SAC 
49.  
All Treated 
Subjects 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting 
 
Y 
50.  
All Treated 
Subjects 
LIVER6 
Listing of Liver Stopping Event Information for RUCAM Score 
 
Y 
51.  
All Treated 
Subjects 
LIVER7 
Listing of Liver Biopsy Details 
 
Y 
52.  
All Treated 
Subjects 
LIVER8 
Listing of Liver Imaging Details 
 
Y 
53.  
All Treated 
Subjects 
EG3 
Listing of ECG Values 
 
Y 
54.  
All Treated 
Subjects 
EG5 
Listing of ECG Findings 
 
Y 
55.  
All Treated 
Subjects 
VS4 
Listing of Vital Signs 
 
Y 
56.  
All Treated 
Subjects 
VS4 
Listing of All Vital Signs for Subjects with Values of PCI 
 
Y 
57.  
All Treated 
Subjects 
SAFE_L2 
Listing of Ophthalmologic Exams 
 
Y 
Pharmacokinetic Parameters 
58.  
PK 
PK07 
Listing of GSK1278863 Pharmacokinetic Concentration-Time Data by 
Dose level 
 
Y 
59.  
PK 
PK13 
Listing of Derived GSK1278863 Pharmacokinetic Parameters by 
Dose level 
 
Y 
 


 
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10.14.12. Patient Profile Listings 
Patient Profile Listings 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title 
Programming Notes 
SAC 
Safety 
60.  
All Treated 
Subjects 
IDSL 
standard 
Patient Profile Listing of Arrhythmias 
 
Y 
61.  
All Treated 
Subjects 
IDSL 
standard 
Patient Profile Listing of Congestive Heart Failure 
 
Y 
62.  
All Treated 
Subjects 
IDSL 
standard 
Patient Profile Listing of Cerebrovascular Events/Stroke/ Transient 
Ischemic Attack 
 
Y 
63.  
All Treated 
Subjects 
IDSL 
standard 
Patient Profile Listing of Deep venous Thrombosis/ Pulmonary Embolism 
 
Y 
64.  
All Treated 
Subjects 
IDSL 
standard 
Patient Profile Listing of Myocardial Infarction /Unstable Angina 
 
Y 
65.  
All Treated 
Subjects 
IDSL 
standard 
Patient Profile Listing of Peripheral Arterial Thrombosis Embolism 
Events will be provided only when a related 
AE sequence number is present 
(Section 10.6.4). 
Y 
66.  
All Treated 
Subjects 
IDSL 
standard 
Patient Profile Listing of Pulmonary Hypertension 
 
Y 
67.  
All Treated 
Subjects 
IDSL 
standard 
Patient Profile Listing of Revascularization 
 
Y 
68.  
All Treated 
Subjects 
IDSL 
standard 
Patient Profile Listing of Valvulopathy 
 
Y 
69.  
All Treated 
Subjects 
IDSL 
standard 
Patient Profile Listing of Deaths 
 
Y 


 
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10.15. 
Appendix 15: Example Mock Shells for Data Displays 
These are provided with separated documents. 
 
 


 
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10.16. 
Appendix 16: RAP Amendment(s) 
Minor wording changes are not included in below. 
Reporting and Analysis Plan_204716_Amendment_Final_V1.1 [11-Oct-2017] 
Section # and Name 
Description of Change 
Brief Rationale 
2.1 
Changes to the Protocol 
Defined Statistical Analysis Plan 
Deleted the table and added statement of ‘’Modified text to align with the latest version of protocol 
as follow: 
1. No interim analysis is planned. 
2. The change in Hgb at Week 4 will be classified into different categories (i.e., -2, >-2 to 
-1, >-1 to 0, >0 to 1, >1 to 2, and >2 g/dL) 
Protocol was amended. 
1. The interim analysis was just 
aiming to meet the clinical result 
disclosure obligation. Given our 
POLICY update, the due date of 
disclosure was changed 
to ’within 12 months of PCA’ 
from ‘within 8 months of PCA’. 
Therefore, a final analysis of 
204716 study can meet the 
current disclosure due date. 
2. Specifying the categories and 
ensuring there is no overlap. 
4 
Analysis populations 
The term of ‘randomized population’ has been changed to ‘assigned population’ 
‘Assigned’ would be more 
appropriate for this single arm study. 
6.1.1 
Planned Summary 
Display Details 
10.6.2 
Study Population 
Clarifications were made for a subject who has multiple numbers as follows: 
 
A subject who has multiple subject numbers (i.e. rescreened subject) will be analyzed 
as a unique subject based on the latest screening result. 
 
Screening status and reason for screening failure for a subject who has multiple subject 
numbers will be unique in the unique subject ID. 
Minor wording changes were also made. 
Clarification 
7.1 
Primary Efficacy 
Analyses 
Updates were made to the summaries for adding categories; within 1 g/dL and over 2 g/dL. 
 
