Clinical trial NCT02969655
Conditions: Anaemia
Keywords: Safety Efficacy Daprodustat Chronic kidney disease
Sponsor: GlaxoSmithKline
Start date: 2016-11-21; Completion date: 2018-07-02
Enrollment: 271 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Daprodustat is a drug that is currently being developed as a treatment for renal anemia . This study is to evaluate the efficacy and safety of daprodustat following a switch from erythropoiesis-stimulating agent (ESA) in Japanese HD subjects with renal anemia who are currently treated with ESA. The primary objective is to demonstrate non-inferiority of daprodustat to darbepoetin alfa. This study is a 52-week, Phase III, double-blind, active-controlled, parallel-group, multi-center study. The total duration of the study will be approximately 58 weeks including screening and follow-up.

Detailed description:

Arms: arm 1: Subjects will receive oral daprodustat once daily and intravenous (IV) darbepoetin alfa placebo once weekly for 52 weeks arm 2: Subjects will receive IV darbepoetin alfa once weekly and oral daprodustat placebo once daily for 52 weeks
Interventions: intervention 1: Daprodustat small intervention 2: Daprodustat small placebo intervention 3: Daprodustat large intervention 4: Daprodustat large placebo intervention 5: Darbepoetin alfa intervention 6: Darbepoetin alfa placebo
Intervention descriptions: intervention 1: Available as 7.0 millimeter (mm) round, standard biconvex, white film coated tablets containing 1 mg, 2 mg, or 4 mg of daprodustat as active ingredient intervention 2: Available as 7.0 mm round, standard biconvex, white film coated tablets containing no daprodustat intervention 3: Available as 9.0 mm round, standard biconvex, white film coated tablets containing 6 mg of daprodustat as active ingredient intervention 4: Available as 9.0 mm round, standard biconvex, white film coated tablets containing no daprodustat intervention 5: Available as 0.5 mL plastic prefilled syringes (PFS) for IV injection each containing 10, 15, 20, 30, 40 or 60 mcg of darbepoetin alfa in a clear and colorless solution. intervention 6: Available as 0.5 mL plastic PFS for IV injection containing no darbepoetin alfa in a clear and colorless solution.

Protocol documents:
Prot_001.pdf: 
2015N266251_02 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
PHI201754 
 
- 1 - 
 
TITLE PAGE 
 
Division：Worldwide Development 
Information Type： Clinical Protocol 
 
 
Title：A 52-week, Phase III, double-blind, active-controlled, parallel-group, multi-center study to 
evaluate efficacy and safety of daprodustat compared to darbepoetin alfa in Japanese hemodialysis-
dependent subjects with anemia associated with chronic kidney disease who are currently ESA users. 
Compound Number： 
Daprodustat 
Development Phase 
III 
Effective Date： 
 
19-Jul-2017 
 
Protocol Amendment Number： 
02 
 
Author(s)： 
 
  
 
Revision Chronology： 
GlaxoSmithKline Document 
Number 
Date 
Version 
2015N266251_00 
19-JUL-2016 
First version 
2015N266251_01 
08-MAR-2017 
Amendment 01 
Clarification of the timing of eligibility assessment regarding exclusion criteria, addition of the 
prohibited medication, and correction of adverse events of special interest 
2015N266251_02 
19-JUL-2017 
Amendment 02 
Change for definition of screen failures, clarification of the withdrawal/dropout criteria for prohibited 
medication, clarification of definition of overdose of daprodustat, update of AESI, addition of details 
of sensitivity analyses for primary efficacy analysis and description adjustment, update of risk 
assessment (Appendix 2) , and correction of erroneous description  
 
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited. 
 
PPD
PPD


2015N266251_02 
CONFIDENTIAL 
 
 
 
PHI201754 
 
- 2 - 
Sponsor Signatory: 
 
 
 
 
Kihito Takahashi 
Director, 
Japan Development and Medical Affairs (JDMA), 
GlaxoSmithKline K. K. 
 
The IMMS document approved is as follows: 
  Unique ID: 090033ec8416fd56 
  System Version:1.0 
  Effective Date: 19 Jul 2017 
 
Date 
 


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- 3 - 
MEDICAL MONITOR/SPONSOR INFORMATION PAGE 
 
Medical Monitor/SAE Contact Information: 
Role 
Name 
Day Time 
Phone 
Number 
Fax Number 
Site Address 
Medical Monitor 
 
M.D., Ph.D. 
GlaxoSmithKline K.K.  
6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-8566 
JAPAN 
 
SAE contact  
information 
Person in charge 
of daprodustat 
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 daprodustat, Clinical Operations dept. R&D, Glaxo Smith Kline K.K 
TEL: 
FAX: 
 
Emergency Contact at night and holiday (Mon to Fri 6pm to 10am, Sat, Sun, national holiday and 
year-end and New Year holidays) 
BI Medical Inc. 
Responsible Person: 
 
TEL: 
(toll free) 
FAX: 
(toll free) 
 
Sponsor Legal Registered Address: 
6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566 JAPAN 
 
 
 
PPD
PPD
PPD
PPD
PPD


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- 4 - 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
• 
I confirm agreement to conduct the study in compliance with the protocol and the amended 
content. 
• 
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 PHI201754 ........................................................ 9 
2. 
INTRODUCTION ............................................................................................................ 13 
2.1. 
Study Rationale .................................................................................................... 13 
2.2. 
Background .......................................................................................................... 13 
3. 
OBJECTIVES AND ENDPOINTS .................................................................................. 14 
4. 
STUDY DESIGN ............................................................................................................. 16 
4.1. 
Overall Design ...................................................................................................... 16 
4.2. 
Treatment Groups and Study Periods ............................................................... 16 
4.3. 
Study Subjects and Number of Subjects .......................................................... 17 
4.4. 
Rationale for Study Design ................................................................................. 17 
4.5. 
Rationale for Dose Levels ................................................................................... 18 
4.6. 
Benefit: Risk Assessment................................................................................... 19 
4.6.1. 
Risk Assessment ........................................................................................ 19 
4.6.2. 
Benefit Assessment .................................................................................... 19 
4.6.3. 
Overall Benefit: Risk Conclusion .............................................................. 20 
5. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ........................................... 21 
5.1. 
Inclusion Criteria.................................................................................................. 21 
5.2. 
Exclusion Criteria ................................................................................................ 22 
5.3. 
Screening Failures ............................................................................................... 23 
5.4. 
Permanent discontinuation of study treatment and study withdrawal ......... 24 
5.4.1. 
Liver Chemistry Stopping Criteria............................................................. 25 
5.4.1.1. 
Study Treatment Restart or Rechallenge......................................... 26 
5.5. 
Subject and Study Completion .......................................................................... 26 
6. 
STUDY TREATMENTS .................................................................................................. 27 
6.1. 
Investigational Product and Other Study Treatment ....................................... 27 
6.2. 
Medical Device ..................................................................................................... 28 
6.3. 
Treatment Assignment ........................................................................................ 28 
6.4. 
Administration Schedule (Starting Dose, Dose Adjustment, and 
Dosing Frequency) .............................................................................................. 29 
6.4.1. 
Daprodustat ................................................................................................. 29 
6.4.1.1. 
Starting Dose ...................................................................................... 29 
6.4.1.2. 
Maintenance Dose .............................................................................. 29 
6.4.2. 
Darbepoetin Alfa ......................................................................................... 30 
6.4.2.1. 
Dose Conversion ................................................................................ 30 
6.4.2.2. 
Maintenance Dose .............................................................................. 31 


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6.5. 
Blinding ................................................................................................................. 31 
6.6. 
Packaging and Labeling ...................................................................................... 32 
6.7. 
Preparation/Handling/Storage/Accountability .................................................. 32 
6.8. 
Compliance with Study Treatment Administration .......................................... 33 
6.9. 
Treatment of Study Treatment Overdose .......................................................... 33 
6.10. 
Treatment after the End of the Study ................................................................ 34 
6.11. 
Concomitant Medications and Non-Drug Therapies ....................................... 34 
6.11.1. 
Permitted Medications and Non-Drug Therapies .................................... 34 
6.11.2. 
Prohibited Medications and Non-Drug Therapies ................................... 34 
6.12. 
Supplemental Iron Therapy ................................................................................ 34 
7. 
Study Assessments and Procedures ......................................................................... 35 
7.1. 
Time and Events Table ........................................................................................ 35 
7.2. 
Screening and Critical Baseline Assessments ................................................ 39 
7.3. 
Efficacy ................................................................................................................. 39 
7.4. 
Safety .................................................................................................................... 39 
7.4.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) .................... 39 
7.4.1.1. 
Time period and Frequency for collecting AE and SAE 
information .......................................................................................... 39 
7.4.1.2. 
Method of Detecting AEs and SAEs ................................................. 40 
7.4.1.3. 
Follow-up of AEs and SAEs .............................................................. 40 
7.4.1.4. 
Cardiovascular and Death Events .................................................... 40 
7.4.1.5. 
Regulatory Reporting Requirements for SAEs ............................... 41 
7.4.2. 
Adverse Events of Special Interest ........................................................... 41 
7.4.3. 
Pregnancy .................................................................................................... 41 
7.4.4. 
Medical Device Incidents (Including Malfunctions) ................................ 42 
7.4.4.1. 
Time Period for Detecting Medical Device Incidents...................... 42 
7.4.4.2. 
Follow-up of Medical Device Incidents ............................................ 42 
7.4.4.3. 
Prompt Reporting of Medical Device Incidents to GSK ................. 42 
7.4.5. 
Vital Signs/Height/Weight .......................................................................... 43 
7.4.6. 
Electrocardiogram (ECG) ........................................................................... 43 
7.4.7. 
Clinical Laboratory Assessments ............................................................. 43 
7.4.8. 
Ophthalmology ............................................................................................ 44 
7.5. 
Pharmacokinetics ................................................................................................ 44 
7.6. 
Genetics ................................................................................................................ 45 
7.7. 
Patient Reported Outcome (PRO) ...................................................................... 45 
7.7.1. 
Health Related Quality of Life (SF-36) ....................................................... 45 