These categories would facilitate 
review the drug efficacy results. 
8 
Secondary statistical 
analyses 
10.6.3 
Efficacy 
It has been clarified that, on-therapy Hgb will be used for several Hgb endpoints and evaluable 
Hgb. 
In addition, 95%CI has been added to descriptive summary statistics for continuous data. 
 
Correction and Clarification 


 
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Reporting and Analysis Plan_204716_Amendment_Final_V1.1 [11-Oct-2017] 
Section # and Name 
Description of Change 
Brief Rationale 
8.1.2 
Planned Efficacy Table 
Displays 
Added the following clarifications in a model specification of Kaplan Meier Method:  Subjects 
within target range at baseline will be excluded from the summary.  Subjects who could not 
reach lower target will be regarded as censored at EoT. 
In addition, in dose adjustment summary, it has been clarified that what subjects will be included 
in summaries of duration of treatment interruption and number of dose adjustments. 
Clarification 
8.1.2 
Planned Efficacy Table 
Displays 
Added summary tables and planed displays detail for number (%) of subjects with each dose 
level by visit 
Tables corresponding to histogram of 
dose level by visit (Fig. 2.10) are 
necessary. 
8.2.1.1 Planed AE Analyses 
Displays 
1. Clarifications were made for the maximum intensity of AEs category and how to treat 
different intensities in the same AE. 
2. It has been modified how to display serious adverse event, for both primary system organ 
class and preferred term. 
1. Clarification 
2. SOC for SAE summary provides 
a consistent presentation style 
that facilitates review 
8.2.2 
Overview of Planned 
Clinical Laboratory Analyses 
8.2.3 
Overview of Planned 
Other Safety Analyses 
Updates were made to the summaries for normal range/PCI criteria. 
Only the worst case results relative to normal range/PCI criteria post-baseline relative to baseline 
will be provided. 
 
IDSL templates based on GSK Core 
RAP requirements in the RAP 
template are updated. 
8.2.3.1 Planned Other Safety 
Analyses Displays 
10.5.2 
Baseline Definition & 
Derivations 
10.14.6 Safety Tables 
Updates were made to the indicated sections of RAP to describe how to summarize vital sign 
assessment. 
Pre- and post-dialysis assessment will be summarized separately and non-dialysis assessment 
will not be summarized. 
Vital sign assessment in non-dialysis 
day would be unlikely, so 
summarization would not be 
necessary. 
 
8.2.3.1 Planned Other Safety 
Analyses Displays 
Text added to make sure the summary display for ECG findings. 
Clarification 
8.2.3.1 Planned Other Safety 
Analyses Displays 
Additional summary added to ophthalmology exam, displayed along with a summary of on-
therapy ophthalmology exam. No additional table is required for this update. 
Worthwhile to add another way of 
summarization 
8.3.3.1 Deriving 
Pharmacokinetic Parameters 
Modifications were made for the definition of C(last), last quantifiable concentration. 
To make sure that the definitions of 
the parameters are consistent 
10.3.1 
Definitions of Analysis 
Time Point 
10.6.1 
General 
Text added to make sure data derivation for multiple measurements at Screening and Day 1 visit.  
The screening-pass visit record will be used for analysis if multiple records are present. 
Clarification 


 
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Reporting and Analysis Plan_204716_Amendment_Final_V1.1 [11-Oct-2017] 
Section # and Name 
Description of Change 
Brief Rationale 
10.4.1.3 Treatment States for 
Concomitant Medications Data 
Updates were made considering the case of EoT missing 
To ensure the definition of treatment 
state to cover all possible cases 
10.5.3 
Reporting Process & 
Standards 
Further clarification has been made about descriptive summary statistics. 
Clarification 
10.6.2 
Study Population 
Age 
Reference date for age calculation was updated 
Exposure 
Text deleted 
Age 
Using randomization date as 
reference may be more appropriate 
rather than using screening date 
based on SDTM standard derivations 
(Note that IG suggests to only expect 
AGE for treated subjects, but the 
study expect AGE for randomized 
subjects).  
Exposure 
Deleted because it may not be 
suitable for this section 
10.6.3 
Efficacy 
Iron Endpoints: Quarterly IV Iron Dose 
Quarterly IV iron dose will be calculated using randomization date and EoT to support on-therapy 
iron definition. 
To ensure that on-therapy iron and 
the quarterly iron are consistently 
defined. 
 
10.6.4 
Safety 
Adverse Events 
Corrections were made to the categories of adverse events of special interest.  In a second 
bullet of the categories, heart failure was added and venous thromboembolism was corrected to 
thromboembolic events 
CV Events 
Updates were added to clarify how to provided patient profiles in PAT form. 
For AEs. protocol was amended for 
AESI terminology. 
For CV events, to make sure how to 
output CV records based on team 
discussion 
10.6.5 
Pharmacokinetic 
1. Derivation of tablet strength was clarified. 
2. Derivation of dose level was updated to see whether PK sampling date is included within a 
period of exposure for each visit as follows: 
 