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7.7.2. 
EuroQol 5 Dimension 5 Level Health Utility Index (EQ-5D-5L)/ 
EuroQol Visual Analogue Scale (EQ-VAS) ............................................... 45 
8. 
DATA MANAGEMENT .................................................................................................. 46 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ..................................... 46 
9.1. 
Hypotheses ........................................................................................................... 46 
9.2. 
Sample Size Considerations .............................................................................. 47 
9.2.1. 
Sample Size Assumptions ......................................................................... 47 
9.2.2. 
Sample Size Sensitivity .............................................................................. 47 
9.2.3. 
Sample Size Re-estimation or Adjustment............................................... 47 
9.3. 
Data Analysis Considerations ............................................................................ 47 
9.3.1. 
Analysis Populations .................................................................................. 47 
9.3.2. 
Interim Analysis .......................................................................................... 48 
9.3.3. 
Adjustment for Multiplicity ......................................................................... 48 
9.4. 
Key Elements of Analysis Plan .......................................................................... 48 
9.4.1. 
Primary Efficacy Analysis .......................................................................... 48 
9.4.2. 
Principal Secondary Efficacy Analysis ..................................................... 49 
9.4.3. 
Other Secondary Efficacy Analyses ......................................................... 49 
9.4.4. 
Safety Analyses ........................................................................................... 49 
9.4.4.1. 
Exposure ............................................................................................. 50 
9.4.4.2. 
Adverse Events ................................................................................... 50 
9.4.4.3. 
Other Safety Parameters ................................................................... 50 
9.4.5. 
Pharmacokinetics Analyses ...................................................................... 50 
9.4.6. 
PRO Data Analysis ...................................................................................... 50 
10. STUDY GOVERNANCE CONSIDERATIONS .............................................................. 51 
10.1. 
Posting of Information on Publicly Available Clinical Trial Registers ........... 51 
10.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process.................................................................................................. 51 
10.3. 
Quality Control (Study Monitoring) .................................................................... 52 
10.4. 
Quality Assurance ............................................................................................... 52 
10.5. 
Study and Site Closure ....................................................................................... 52 
10.6. 
Records Retention ............................................................................................... 53 
10.7. 
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publicatio.................... 53 
10.8. 
Study Period ......................................................................................................... 54 
10.9. 
Study Administrative Structure .......................................................................... 54 
11. REFERENCES ............................................................................................................... 55 
12. APPENDICES ................................................................................................................ 56 


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12.1. 
Appendix 1: Abbreviations and Trademarks .................................................... 56 
12.2. 
Appendix 2:  Risk Assessment ......................................................................... 58 
12.3. 
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of reproductive potential ............................................. 64 
12.4. 
Appendix 4: Collection of Pregnancy Information ........................................... 65 
12.5. 
Appendix 5: Liver Safety Required Actions and Follow up 
Assessments ........................................................................................................ 66 
12.6. 
Appendix 6: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events ................................................... 69 
12.6.1. 
Definition of Adverse Events ..................................................................... 69 
12.6.2. 
Definition of Serious Adverse Events ....................................................... 70 
12.6.3. 
Definition of Cardiovascular Events ......................................................... 71 
12.6.4. 
Recording of AEs and SAEs ...................................................................... 71 
12.6.5. 
Evaluating AEs and SAEs .......................................................................... 72 
12.6.6. 
Reporting of SAEs to GSK ......................................................................... 73 
12.7. 
Appendix 7 - Genetic Research .......................................................................... 74 
12.8. 
Appendix 8: Definition of and Procedures for Documenting Medical 
Device Incidents................................................................................................... 77 
12.8.1. 
Definitions of a Medical Device Incident .................................................. 77 
12.8.1.1. 
Documenting Medical Device Incidents ........................................... 77 
12.9. 
Appendix 9: Protocol Changes .......................................................................... 79 
12.9.1. 
Amendment 1 － Summary of Changes and Rationale ..................... 79 
12.9.2. 
Amendment 2 － Summary of Changes and Rationale ..................... 82 
 


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1. PROTOCOL SYNOPSIS FOR STUDY PHI201754 
 
Rationale 
This Phase III study will evaluate the efficacy and safety of daprodustat following a switch from 
erythropoietin-stimulating agents (ESA) in Japanese subjects with anemia associated with chronic 
kidney disease (CKD) on hemodialysis (HD) who are currently treated with ESA.  The primary 
objective is to demonstrate non-inferiority of daprodustat to darbepoetin alfa based on hemoglobin 
(Hgb) in the HD patient population included in this study. Study results will be used as pivotal study 
data for an NDA submitted for daprodustat for the treatment of renal anemia in Japan.  
 
Objective(s)/Endpoint(s) 
Objective 
Endpoint 
Primary (efficacy) 
• 
To demonstrate non-inferiority of 
daprodustat to darbepoetin alfa based on 
hemoglobin (Hgb) 
• 
Mean Hgb during the primary efficacy 
evaluation period (Weeks 40 to 52) 
Principal secondary (efficacy) 
• 
To demonstrate superiority of daprodustat 
to darbepoetin alfa in terms of 
achievement/maintenance of target Hgb 
• 
Number (%) of subjects with mean Hgb in the 
target range (10.0-12.0 g/dL) during the 
primary efficacy evaluation period (Weeks 40 
to 52) 
Other secondary (efficacy, PK) 
• 
To evaluate the appropriateness of the 
starting dose of daprodustat 
• 
Change from baseline in Hgb at Week 4 (Hgb 
increase rate) 
• 
Number (%) of subjects by Hgb change from 
baseline category at Week 4 
• 
To evaluate dose adjustment scheme of 
daprodustat 
• 
Distribution of the dose level 
• 
Duration of treatment interruption due to Hgb 
>13.0 g/dL 
• 
Frequency of dose adjustments 
• 
To evaluate the overall Hgb control of 
daprodustat using darbepoetin alfa as 
control 
• 
Hgb and change from baseline at each 
assessment visit 
• 
Number (%) of subjects who have a Hgb level 
within the target range (10.0–12.0 g/dL) at 
each assessment visit 
• 
Time (%) in Hgb target range (10.0–12.0 g/dL) 
during the primary efficacy evaluation period 
(Weeks 40 to 52) 
• 
Number (%) of subjects who have an Hgb 
level of less than 7.5 g/dL 
• 
Number (%) of subjects who have an Hgb 
increase of more than 2.0 g/dL over any 4 


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Objective 
Endpoint 
weeks  
• 
Number (%) of subjects who have an Hgb 
level of more than 13.0 g/dL and number of 
episodes 
• 
To evaluate the PK of daprodustat 
• 
AUC and Cmax of plasma daprodustat 
Exploratory 
• 
To evaluate the effect of daprodustat on 
iron use using darbepoetin alfa as control 
• 
Dose of i.v. iron during the study period and 
the primary efficacy evaluation period 
(Weeks 40 to 52)  
• 
Number (%) of subjects who use i.v. iron 
during the study period and the primary 
efficacy evaluation period (Weeks 40 to 52) 
• 
To evaluate the effect of daprodustat on 
iron metabolism using darbepoetin alfa as 
control 
• 
Change from baseline in ferritin 
• 
Change from baseline in transferrin saturation 
(TSAT) 
• 
Changes from baseline in hepcidin 
• 
Change from baseline in serum iron 
• 
Change from baseline in total iron binding 
capacity (TIBC) 
Patient reported outcome 
• 
To evaluate the effect of daprodustat on 
health-related QoL (HR-QoL) using 
darbepoetin alfa as control 
SF-36 
• 
Changes from baseline in SF-36 HRQoL 
scores [Physical Component Summary (PCS), 
Mental Component Summary (MCS), and 8 
subscales] at Week 12, 28 and 52  
EQ-5D-5L/EQ-VAS 
• 
Change from baseline in EQ-5D-5L score at 
Week 12, 28 and 52 
• 
Change from baseline in EQ-VAS at Week 12, 
28 and 52 
Safety 
• 
To evaluate the safety and tolerability of 
daprodustat using darbepoetin alfa as 
control 
• 
Incidence and severity of AEs and SAEs, 
including AEs of special interest 
• 
Reasons for discontinuation of study 
medication 
• 
Laboratory tests, ECG, vital signs, and 
ophthalmology assessments 
 


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Study Design 
This is a Phase III, double-blind (double-dummy), active-controlled, parallel-group, multi-center study 
designed to evaluate the efficacy (non-inferiority) and safety of daprodustat, when administered for 52 
weeks, compared to darbepoetin alfa in approximately 270 Japanese HD subjects with anemia associated 
with CKD who are currently treated with ESA.   
 
Approximately 270 eligible HD subjects will be randomized in a 1:1 ratio on Day 1to receive 
daprodustat or darbepoetin alfa (approximately 135 subjects per group).  
 
This study consists of a 2~4 week screening phase, a 52 week treatment phase [including the primary 
efficacy evaluation period (Weeks 40 to 52)], and a 2-week follow-up phase following the treatment 
phase.  The study design is shown below.  
 
 
 
 
 
 
 
 
 
 
Screening phase 
(2~4 weeks) 
 
Treatment phase (52 weeks) 
 
Follow-up phase 
(2 weeks) 
 
 
Primary efficacy 
evaluation period 
 
 
 
 
 
 
 
 
 
 
 (HD)／ 
 
Daprodustat group (N=135) 
 
 
 
 
hemodiafiltration 
(HDF) 
 
 
 
 
 
 
patients 
 
Darbepoetin alfa group (N=135) 
 
 
 
 
 
 
 
 
 
 
Week -4~-2       Day 1            Week 40       Week 52     Week 54 
 
 
Method of Administration of Study Medication in Each Treatment Group 
In each treatment group, study medication will be administered as follows:  
• 
Daprodustat group: Subjects will receive oral daprodustat once daily and intravenous darbepoetin 
alfa matching placebo once weekly. Daprodustat will be started at a dose of 4 mg once daily 
(starting dose) on Day 1. From Week 4 onwards, dose adjustments will be made within the dose 
range of 1-24 mg every 4 weeks according to the prespecified dose adjustment algorithm to 
achieve and/or maintain Hgb within the target range (10.0-12.0 g/dL). 
• 
Darbepoetin alfa group: Subjects will receive oral daprodustat matching placebo once daily and 
intravenous darbepoetin alfa once weekly. Prior ESA therapy will be replaced with intravenous 
treatment with darbepoetin alfa at the corresponding dose once weekly according to the 
prespecified dose conversion. Subsequently, dose adjustments will be made within the dose 
range of 10-60 µg once every 2 weeks according to the prespecified dose adjustment algorithm to 
achieve and/or maintain Hgb within the target range (10.0-12.0 g/dL). 
 
Analysis 
Assuming a non-inferiority margin of -1.0 g/dL, a treatment difference of 0.0 g/dL, and a standard 
deviation of 1.5 g/dL for mean Hgb during the primary efficacy evaluation period in HD subjects, 
two-sample t-test has at least 99% power at a one-sided significance level of 2.5% (i.e. two-sided 


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significance level of 5%) with a sample size of 100 subjects per group. Assuming a dropout rate of 
approximately 25%, aproximately 135 subjects will be randomized to each group.  
 
The primary endpoint, which is the mean Hgb during the primary efficacy evaluation period, will be 
analyzed to demonstrate the non-inferiority of daprodustat to darbepoetin alfa in HD subjects.  
A mixed model for repeated measurements (MMRM) will be used to estimate the mean Hgb during 
the primary efficacy evaluation period and its 95% CI by treatment groups. As a preliminary 
assessment, it will be confirmed if the lower and upper limit of 95% CI for mean Hgb during the 
primary efficacy evaluation period in daprodustat group would lie fully within target range (10.0-
12.0 g/dL) at first. In addition, the point estimate and 95% CI for the treatment difference (daprodustat 
- darbepoetin alfa) in mean Hgb during the primary efficacy evaluation period will be estimated. Non-
inferiority will be established if the lower limit of the 95% CI is greater than -1.0 g/dL. Even if the 
95% CI for the difference is completely negative (i.e. lies fully within the range -0.75 to <0 g/dL) non-
inferiority would still be concluded on condition that the mean Hgb estimate in the daprodustat group 
is within the target range. 
The primary efficacy population will be the Intent-to-Treat (ITT) Population, and the analysis will be 
repeated in the modified ITT (mITT) and Per-Protocol (PP) Population to evaluate the robustness of 
the conclusion.  Following sensitivity analyses will be conducted to assess robustness of study result.  
• 
If there are Hgb considered to be impacted by blood transfusion or marketed rhEPO/ESAs, 
sensitivity analysis excluding the Hgb values from the analyses of primary endpoint will be 
conducted. 
• 
Analysis of covariance (ANCOVA) will be conducted as sensitivity analysis to MMRM. This 
model includes treatment group and baseline Hgb. The analysis population will be mITT 
population and the similar analysis will be repeated in the PP population. 
• 
A tipping point analysis based on multiple imputation will be conducted as sensitivity analysis to 
missing data assumption. This analysis explores a point where non-inferiority is not confirmed 
(tipping point) by changing assumption to missing data and repeating imputation. The analysis 
population will be ITT population and the similar analysis will be repeated in the mITT and PP 
population. 
Further details of sensitivity analyses will be provided in the Reporting and Analysis Plan (RAP). 
 
The principal secondary endpoint, which is the proportion of subjects whose mean Hgb during the 
primary efficacy evaluation period is within the target range, will be analyzed to demonstrate the 
superiority of daprodustat to darbepoetin alfa in HD subjects.  
In the mITT Population, a logistic regression model including treatment group and baseline Hgb as 
covariates will be used to estimate the point estimate and 95% CI for the odds ratio (daprodustat / 
darbepoetin alfa). This analysis will be performed to demonstrate the superiority at a two-sided 
significance level of 5%, conditional on the primary endpoint achieving noninferiority. Superiority 
will be established if the lower limit of the 95% CI for the odds ratio is greater than 1.0. 
 
 


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2. INTRODUCTION 
Daprodustat is a hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (PHI) that stimulates 
erythropoiesis in the same manner as innate response to hypoxia and is currently being developed as a 
new treatment for renal anemia.  
 
2.1. 
Study Rationale  
This is a Phase III study to evaluate the efficacy and safety of daprodustat following a switch from 
ESA in Japanese HD subjects with renal anemia who are currently treated with ESA. The primary 
objective is to demonstrate non-inferiority of daprodustat to darbepoetin alfa based on Hgb in the HD 
patient population included in this study. Study results will be used as pivotal study data for an NDA 
submitted for daprodustat for the treatment of renal anemia in Japan.  
 
2.2. 
Background 
Renal anemia is diagnosed in many patients with CKD, and the prevalence of renal anemia increases 
with progression of CKD [Akizawa, 2011]. Causes of anemia in CKD patients include absolute or 
relative deficiency of erythropoietin (EPO), shortened erythrocyte survival, and reduced iron 
availability. Anemia is further exacerbated by chronic blood loss associated with hemodialysis 
procedure, infection, and functional hemolysis [Japanese Society for Dialysis Therapy, 2016].  
 
Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor that is currently being 
developed as a treatment for renal anemia. Data in Japanese patients have been collected from a 
Japanese Phase II 4-week treatment study in Japanese hemodialysis (HD) subjects (PHI116099: 97 
Japanese subjects), an international multi-center Late Phase II 24-week treatment study in HD subjects 
(PHI113633: including 24 Japanese subjects), and an international multi-center Late Phase II 24-week 
treatment study in Non-dialysis subjects (PHI113747: including 42 Japanese subjects). In these 
clinical studies, daprodustat increased endogenous EPO, reduced hepcidin, and increased Hgb in HD 
and ND subjects including Japanese subjects. In addition, daprodustat increased Hgb at lower blood 
EPO concentrations than existing ESAs.  
 
Summaries of findings from both clinical and non-clinical studies conducted with daprodustat can be 
found in the daprodustat Investigator’s Brochure (IB) and IB supplement(s) (if applicable).  
A benefit: risk assessment, including risk mitigation strategies, is outlined in Section 4.6. 
 


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3. OBJECTIVES AND ENDPOINTS 
Objective 
Endpoint 
Primary (efficacy) 
• 
To demonstrate non-inferiority of 
daprodustat to darbepoetin alfa based on 
hemoglobin (Hgb) 
• 
Mean Hgb during the primary efficacy 
evaluation period (Weeks 40 to 52) 
Principal secondary (efficacy) 
• 
To demonstrate superiority of daprodustat 
to darbepoetin alfa in terms of 
achievement/maintenance of target Hgb 
• 
Number (%) of subjects with mean Hgb in the 
target range (10.0-12.0 g/dL) during the 
primary efficacy evaluation period (Weeks 40 
to 52) 
Other secondary (efficacy, PK) 
• 
To evaluate the appropriateness of the 
starting dose of daprodustat 
• 
Change from baseline in Hgb at Week 4 (Hgb 
increase rate) 
• 
Number (%) of subjects by Hgb change from 
baseline category at Week 4 
• 
To evaluate dose adjustment scheme of 
daprodustat 
• 
Distribution of the dose level 
• 
Duration of treatment interruption due to Hgb 
>13 g/dL 
• 
Frequency of dose adjustments 
• 
To evaluate the overall Hgb control of 
daprodustat using darbepoetin alfa as 
control 
• 
Hgb and change from baseline at each 
assessment visit 
• 
Number (%) of subjects who have a Hgb level 
within the target range (10.0–12.0 g/dL) at 
each assessment visit 
• 
Time (%) in Hgb target range (10.0–12.0 g/dL) 
during the primary efficacy evaluation period 
(Weeks 40 to 52) 
• 
Number (%) of subjects who have an Hgb 
level of less than 7.5 g/dL 
• 
Number (%) of subjects who have an Hgb 
increase of more than 2 g/dL over any 4 weeks  
• 
Number (%) of subjects who have an Hgb 
level of more than 13.0 g/dL and number of 
episodes 
• 
To evaluate the PK of daprodustat 
• 
AUC and Cmax of plasma daprodustat 
Exploratory 
• 
To evaluate the effect of daprodustat on 
iron use using darbepoetin alfa as control 
• 
Dose of i.v. iron during the study period and 
the primary efficacy evaluation period 
(Weeks 40 to 52)  
• 
Number (%) of subjects who use i.v. iron 
during the study period and the primary 


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Objective 
Endpoint 
efficacy evaluation period (Weeks 40 to 52) 
• 
To evaluate the effect of daprodustat on 
iron metabolism using darbepoetin alfa as 
control 
• 
Change from baseline in ferritin 
• 
Change from baseline in transferrin saturation 
(TSAT) 
• 
Changes from baseline in hepcidin 
• 
Change from baseline in serum iron 
• 
Change from baseline in total iron binding 
capacity (TIBC) 
Patient reported outcome 
• 
To evaluate the effect of daprodustat on 
health-related QoL (HR-QoL) using 
darbepoetin alfa as control 
SF-36 
• 
Changes from baseline in SF-36 HR-QoL 
scores [Physical Component Summary (PCS), 
Mental Component Summary (MCS), and 8 
subscales] at Week 12, 28 and 52  
EQ-5D-5L/ EQ-VAS 
• 
Change from baseline in EQ-5D-5L score at 
Week 12, 28 and 52 
• 
Change from baseline in EQ-VAS at Week 12, 
28 and 52  
Safety 
• 
To evaluate the safety and tolerability of 
daprodustat using darbepoetin alfa as 
control 
• 
Incidence and severity of AEs and SAEs, 
including AEs of special interest 
• 
Reasons for discontinuation of study 
medication 
• 
Laboratory tests, ECG, vital signs, and 
ophthalmology assessments 
 


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4. STUDY DESIGN 
4.1. 
Overall Design  
This is a Phase III, double-blind (double-dummy), active-controlled, parallel-group, multi-center study 
designed to evaluate the efficacy (non-inferiority) and safety of daprodustat, when administered for 52 
weeks, compared to darbepoetin alfa in approximately 270 Japanese HD subjects with anemia 
associated with CKD who are currently treated with ESA.   
 
Two hundreds seventy (270) eligible HD subjects will be randomized in a 1:1 ratio to receive 
daprodustat or darbepoetin alfa (135 subjects per group).  
 
This study consists of a 2~4 week screening phase, a 52 week treatment phase [including the primary 
efficacy evaluation period (Weeks 40 to 52)], and a 2-week follow-up phase following the treatment 
phase. The study design is shown in Figure 1. 
 
 
 
 
 
 
 
 
 
 
Screening phase 
(2~4 weeks) 
 
Treatment phase (52 weeks) 
 
Follow-up phase 
(2 weeks) 
 
 
Primary efficacy 
evaluation period 
 
 
 
 
 
 
 
 
 
 
 (HD)／ 
 
Daprodustat group (N=135) 
 
 
 
 
hemodiafiltration 
(HDF) 
 
 
 
 
 
 
patients 
 
Darbepoetin alfa group (N=135) 
 
 
 
 
 
 
 
 
 
 
Week -4~-2       Day 1            Week 40       Week 52     Week 54 
Figure 1 Study Design 
 
 
4.2. 
Treatment Groups and Study Periods 
Details for each study period and treatments are described below. In this study, a point-of-care Hgb 
analyzer (HemoCue®) will consistently be utilized for confirmation of subjects’ eligibility, 
withdrawal criteria and dose adjustments of study medication. 
 