Treatment Start Date  Date of last dose taken prior to PK sampling  Treatment Stop 
Date 
1. Clarification 
2. To make sure that the derivation 
can apply to an irregular PK 
sampling such as sampling at 
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Reporting and Analysis Plan_204716_Amendment_Final_V1.1 [11-Oct-2017] 
Section # and Name 
Description of Change 
Brief Rationale 
Dose level is derived from actual dose of a visit which meets the above exposure record. 
allowance of visit window. 
10.8 
Appendix 8: Values of 
Potential Clinical Importance 
PCI values were updated in Section 10.8.1. 
To maintain consistency between 
global and Japan Ph3 program, use 
the same PCI cut off values. 
10.14 
Appendix 14: List of 
Data Displays 
 
The following bullets were modified: 
 
General 
Changed from ‘Randomized population’ to ‘Assigned population’ 
 
Table 1.9, Listing 6 
Corrected title from ‘Exclusions from Randomized Population’ to ‘Exclusions from All Treated 
Subjects Population’ 
 
Table 2.13, 2.14, 2.19, 2.20, 2.43 to 2.46, 3.27, Figure 3.1 
Corrected titles 
 
Table 2.47, 2.48 
Added summary tables for number (%) of subjects with each dose level by visit 
 
Table 3.18, 3.19 
Corrected example shell ID 
 
Table 3.42, 3.43, 3.44 
Excluded statement to non-dialysis in Programming Notes of Vital Signs  
 
Listing 2,3, 22 
Corrected analysis population 
 
Listing 16 
Added iron parameter listing 
 
Listing 25 
Deleted duplicate (listing 39) and updated IDSL example 
 
Listing 38, 39 
Modified titles 
 
Listing 65 
Added programming notes 
Corrections and Clarifications 
 


 
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Reporting and Analysis Plan_204716_Amendment_Final_V1.2 [29-NOV-2017] 
Section # and Name 
Description of Change 
Brief Rationale 
6.1 
Overview of Planned 
Analyses 
Modification was made for the title; from ‘Baseline Dialysis‘ to ‘Baseline Mode of Dialysis’  
Correction 
8.1 
Secondary Efficacy 
Analyses 
1. Added summaries of number of dose adjustment to reach the lower Hgb target Hgb level 
(10.0 g/dL) 
2. For the summary of time to reach the lower target Hgb level, modification was made to 
include all subjects in the analysis. 
1. This will facilitate review of the 
study results 
2. Correction according to team 
discussion 
8.1.2 
Planned Efficacy Table 
Displays 
1. Text added to clarify that the analysis of scatter plot includes Pearson’s correlation 
coefficient. 
2. Updates were made to the summaries of dose level (mg) for adding P25 and P75. 
3. In dose adjustment summary, it has been re-corrected that all subjects including those with 
no dose adjustment will include a summary. 
1. Clarification 
2. These will facilitate review of the 
study results. 
3. Reconsideration clinically for the 
dose adjustment summary. 
8.2 
Safety Analyses 
10.14 
Appendix 14: List of 
Data Displays 
Added additional tables: 
 
On-therapy Serious Drug-Related AEs 
 
On-therapy Non-Serious Drug-Related AEs 
Required for a Plain Language 
Summary (PLS) for GSK 
10.4.1 
Treatment States 
Clarification has been made for treatment states of follow-up visit assessments. 
Clarification 
10.6.1 
General 
Updates were made for definitions of treatment states; use study treatment stop date instead of 
end of treatment date (EoT). In addition to general changes of the treatment states due to this, 
note that this change has impact on the following endpoints for specific derivations: 
 
Time (in days) to reach the lower target Hgb level (10.0 g/dL) 
 
Dose of i.v. iron during the treatment period 
For daprodustat, the treatment states 
will be more explainable on the basis 
of study treatment stop date derived 
from the exposure record rather on 
the basis of EoT derived from the 
assessment visit.  
10.6.2 
Study Population 
Text added for treatment compliance up to Week 4. 
Compliance up to Week 4 will 
facilitate review of the study results. 
10.6.3 
Efficacy 
Deleted text that mentioned the baseline Hgb value might include that at unscheduled visits. 
Missing the Hgb value at Day 1 will 
never happen so that no need to 
mention the unscheduled visits for 
the baseline Hgb derivation.  
10.6.3 
Efficacy 
Added the candidate covariates (body weight at screening and baseline Hgb) to provide the 
This will facilitate review of 


 
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Reporting and Analysis Plan_204716_Amendment_Final_V1.2 [29-NOV-2017] 
Section # and Name 
Description of Change 
Brief Rationale 
10.10.1 Handling of Covariates, 
Subgroups & Other Strata 
10.14.5 Efficacy Figures 
following scatter plot figures: 
 
Change from baseline in Hgb at Week 4 vs. candidate covariates 
 
Mean dose vs. candidate covariates 
appropriateness of starting dose or 
maintenance dose. 
10.6.4 
Safety 
1. Clarification has been made for the definition of AEs up to Week 4 
2. It has been corrected how to display the CV events in PAT form.  
Clarification and correction 
10.6.5 
Pharmacokinetic 
Clarifications were made for the derivation of dose normalized PK parameters and the definition 
of time deviated concentration. 
Clarification