Screening phase 
Subjects who have provided informed consent and meet all of the eligibility criteria at screening 
(Week -4~-2) (Sections 5.1 and 5.2) will be provisionally enrolled in the study. Subjects who have 
used oral iron since before the start of the study must remain on the same regimen throughout the 
screening phase (intravenous iron will not be allowed). Subjects will also continue to use ESA 
throughout the screening phase. The regimen of ESA therapy should remain unchanged throughout 
the screening phase. 
 


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Treatment phase 
Subjects who meet all of the eligibility criteria at the start of the treatment phase (Day 1) will be 
randomized in a 1:1 ratio to receive daprodustat or darbepoetin alfa and enrolled in the study. Subjects 
will be ESA users and will switch their ESA therapy to darprodustat at Day 1 so that the 
randomization date (Day 1) should coincide, as closely as possible, with the date of next scheduled 
ESA administration. In accordance with the randomization instructions, subjects randomized to the 
daprodustat group will receive daprodustat and darbepoetin alfa matching placebo for 52 weeks. 
Subjects randomized to the darbepoetin alfa group will receive daprodustat matching placebo and 
darbepoetin alfa for 52 weeks. Daprodustat will be orally administered once daily, and darbepoetin 
alfa will be intravenously administered once weekly. In both groups, dose adjustments for study 
medication during the treatment phase will be made according to the administration schedule specified 
in Section 6.4 to achieve and/or maintain Hgb within the target range (10.0-12.0 g/dL). In addition, 
supplemental iron therapy will be administered according to the standard initiation criteria as 
described in Section 6.12. It should be noted that intravenous iron or dose change for oral iron will not 
be allowed from Day 1 to Week 4.  
 
Follow-up phase 
Subjects will visit the site for follow-up assessments and observations 2 weeks after the 
completion/discontinuation of study treatment. During the follow-up phase, treatment of renal anemia 
will be allowed as necessary at the discretion of the investigator (or subinvestigator).  
 
4.3. 
Study Subjects and Number of Subjects 
A total of 270 subjects will be randomized (daprodustat group: 135 subjects, darbepoetin alfa group: 
135 subjects). Assuming a dropout rate of 30% during the screening phase, approximately 386 
subjects need to be screened. Assuming a dropout rate of 25% after the start of study treatment, a total 
of 202 subjects are expected to complete the 52-week treatment.  
 
Table 1    Target Number of Subjects 
Screened 
386 
Randomized/enrolled 
270 
Completed 52-week treatment 
202 
 
 
4.4. 
Rationale for Study Design 
Objectives and evaluations 
This is a Phase III study to evaluate the efficacy and safety of daprodustat in Japanese HD subjects 
with renal anemia who are currently treated with ESA. The study is designed as an active-controlled, 
parallel-group comparative study which will be conducted under double blind to meet the primary 
objective, that is, to demonstrate non-inferiority of daprodustat to the existing drug based on Hgb in 
HD subjects. The target Hgb range was set for study treatment in line with the Guidelines for Renal 
Anemia in Chronic Kidney Disease issued by the Japanese Society for Dialysis Therapy in 2015 [The 
Japanese Society for Dialysis Therapy, 2016] to demonstrate that treatment with daprodustat can 


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result in achievement and/or maintenance of target Hgb in HD subjects, and evaluate the 
appropriateness of the starting dose of daprodustat.  
 
Control 
Darbepoetin alfa, which has been widely used in Japanese patients with renal anemia, primarily HD 
patients, since its approval in Japan in 2007, was selected as control.  
 
 
4.5. 
Rationale for Dose Levels 
Starting dose and dose adjustments of daprodustat 
The starting dose (4 mg) and the dose adjustment method (maintenance dose range: 1-24 mg) for 
daprodustat are described in Section 6.4.  
The starting dose and the dose adjustment algorithm selected for Japanese HD subjects in the present 
study are based on the results from a review of the longitudinal model constructed using Hgb data 
from six Japanese or overseas Phase II studies (PHI112844, PHI116581, PHI116582, PHI113633, 
PHI113747, and PHI116099) as well as the results from clinical studies. The data set used in the 
model analyses was based on the data of daprodustat administered in a wide dose range (0-25 mg) and 
included a Japanese Phase II 4-week treatment study (PHI116099) and international multi-center late 
Phase II 24-week treatment studies (PHI113633 and PHI113747) in which subjects in Japan 
participated. 
 
Starting dose 
Simulations using a longitudinal model as well as clinical data for HD subjects suggested that Hgb 
levels observed with prior ESA therapy is maintained for 4 weeks after a switch from prior ESA to 
study medication, with no rapid increase greater than 2 g/dL, at the dose level of 4 mg in ESA user 
subjects. Covariate analyses identified baseline Hgb, body weight, and dose level of prior ESA as 
major factors affecting Hgb. However, Hgb was more greatly affected by inter-subject differences in 
drug response to daprodustat than these factors.  
Taken together, 4 mg may be an appropriate starting dose of daprodustat for the majority of ESA users.  
 
Maintenance dose range and dose adjustment algorithm 
Simulation results using the longitudinal model showed that drug response to daprodustat regarding 
Hg greatly varied among subjects, indicating that the dose range from 1 to 24 mg may be necessary to 
achieve and maintain target Hgb. Accordingly, a total of 8 dose levels (1, 2, 4, 6, 8, 12, 18, and 24 mg) 
were selected as the maintenance doses, with 4 mg intended for subjects with a standard drug response.  
The dose adjustment algorithm was defined so that target Hgb (10.0-12.0 g/dL) set for the present 
study according to the Guidelines for Renal Anemia [The Japanese Society for Dialysis Therapy, 
2016] can be maintained. Given a difference of 1.0 g/dL between the the upper limit of Hgb target 
range (12.0 g/dL) and ESA dose interruption criteria value (13.0 g/dL), the dose of daprodustat will be 
reduced to the one step lower dose level when Hgb increases into the range of 12.0−13.0 g/dL. Since it 
is well known that an Hgb increase of 0.5 g/dL or less per week is appropriate to prevent adverse 
reactions, the dose level will be reduced by one step when Hgb increases by more than 2 g/dL over 4 
weeks [KDIGO, 2012]. For subjects whose anemia needs to be corrected (≥7.5 g/dL and <10.0 g/dL), 


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the dose level will be maintained while the Hgb increase per 4 weeks is 0.5-2 g/dL, and the dose level 
will be increased by one step when the Hgb increase per 4 weeks is less than 0.5 g/dL.  
 
Starting dose and dose adjustments of control (darbepoetin alfa) 
The starting doses and dose adjustment algorithm for darbepoetin alfa are described in Section 6.4.  
The starting doses of darbepoetin alfa for subjects currently treated with epoetin were selected based 
on the prescribing information in Japan. For subjects on epoetin beta pegol, given that no 
recommended starting doses of darbepoetin alfa when switched from epoetin beta pegol approved in 
Japan is available, switchig will be performed in the epoetin beta pegol-to-darbepoetin alfa dose ratio 
of 5:6 at the middle dose level of darbepoetin alfa according to the overseas prescribing information 
[MIRCERA. Product information in Europe, 2012]. At the other dose levels, dose conversion will be 
performed within the approved dose levels and in a dose ratio close to 5:6. 
The dose adjustment algorithm for darbepoetin alfa was determined based on the product information 
and previous Japanese clinical studies in accordance with the Guideline for Renal Anemia in Chronic 
Kidney Disease [Japanese Association for Dialysis Therapy, 2016]. 
 
4.6. 
Benefit: Risk Assessment 
Summaries of findings from clinical and nonclinical studies of daprodustat can be found in the IB and 
the IB supplements. The risk assessment and risk minimization strategies for the present study are 
outlined in the following sections:  
 
4.6.1. 
Risk Assessment 
The potential risks of clinical significance including AEs of special interest (Section 7.4.2) and the 
mitigation strategies for this protocol taking into account the results of completed clinical and 
nonclinical studies of daprodustat, are outlined in Section 12.2. Appendix 2. 
 
4.6.2. 
Benefit Assessment  
Study PHI201754 is a Phase 3 study in Japanese HD subjects with renal anemia who are treated with 
ESA. Previous clinical studies of daprodustat, administered for up to 24 weeks in ND or HD subjects 
have demonstrated clinical efficacy (increase in and/or maintenance of Hgb) with blood EPO 
concentrations increased within the normal physiologic range in CKD subjects. Data obtained in 
Study PHI201754 will generate safety and efficacy data in Japanese HD subjects with renal anemia 
who are treated with ESA, for a 52-week treatment period. Study participants who will receive 
daprodustat, may benefit from the expected clinical efficacy.  
Daprodustat, may have important advantages over existing ESAs. Daprodustat, which is orally 
administered and requires no cold chain management unlike ESAs, is more convenient to patients and 
health care provider. Daprodustat is shown to increase Hgb at lower EPO concentrations than ESAs. 
Since increased exposure to EPO following administration of ESAs may be associated with an 
increased cardiovascular risk [Szczech, 2008], daprodustat may increase Hgb without increasing the 
cardiovascular risk.  
 


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4.6.3. 
Overall Benefit: Risk Conclusion 
Daprodustat is shown to have a positive benefit-risk balance based on the following findings: in 
studies of daprodustat administered for up to 24 weeks, treatment with daprodustat resulted in 
achievement of target Hgb, and no adverse events have been identified as related to treatment with 
daprodustat.  
 
This protocol employs precautions to mitigate known and potential risks to enrolled subjects (see 
Section 12.2. Appendix 2). Given these precautions, as well as the potential benefit that daprodustat 
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 GSK investigational product or other study treatment that may impact 
subject eligibility is provided in the IB/IB supplement(s) and/or other pertinent documents. 
 
Deviations from inclusion/exclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to 
the criteria as specified in the protocol is essential. 
 
5.1. 
Inclusion Criteria 
Subjects eligible for enrolment in the study must meet all of the inclusion criteria. 
Note: Verification at both provisional enrolment (screening) and official enrolment (Day 1) is required, 
unless otherwise specified.  
 
1. 
Age (informed consent): ≥20 years of age 
2. 
Dialysis: On hemodialysis (HD) or hemodiafiltration (HDF) given three times weekly for at least 
12 weeks prior to screening 
3. 
ESAs: Use of one and the same ESA for at least 10 weeks prior to screening 
4. 
ESA dose: Darbepoetin alfa 10 - 60 µg per week, epoetin (including biosimilars) ≤9000 IU per 
week, or epoetin beta pegol up to 250 μg per 4 weeks 
Note: ESA dose must be greater than the minimum ESA dose if Hgb >12 g/dL to 12.5 g/dL 
(Minimum ESA dose: epoetins (including biosimilars): 1500 units (U) per week; darbepoetin 
alfa: 10 μg per week; epoetin beta pegol: 25 μg per evey 4 weeks) 
5. 
Hemoglobin (Hgb): ≥9.5 g/dL and ≤12.5 g/dL. Determined at the site using an Hgb analyzer 
(HemoCue®)  
6. 
Iron parameters: Ferritin >100 ng/mL or TSAT >20% (screening verification only) 
7. 
Gender (screening verification only): Female or male 
Females: Not pregnant [demonstrated to be negative for human chorionic gonadotropin (hCG) in 
serum], not breast-feeding, and meet at least one of the following:  
1) 
Females of non-childbearing potential are defined as follows:  
• 
Pre-menopausal with at least one of the following and no plans to utilise assisted 
reproductive techniques (e.g., in vitro fertilisation or donor embryo transfer): 
• 
History of bilateral tubal ligation or salpingectomy 
• 
History of hysteroscopic tubal occlusion and postoperatively documented bilateral 
tubal obstruction  
• 
History of hysterectomy 
• 
History of bilateral oophorectomy 
• 
Postmenopausal defined as A) females 60 years of age or older or B) In females < 60 years 
of age, 12 months of spontaneous amenorrhea [in questionable cases a blood sample with 
postmenopausal follicle stimulating hormone (FSH) and estradiol concentrations is 
confirmatory (see separately specified reference ranges)]. Females on HRT whose 
menopausal status is in doubt will be required to use one of the most effective contraception 


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methods if they wish to continue their HRT during the study. Otherwise they must 
discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.  
2) 
Females of childbearing potential must agree to comply with one of the contraception 
methods listed as requirements in “GSK Listing of Most Effective Contraceptive Methods for 
Females of Childbearing Potential (Section 12.3. Appendix 3: Modified List of Highly Effective 
Methods for Avoiding Pregnancy in Females of reproductive potential)” from at least 28 days 
prior to the first dose of study medication until the completion of the follow-up visit. 
8. 
Informed consent: Written informed consent, including adherence to the requirements and 
conditions specified in the consent form and the protocol, must be obtained from each subject as 
specified in Section10.2...  
 
5.2. 
Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study.  
Note: Verification at both provisional enrolment (screening) and official enrolment (Day 1) is required, 
unless otherwise specified. 
 
Chronic kidney disease (CKD)-related criteria  
1. 
Kidney transplant: Planned living-related kidney transplant during the study 
 
Anemia-related criteria 
2. 
Aplasia: History of bone-marrow hypoplasia or pure red cell aplasia 
3. 
Other causes of anemia: pernicious anemia, thalassemia, sickle cell anemia, or myelodysplastic 
syndromes 
4. 
Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal 
ulcer disease OR clinically significant GI bleeding within 10 weeks prior to screening or during a 
period from screening to Day 1. 
 
Cardiovascular disease-related criteria 
5. 
Myocardial infarction, acute coronary syndrome, stroke, or transient ischemic attack: Diagnosed 
within 10 weeks prior to screening or during a period from screening to Day 1.  
6. 
Heart failure: Chronic Class IV heart failure, as defined by the New York Heart Association 
(NYHA) functional classification system 
7. 
Corrected QT (QTc) Interval (screening verification only): QTc >500 msec; or QTc >530 msec 
in subjects with bundle branch block  
Note: QT interval corrected using the Bazett’s formula (QTcB) will be used, and ECG can be 
mechanically or manually read.  
 
Other disease-related criteria 
8. 
Liver disease (if any of the following occurs):  
• 
(Screening verification only): Alanine transaminase (ALT) >2×upper limit of normal (ULN) 
• 
(Screening verification only): Bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is 
acceptable if bilirubin is fractionated and direct bilirubin is <35%) 


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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 2 years prior to screening, currently receiving 
treatment for cancer, or complex kidney cyst >3 cm (II F, III or IV based on the Bosniak 
classification) 
Note: The only exception is localized squamous cell or basal cell carcinoma of the skin that has 
been definitively treated ≥ 10 weeks before screening. 
 
Concomitant medication and other study treatment-related criteria 
10. Iron: Planned use of intravenous iron during the screening phase or during a period from Day 1 
to Week 4 
Note: Oral iron is acceptable. However, the same dose regimen must be used throughout the 
screening phase and from Day 1 to Week 4. Antihyperphosphatemic agents containing iron (e.g., 
ferric citrate hydrate) are also acceptable only if used for at least 12 weeks prior to screening. 
However, they must be continued throughout the screening phase from Day 1 to Week 4.  
11. Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity 
to excipients in the investigational product (see the daprodustat IB or the Prescribing Information 
of the darbepoetin alfa) 
12. Drugs and supplements: Use or planned use of any prescription or non-prescription drugs or 
dietary supplements that are prohibited during the study period [prohibited medications: strong 
inducers and inhibitor of Cytochrome P450 (CYP) 2C8, see Section 6.11.2] 
13. Prior investigational product exposure: Use of an investigational agent within 30 days or five half 
lives of the investigational agent (whichever is longer) 
14. Prior treatment with daprodustat: Any prior treatment with daprodustat for a treatment duration 
of >30 days 
 
General health-related criteria 
15. Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding 
that the investigator (or subinvestigator) considers would put the subject at unacceptable risk, 
which may affect study compliance or prevent understanding of the aims or investigational 
procedures or possible consequences of the study 
 
5.3. 
Screening Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial, but are not 
subsequently randomized in the study. A minimum set of information is required from screen failure 
subjects including Demography, Screen Failure details, Eligibility Criteria, and SAEs in order to 
report screen failures in a reliable manner, satisfy the requirements for publication defined by the 
Consolidated Standards of Reporting Trials (CONSORT), and respond to requests of the regulatory 
authorities.  


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Subjects that fail screening are eligible to be rescreened up to 3 times as soon as the investigator 
assesses they may meet study entry criteria. For re-screening subjects, ophthalmology exam to be 
performed at re-screening could be replaced with the results of the most recent ophthalmology 
screening, on the investigator’s (or subinvestigator’s) discretion (See Table 10). 
 
5.4. 
Permanent discontinuation of study treatment and study withdrawal  
If subjects meet one of the following criteria, study treatment should be permanently discontinued and 
subjects will be withdrawn from the study. The withdrawal reason should be recorded.  
 
• 
Hgb <7.5 g/dL 
Note: HemoCue Hgb values will be employed. If an initial Hgb value meets the Hgb stopping 
criteria, measurement will be repeated at the same study visit (using the same sample) to 
calculate the average. If the average meets the Hgb stopping criteria, study treatment will be 
discontinued.  
• 
Kidney transplant 
• 
Subject becomes pregnant or intends to become pregnant during the study. 
• 
Diagnosis of new or recurrent cancer 
• 
Liver chemistry abnormalities exceeding the threshold criteria (see Section5.4.1.) 
• 
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 Section can be found in Section 12.5. 
Appendix 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. Accordingly, ‘study treatment’ sometimes refers to each product 
and sometimes refers to multiple products.  
 
Daprodustat (study drug) 
The study drug daprodustat will be supplied as fast-release film coated tablets for oral administration 
containing 1 mg, 2 mg, 4 mg, or 6 mg of daprodustat (Table 2). The daprodustat matching placebo 
will be supplied as film coated tablets, it visually matches the daprodustat tablets, for oral 
administration containing no daprodustat (Table 2). There are two sizes each for the daprodustat and 
placebo tablets. 
 
Table 2   Description of daprodustat and placebo tablets 
Daprodustat or placebo tablets 
Description 
Daprodustat (small) 
(1 mg, 2 mg, and 4 mg tablets 
7.0 mm round, standard biconvex, white film coated tablets containing 
1 mg, 2 mg, or 4 mg of daprodustat as active ingredient 
Daprodustat (large) 
(6 mg tablets) 
9.0 mm round, standard biconvex, white film coated tablets containing 
6 mg of daprodustat as active ingredient 
Placebo (small) 
7.0 mm round, standard biconvex, white film coated tablets containing no 
daprodustat 
Placebo (large) 
9.0 mm round, standard biconvex, white film coated tablets containing no 
daprodustat 
 
Daprodustat and placebo tablets are packed by strength or by size in high density polyethylene 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 daprodustat tablets without 
regard to food or hemodialysis. The administration schedule (starting dose and dose adjustment) 
described in Section 6.4.1 should be followed.  
 
Table 3    Dose levels of daprodustat and number of tablets taken 
Dose level of 
daprodustat 
(once daily) 
1 mg 
2 mg 
4 mg 
6 mg 
8 mg 
12 mg 
18 mg 
24 mg 
Number of 
daprodustat 
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 daprodustat/placebo tablets with bottles at each study visit, and 
all unused daprodustat tablets will be collected from subjects at every 4 week’s study visit. 
 
Darbepoetin Alfa (Control) 
GSK will provide the control drug of darbepoetin alfa (NESP Injection) and its matching placebo. 
Darbepoetin alfa is provided as 0.5 mL plastic prefilled syringes (PFS) for IV injection each 
containing 10, 15, 20, 30, 40 or 60 µg of darbepoetin alfa in a clear and colorless solution. 


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Darbepoetin alfa placebo is provided as 0.5 mL plastic prefilled syringes (PFS) for IV injection 
containing no darbepoetin alfa in a clear and colorless solution. 
Subjects will receive intravenous darbepoetin alfa or placebo once weekly at the study site (Table 4) 
according to the dosing schedule (including starting doses and dose adjustment algorithm) provided in 
Section 6.4.2. 
 
Table 4    Dose levels of darbepoetin alfa and injection frequency 
Dose level of darbepoetin alfa   
(once weekly) 
10 µg 
15 µg 
20 µg 
30 µg 
40 µg 
60 µg 
Number of IV injection of 
darbepoetin alfa 
10 µg IV 
×1 
15 µg IV 
×1 
20 µg IV
×1 
30 µg IV 
×1 
40 µg IV 
×1 
60 µg IV 
×1 
 
 
6.2. 
Medical Device 
The darbepoetin alfa (Brand name : NESP Injection) marketed with the device (kit formulation which 
was filled liquid medication in plastic prefilled syringes) provided for use in this study. 
Instructions for medical device are described in the Prescribing Information of NESP Injection. 
The medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study – see Section 7.4.4. 
 
6.3. 
Treatment Assignment 
The randomization schedule will be generated by GSK statistician using the randomization system 
(Randall).  
 
Subjects will be randomized centrally in a 1:1 ratio to one of the two treatment groups according to 
the randomization schedule. Randomization should precede the study treatment.  
• 
Daprodustat group 
• 
Darbepoetin alfa group 
 
Subjects will be assigned a randomization number by the Interactive Web Recognition System 
(IWRS). Once a randomization number has been assigned, it must not be re-assigned. Further details 
are provided in the Study Reference Manual (SRM).  
 


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6.4. 
Administration Schedule (Starting Dose, Dose Adjustment, and Dosing 
Frequency) 
Instructions regarding container number assignment and dose adjustments for all study treatments are 
given by the Interactive Web Recognition System (IWRS). 
 
6.4.1. 
Daprodustat 
HD subjects randomized to the daprodustat group will receive oral daprodustat according to the 
following regimen. Furthermore, these subjects will receive i.v. darbepoetin alfa placebo in the same 
manner with darbepoetin alfa.  
 
6.4.1.1. 
Starting Dose 
At Day 1, subjects will skip ESA and will start oral treatment with daprodustat at the starting dose of 
4 mg once daily and remain on the same regimen until the day of Week 4. 
 
6.4.1.2. 
Maintenance Dose 
From Weeks 4 to 52, interruption of treatment or dose adjustments will be made within the 
maintenance dose range of 1-24 mg (Table 5) according to the dose adjustment algorithm (Table 6) to 
achieve and/or maintain Hgb within the target range (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 (and administer placebo); once the one-step dose increase criteria are met, treatment at 
1 mg will be resumed. If the one-step dose increase criterion is met during treatment at the maximum 
maintenance dose (24 mg), treatment at 24 mg should be continued.  
 
Table 5    Maintenance dose of daprodustat 
Dose step 
1 
2 
3 
4 
5 
6 
7 
8 
Dose level of 
daprodustat 
(once daily) 
1 mg 
2 mg 
4 mg 
6 mg 
8 mg 
12 mg 
18 mg 
24 mg 
Number of 
daprodustat 
tablets taken 
1 mg 
tablet 
×1 
2 mg 
tablet 
×1 
4 mg 
tablet 
×1 
6 mg 
tablet 
×1 
4 mg 
tablet 
×2 
6 mg 
tablet 
×2 
6 mg 
tablet 
×3 
6 mg 
tablet 
×4 
 


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Table 6   Dose adjustment algorithm (daprodustat) 
Hgb 
(g/dL) 
Hgb increase over 4 weeks 
(g/dL) 
Treatment 
>13.0 
NA 
Interrupt treatment (and administer placebo) until 
Hgb decreases to less than 12.0 g/dL, and resume 
treatment at the one lower dose level 
[If interrupted (and placebo administered) at 1 mg, 
resume treatment at 1 mg after the one-step dose 
increase criterion is met] 
≥12.0 and ≤13.0 
NA 
One-step dose reduction 
≥10.0 and <12.0 
>2.0 
One-step dose reduction 
 
≤2.0 
Continue treatment at the current dose level 
≥7.5 and <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 permanently 
discontinued. 
 
6.4.2. 
Darbepoetin Alfa 
HD subjects randomized to the darbepoetin alfa group will receive intravenous darbepoetin alfa 
according to the following regimen. Furthermore, these subjects will receive oral daprodustat placebo 
in the same manner with daprodustat.  
 
6.4.2.1. 
Dose Conversion 
On Day 1, prior ESA will be replaced with darbepoetin alfa at the corresponding dose once weekly 
(Table 7). 
 
Table 7    Replacement with darbepoetin alfa - initial dose (ESA users) 
Prior ESA 
Darbepoetin alfa 
Epoetin 
≤3000 IU, per week 
15 µg, once weekly 
 
4500 IU, per week 
20 µg, once weekly 
 
6000 IU, per week 
30 µg, once weekly 
 
9000 IU, per week 
40 µg, once weekly 
Epoetin beta pegol 
≤50 µg, once every 4 weeks* 
15 µg, once weekly 
 
75 µg, once every 4 weeks* 
20 µg, once weekly 
 
100 µg, once every 4 weeks* 
30 µg, once weekly 
 
150 µg, once every 4 weeks* 
40 µg, once weekly 
 
≥200 µg, once every 4 weeks* 
60 µg, once weekly 
Darbepoetin alfa 
10, 15, 20, 30, 40, 60 µg, per week 
10, 15, 20, 30, 40, 60 µg, per week 
*: Allowance of ±1 week 
Maintenance treatment will be started at Week 2 as described in Section 6.4.2.2.  
 


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6.4.2.2. 
Maintenance Dose 
From Weeks 2 to 52, dose interruptions or adjustments will be performed within the maintenance dose 
range of 10~60 μg (Table 8) according to the dose adjustment algorithm (Table 9) so that the 
HemoCue Hgb value measured every other week will achieve or remain within the target range (10.0-
12.0 g/dL). Dose adjustments will be made once every 2 weeks. If any of the one-step dose reduction 
criteria is met during treatment at the minimum maintenance dose (10 μg), treatment should be 
interrupted (and placebo administered); once the one-step dose increase criteria are met, treatment at 
10 μg will be resumed. If the one-step dose increase criterion is met during treatment at the maximum 
maintenance dose (60 μg), treatment at 60 μg should be continued. 
 
Table 8    Maintenance dose of darbepoetin alfa 
Dose level 
1 
2 
3 
4 
5 
6 
Darbepoetin alfa 
(once weekly) 
10 µg 
15 µg 
20 µg 
30 µg 
40 µg 
60 µg 
 
Table 9  Dose adjustment algorithm (darbepoetin alfa) 
Hgb (g/dL) 
Treatment 
>13.0 
Interrupt treatment (and administer placebo) until Hgb decreases to less than 
12.0 g/dL, and resume treatment at the one lower dose level 
[If interrupted (and placebo administered) at 10 µg, resume treatment at 10 µg 
after the one-step dose increase criterion is met] 
≥12.0 and ≤13.0 
One-step dose reduction 
≥10.0 and <12.0 
Continue treatment at the current dose level* 
≥7.5 and <10.0 
One-step dose increase** 
<7.5 
Discontinue treatment permanently*** and initiate another appropriate treatment 
* If an increase of 1 g/dL is observed in 2 weeks, the dose will be reduced to the one-step lower dose level. 
** If an increase of >1 g/dL is observed in 2 weeks, treatment will be continued at the curent dose level. If there is a 
safety concern, however, the dose may be reduced at the investigator's (or subinvestigator's) discretion to the one-step 
lower dose level. 
*** If an initial Hgb value is less than 7.5 g/dL, measurement will be repeated at the same study visit (using the same 
sample) to calculate the average. If the average meets the Hgb stopping criteria, study treatment will be permanently 
discontinued. 
 
 
6.5. 
Blinding 
This will be an active-controlled, double-blind study. The study medication will be blinded through 
the study period to the subjects, investigator (or subinvestigator), study site staff and GSK study team.  
Neither the investigator (or subinvestigator) nor the subject will know which study medication the 
subject is receiving as all instructions regarding container number assignment and dose adjustment are 
given by IWRS. 
 
Roles of Person Responsible for Allocation 
The person responsible for allocation will prepare a procedure specifying the method of allocation of 
study treatment (study drug and control drug) and perform its duties in accordance with this document. 
The person responsible for allocation will confirm the indistinguishability of study treatment (study 
drug and control drug) and its package, and indicate the drug number on a study treatment (study drug 
and control drug) container. The indistinguishability of study treatment (study drug and control drug) 


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and its package should be checked again after completion of the study. Furthermore, the person 
responsible for allocation will prepare a procedure for case of an emergency that knowledge of the 
study treatment is essential, and break the key code of only the treatment concerned, as per request. 
 
Emergency Unblinding 
• 
The investigator or treating physician may unblind a subject’s treatment assignment only in the 
case of an emergency OR in the event of a serious medical condition when knowledge of the 
study treatment (daprodustat or darbepoetin alfa) is essential for the appropriate clinical 
management or welfare of the subject as judged. 
• 
Investigators (or subinvestigators) have direct access to the subject’s individual study treatment. 
• 
It is preferred (but not required) that the investigator (or subinvestigator) first contacts the 
Medical Monitor or appropriate GSK study personnel to discuss options before unblinding the 
subject’s treatment assignment. 
• 
If GSK personnel are not contacted before the unblinding, the investigator (or subinvestigator) 
must notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the safety of 
subjects currently in the study. 
• 
The date and reason for the unblinding must be fully documented in an appropriate page of the 
CRF by the investigator (or subinvestigator). 
• 
Further details of unblinding is provided in the SRM. 
 
A subject will be withdrawn if the subject’s treatment code is unblinded by the investigator (or 
subinvestigator). The primary reason for discontinuation (the event or condition which led to the 
unblinding) will be recorded in the CRF. 
 
• 
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment 
assignment for any subject with an SAE. If the SAE requires that an expedited regulatory report 
be sent to one or more regulatory agencies, a copy of the report, identifying the subject’s 
treatment assignment, may be sent to investigators in accordance with local regulations and/or 
GSK policy. 
 
 
6.6. 
Packaging and Labeling 
The contents of the label will be in accordance with all applicable regulatory requirements. 
 
6.7. 
Preparation/Handling/Storage/Accountability 
• 
No special preparation of study treatment is required.  
• 
Only subjects enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study medications must be stored in a secure 
environmentally controlled and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator (or subinvestigator) and 
authorized site staff. 


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• 
Subjects must bring all of supplied study medication bottles of daprodustat/placebo at every 4 
week’s study visit. Study staff will collect all of study medication bottles supplied at the previous 
study visit and supply new study medication bottles.  
• 
The investigator (or subinvestigator), institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).  
• 
Under normal conditions of handling and administration, study medication is not expected to 
pose significant safety risks to site staff.  
• 
GSK will provide a document describing occupational hazards and recommended handling 
precautions either to the investigator (or subinvestigator) when necessary or upon request of the 
medical institution.  
• 
Further details are provided in the SRM.  
 
6.8. 
Compliance with Study Treatment Administration 
Daprodustat 
Since daprodustat is self-administered, compliance with daprodustat 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 daprodustat tablets dispensed to and taken by each subject will be 
maintained and reconciled with study treatment and compliance records. In addition, the number of 
daprodustat doses dispensed, used, and unused, as well as study treatment start and stop dates will be 
recorded in the source document and eCRF (the number of doses returned and unreturned will also be 
recorded separately). 
Darbepoetin alfa 
Darbepoetin alfa will be administered to subjects once weekly at the site. Dosing details will be 
recorded in the source document and eCRF. Administration of darbepoetin alfa will be performed at 
the scheduled visit dates in principle.  
 
6.9. 
Treatment of Study Treatment Overdose 
For the purposes of this study, an overdose of daprodustat is defined as any dose greater than the 
highest daily dose included in the protocol. There is no specific antidote for overdose with daprodustat. 
The expected manifestations of daprodustat overdosage include signs and symptoms associated with 
an excessive and/or rapid increase in Hgb concentration. Daprodustat is highly protein bound; thus, 
clearance of unchanged daprodustat by hemodialysis or peritoneal dialysis is very low and these are 
not effective methods to enhance the elimination of daprodustat. Daprodustat metabolites are, in part, 
cleared via hemodialysis. In the event of a suspected overdose, it is recommended that the appropriate 
supportive clinical care be instituted, as dictated by the subject’s clinical status. Additionally, subjects 
should be monitored closely for cardiovascular events, increased heart rate and hematologic 
abnormalities. 
 
Consult the respective approved Prescribing Information for information on overdose for darbepoetin 
alfa. 
 


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6.10. Treatment after the End of the Study 
Since the target disease studied is not life-threatening or severely debilitating and there is the 
alternative therapy, subjects will not receive any additional treatment from GSK after completion of 
the study. The investigator (or subinvestigator) is responsible for ensuring that consideration has been 
given to post-study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment. 
 
6.11. Concomitant Medications and Non-Drug Therapies 
Concomitant medications, including over-the-counter medications and supplements, taken during the 
study will be recorded in the eCRF. Drug names and start/stop dates will be recorded for general 
concomitant medications, while additional details, including dose, route of administration, and dosing 
frequency, will be recorded for certain medications (e.g., ESAs, iron, anti-hypertensive medications). 
Further details are provided in the SRM. 
 
6.11.1. 
Permitted Medications and Non-Drug Therapies 
Unless specified as a prohibited medication in Section 6.11.2, all concomitant medications should be 
considered permitted provided they are not contraindicated for the individual subject concerned. 
Regular multivitamins (at recommended daily allowance) and other supplements such as calcium and 
vitamin D may be used if permitted by the investigator or his/her designee.  
CYP2C8 is involved in the primary route of metabolism of daprodustat. Accordingly, co-
administration of daprodustat with moderate CYP2C8 inhibitors (e.g., clopidogrel, teriflunomide, 
deferasirox) should be performed with caution. 
Antihyperphosphatemic agents containing iron (e.g., ferric citrate hydrate) may be started from 
Week 4 onwards unless any other antihyperphosphatemic agents are appropriate. Once started, iron-
containing antihyperphosphatemic agents must be continued until the end of the study wherever 
possible.  
 
6.11.2. 
Prohibited Medications and Non-Drug Therapies 
Use of any of the following drugs from screening until 7 days after the last dose of study treatment is 
prohibited: 
• 
Strong inhibitors of CYP2C8 (e.g., gemfibrozil) 
• 
Strong inducers of CYP2C8 (e.g., rifampin/rifampicin) 
 
Use of the following drug; during the treatment period: 
• 
Erythropoietin (e.g., epoetin/ darbepoetin alfa/ epoetin beta pegol) 
 
Note: excluding darbepoetin alfa (brand name: Nesp) supplied by GSK. 
 
6.12. Supplemental Iron Therapy 
From Week 4, Supplemental iron therapy will be administered according to the Guidelines for Renal 
Anemia [The Japanese Society for Dialysis Therapy , 2016] if ferritin is ≤100 ng/mL and TSAT is 
≤20%. The investigator (or subinvestigator) can choose the route of administration and dose of 


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prescription iron, and they should consider to discontinue their patient’s iron therapy if ferritin is 
≥300 ng/mL [The Japanese Society for Dialysis Therapy , 2016]. 
Refer to 4.2. regading iron use until Week 4.    
 
 
7. Study Assessments and Procedures 
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the Time and 
Events Table, are essential and required for study conduct. 
 
7.1. 
Time and Events Table 
The time and events tables for the entire study and PK assessment are presented as Table 10 and Table 
11, respectively. 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) and Visit days will be 
counted from Day 1. To allow for a flexible schedule, the allowable window for Screening Visit will 
be “2-4 weeks ± 3 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 10    Time and Events Table 
Phase 
Screening 
Treatment 
Visit 
 
All assessments pre-dialysis, unless noted. 
-4～-2 11 
Day 1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
Allowance range (days) 
±3 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, demography, height1, 
weight 1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration with IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study medication dispensing 2, 3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study treatment compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (before and after dialysis) 4 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Ophthalmology 5 
X12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
HemoCue Hgb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
 
X 
 
Hgb 
only 
 
Hgb 
only 
 
X 
 
Hgb 
only 
 
Hgb 
only 
 
X 
Clinical chemistry 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pregnancy test (serum hCG) 6 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Estradiol, FSH 7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK 8 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Ferritin, TSAT 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum iron, TIBC, UIBC, serum transferrin, 
hepcidin 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
iPTH 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HR-QoL (SF-36, EQ-5D-5L/ EQ-VAS) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Genetics sample 9 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE assessment 10 
X 13 
 
Concomitant Medications Review 
 


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Phase 
Treatment 
Follow-up 
Visit 
 
All assessments pre-dialysis, unless noted. 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
Early 
withdrawal 
14 
2 weeks  
after Week 52 
or early 
withdrawal 
Allowance range (days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, demography, height1, 
weight 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration with IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study medication dispensing 2, 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study treatment compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs (before and after dialysis) 4 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Ophthalmology 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
HemoCue Hgb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology 
 
Hgb 
only 
 
Hgb 
only 
 
X 
 
Hgb 
only 
 
Hgb 
only 
 
X 
X 
X 
Clinical chemistry 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Pregnancy test (serum hCG) 6 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Estradiol, FSH 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ferritin, TSAT 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Serum iron, TIBC, UIBC, serum transferrin, 
hepcidin 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
iPTH 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
HR-QoL 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Genetics sample 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE assessment 10 
 
Concomitant Medications Review 
 
1. 
Body weight is measured after dialysis. Both height and body weight are measured only at screening. 
2. 
Daprodustat/placebo will be dispensed once every 4 weeks, and darbepoetin alfa/placebo will be dispensed once every 2 weeks 
3. 
If a subject visit the study site only to receive study medication, only registration with the IWRS  study medication dispensing, and study medication compliance will be required.  


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4. 
At visits without dialysis, only one measurement of each parameter will be obtained. 
5. 
Ophthalmology exams should be conducted at the following time points. 
• 
Screening: anytime after consenting and prior to first dose of study medication (Day 1) 
• 
Week 12: window from weeks 10-14 (inclusive) 
• 
End of study: window from weeks 48-52 (inclusive) 
• 
Early study medication discontinuation: withdrawal eye exam as close to the last dose as possible (the repeat exams are not required if one has been performed within the 2 prior weeks). 
6. 
Performed in females of childbearing potential. 
7. 
Measured in female subjects only to determine the menopausal status (see Section 5.1.) 
8. 
See Table 11. 
9. 
Informed consent for optional Genetic research should be obtained before collecting a sample (see Section 7.6.). 
10. See Section7.4.1.1.. 
11. The interval between screening and Day 1 should be 4 weeks in subjects treated with epoetin beta pegol every 4 weeks or darbepoetin alfa every 4 weeks in the prior ESA therapy. 
12. For re-screening subjects, no repeated ophthalmology exams could be required at re-screening, in which case the results of ophthalmology exams at the most recent screening could be replaced on the 
investigator’s (or subinvestigator’s) discretion if re-screening subjects meet all of the following criteria: 
• 
There were no findings that would suggest a repeat ophthalmology exam performed within the next 3 months at the latest screening ophthalmology exam. 
• 
No new ocular symptoms or complaints were noted after the most recent ophthalmologic screening and before the next re-screening. 
• 
The most recent ophthalmology screening was performed within 3 months prior to anticipated Day 1. 
13. Only SAEs assessed as related to study participation or a GSK product are collected. 
14. For withdrawn subjects, specified assessments should be done wherever possible.  
 


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Table 11    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 daprodustat or placebo 
Subjects must take the study medication with regard to blood sampling time. Subjects will record the date and time of the last two 
study medication doses taken prior to blood sampling in the medication diary. There should be an interval of at least 12h (preferably, 
almost 24 h) between these two doses. 
1. 
Blood sampling should be completed within +/- 30 min of the planned collected time. 
2. 
Blood sampling not performed at this visit may be postponed until the following visits.  
 
7.2. 
Screening and Critical Baseline Assessments 
Cardiovascular medical history/risk factors will be assessed (documented in the eCRF) at baseline. 
In addition, the following demographic information will be collected: 
• 
Year of birth 
• 
Gender 
• 
Race and ethnic 
• 
Medical history/treatment history/family history will be assessed in relation to the 
inclusion/exclusion criteria (Section 5.1, 5.2).  
 
Full details of baseline assessments are provided in Time and Events Table (Table 10).  
 
7.3. 
Efficacy 
Efficacy will be assessed according to the Time and Event Table (Table 10).  
Hgb concentrations measured by the central laboratory will be mainly used for efficacy assessment.  
GSK will supply a point-of-care Hgb analyzer (HemoCue) to each site for rapid and convenient 
measurement of Hgb and to ensure consistency of Hgb measurements across all sites participating in 
the study. Assessment for Hgb concentrations via HemoCue will be used for eligibility (Section 5.1), 
permanent discontinuation of study treatment (Section 5.4), and dose adjustment criteria (Section 6.4).  
In addition, assessments of iron metabolism parameters used for exploratory assessment is outlined 
with specific procedures in Section 7.4.7.  
 
7.4. 
Safety 
Planned time points for all safety assessments are listed in the Time and Events Table (Table 10).  
Additional time points for safety tests (such as vital signs, physical exams and laboratory safety tests) 
may be added during the course of the study based on newly available data to ensure appropriate 
safety monitoring 
 
7.4.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) 
The definitions of an AE or SAE can be found in Section 12.6. Appendix 6. 
The investigator and their designees are responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE. 
 
7.4.1.1. 
Time period and Frequency for collecting AE and SAE information 
• 
AEs and SAEs will be collected from the start of Study Treatment until the follow-up contact 
(see Section 7.4.1.3.), at the timepoints specified in the Time and Events Table (Table 10). 


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• 
Medical occurrences that begin prior to the start of study treatment but after obtaining informed 
consent may be recorded on the Medical History/Current Medical Conditions section of the CRF. 
• 
Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a GSK product will be recorded from 
the time a subject consents to participate in the study up to and including any follow-up contact.  
• 
All SAEs will be recorded and reported to GSK within 24 hours, as indicated in Section 12.6. 
Appendix 6. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify GSK. 
• 
 
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs plus procedures 
for completing and transmitting SAE reports to GSK are provided in Section 12.6. Appendix 6. 
 
7.4.1.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about AE occurrence.  
Appropriate questions include: 
• 
“How are you feeling?”  
• 
“Have you had any (other) medical problems since your last visit/contact?” 
• 
“Have you taken any new medicines, other than those provided in this study, since your last 
visit/contact?” 
 
7.4.1.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in Section 
7.4.2.) will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up (as defined in Section5.4.). Further information on 
follow-up procedures is given in Section 12.6. Appendix 6.. 
 
 
7.4.1.4. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Section 12.6. Appendix 6 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be required to 
be completed.  These sections include questions regarding cardiovascular (including sudden cardiac 
death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV Medical Dictionary for 
Regulatory Activities (MedDRA) terms.  The CV information should be recorded in the specific 
cardiovascular section of the CRF within one week of receipt of a CV Event data query prompting its 
completion.   


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The Death CRF is provided immediately after the occurrence or outcome of death is reported. Initial 
and follow-up reports regarding death must be completed within one week of when the death is 
reported. 
 
7.4.1.5. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to study 
treatment (even for non- interventional post-marketing studies) is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects and the safety of a product under clinical 
investigation are met.  
 
GSK has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a product under clinical investigation. GSK will comply with country 
specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) and investigators. 
 
Investigator safety reports are prepared for suspected unexpected serious adverse reactions according 
to local regulatory requirements and GSK policy and are forwarded to investigators as necessary. 
 
An investigator who receives an investigator safety report describing a SAE(s) or other specific safety 
information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements. 
 
7.4.2. 
Adverse Events of Special Interest 
The investigator (or subinvestigator) or designee will be responsible for detecting, documenting, and 
reporting any AEs of special interest listed below. These events have been identified based on the 
known safety profiles of ESAs, theoretical or potential risks based on the mechanism of action of 
daprodustat, and findings from completed nonclinical studies of daprodustat.  
 
• 
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis  
• 
Death, myocardial infarction, stroke, heart failure, thromboembolic events, thrombosis of 
vascular access 
• 
Cardiomyopathy   
• 
Pulmonary artery hypertension (PAH) 
• 
Cancer-related mortality and tumor progression and recurrence  
• 
Esophageal and gastric erosions 
• 
Proliferative retinopathy, macular edema, choroidal neovascularization  
• 
Exacerbation of rheumatoid arthritis 
 
Any relevant AE should be recorded in the relevant section of the subject’s eCRF. 
 
7.4.3. 
Pregnancy 
• 
Details of all pregnancies in female subjects will be collected after the start of dosing and until 
the follow-up contact. 


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


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7.4.5. 
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. 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. 
 
7.4.6. 
Electrocardiogram (ECG) 
12-lead ECGs will be recorded in supine position. The heart rate, PR, QRS, and QT (pre-corrected) 
intervals will be measured.  QTcB should be calculated by machine or manually by designated staff 
at each site. The investigator determines whether the ECG data is assessable or not. 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 QTc. The average QTcB value of all three ECGs will be used to determine 
eligibility. 
QTc exclusion criteria can be found in Section 5.2.  Refer to SRM for further details. 
 
7.4.7. 
Clinical Laboratory Assessments 
All study-required laboratory assessments will be performed by a central laboratory with the exception 
of HemoCue Hgb. The results of each HemoCue Hgb must be entered into the subject’s eCRF. Details 
are provided in the SRM.  
All laboratory assessments, as defined in Table 12, must be conducted in accordance with the 
Laboratory Manual and Protocol Time and Events Schedule (Table 10). 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 daprodustat is outlined in Section 7.5. 


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Table 12    Laboratory Assessments 
Laboratory 
assessment 
Parameter 
Hematology 
Platelet count 
RBC indices: 
WBC dfferential 
RBC count 
MCV 
Neutrophils 
Reticulocyte count 
MCH 
Lymphocytes 
Hemoglobin 
MCHC 
Monocytes 
Hematocrit 
RDW 
Eosinophils 
WBC count 
 
Basophils 
Clinical chemistry 
Sodium 
AST 
Bicarbonate 
Potassium 
ALT 
Inorganic phosphate 
Chloride 
Creatinine 
Glucose 
Calcium (total and albumin-
corrected) 
Total bilirubin 
Direct/indirect bilirubin  
Albumin 
Urea nitrogen 
 
Total cholesterol 
HDL cholesterol 
LDL cholesterol 
Iron parameters 
Serum iron 
Serum ferritin 
Serum transferrin 
TIBC 
UIBC 
TSAT 
Hepcidin 
 
 
Other laboratory 
tests 
FSH 1 
Estradiol 1 
iPTH 
serum hCG 2 
 
 
1. 
Measured in female subjects only to determine the menopausal status (see Section 5.1). 
2. 
Performed in females of childbearing potential.  
 
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. 
 
7.4.8. 
Ophthalmology 
Ophthalmology exams will be performed by a study-designated ophthalmology specialist. Each 
assessment will include a comprehensive eye exam with at least the following components: 
measurement of best corrected visual acuity, intraocular pressure, an anterior chamber exam, and a 
fundoscopic exam. These exams will be used for assessment of ocular adverse events. Assessment 
results will be captured on worksheets which will be transferred to the eCRF. Additional details on the 
process for completing these assessments are provided in the SRM. 
 
7.5. 
Pharmacokinetics 
Blood samples for PK analysis of daprodustat will be collected as outlined in Table 11, 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.  


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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 daprodustat will be determined 
in blood samples using the currently established analytical methodology. Raw data will be archived at 
the bioanalytical site. 
Procedures for processing, storage, and shipment of samples are provided in the SRM.  
 
7.6. 
Genetics 
A blood sample will be collected for genetic analysis from consenting subjects. This sample can be 
collected on Day 1 once written informed consent has been obtained. Information regarding genetic 
research is included in Section 12.7. Appendix 7. 
 
7.7. 
Patient Reported Outcome (PRO)  
The patient reported outcome (PRO) [e.g.health-related QOL (HRQoL), health status and health 
utility] will be assessed using several rating scales.  
 
All questionnaires used in this study have been translated into Japanese and are validated and will be 
administered in paper version.  
Specific instructions on how the subject is to complete the scales and the process for data entry are 
provided in the SPM. 
 
7.7.1. 
Health Related Quality of Life (SF-36)  
The SF-36 acute version is a general health status questionnaire designed to elucidate the patient’s 
perception of his/her health on several domains, including physical functioning, role physical, bodily 
pain, vitality, social functioning, role emotional, mental health, and general health over the past seven 
days. The questionnaire contains 36 Likert type questions that ask the patient to recall how he/she felt 
during the past seven days. 
• 
 
7.7.2. 
EuroQol 5 Dimension 5 Level Health Utility Index (EQ-5D-5L)/ EuroQol Visual 
Analogue Scale (EQ-VAS) 
The EQ-5D-5L is intended to measure the general health status and health utility. The EQ-5D-5L 
consists of 2 concepts: self-reported health status consisting of five dimensions (mobility, self-care, 
usual activities, pain/discomfort, anxiety/depression) each of which can take one of five responses (no 
problems/slight problems/moderate problems/severe problems/extreme problems) and self-rated 
health utility on a visual analogue scale (VAS),from ‘best imaginable health state’ and ‘worst 
imaginable health state’.  
 


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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 RAP. Any deviations from the 
analyses described in the protocol will be documented in the RAP or the final study report.  
 
9.1. 
Hypotheses 
The primary objective of the study is to demonstrate the non-inferiority of daprodustat to darbepoetin 
alfa based on mean Hgb during the primary efficacy evaluation period (Weeks 40 to 52) in HD 
subjects. As a preliminary assessment, it will be confirmed whether the lower and upper limit of 95% 
CI for mean Hgb during the primary efficacy evaluation period in daprodustat group would be in 
target range (10.0-12.0 g/dL) at first. And then the following non-inferiority statistical hypotheses are 
to be tested at a one-sided significance level of 2.5% (i.e. two-sided significance level of 5%): 
 
• 
H0: Treatment difference in mean Hgb during the primary efficacy evaluation period is -1.0 g/dL 
or less. 
• 
H1: Treatment difference in mean Hgb during the primary efficacy evaluation period is greater 
than -1.0 g/dL. 
 
Only when the primary endpoint achieves non-inferiority, statistical testing will progress to the 
principal secondary endpoint with a focus on superiority according to the step-down procedure. More 
specifically, the superiority of daprodustat to darbepoetin alfa in terms of target Hgb control in HD 
subjects is to be demonstrated at a two-sided significance level of 5% by testing the following 
statistical hypotheses: 
 
• 
H0: The proportion of subjects whose mean Hgb during the primary efficacy evaluation period is 
within the target range (10.0-12.0 g/dL) is equal between the treatment groups. 
• 
H1: The proportion of subjects whose mean Hgb during the primary efficacy evaluation period is 
within the target range (10.0-12.0 g/dL) is different between the treatment groups.  
 


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9.2. 
Sample Size Considerations 
9.2.1. 
Sample Size Assumptions 
Assuming a non-inferiority margin of -1.0 g/dL, a treatment difference of 0.0 g/dL, and a standard 
deviation of 1.5 g/dL for mean Hgb during the primary efficacy evaluation period in HD subjects, 
two-sample t-test has at least 99% power at a one-sided significance level of 2.5% (i.e. two-sided 
significance level of 5%) with a sample size of 100 subjects per group. Assuming a dropout rate of 
approximately 25%, 135 subjects will be randomized to each group. Given the results from previous 
non-inferiority studies of similar drugs (darbepoetin alfa, epoetin beta pegol, and peginesatide), the 
non-inferiority margin of -1.0 g/dL is set. Since an increase of 1.0 g/dL indicates improvement in 
anemia according to the guidelines for renal anemia in Japan, the non-inferiority margin of -1.0 g/dL 
may be the clinically acceptable largest difference in renal anemia.   
While the present study is designed to ensure long-term safety data from 100 HD subjects, and the 
primary hypothesis test has at least 99% power to estimate the efficacy very precisely, non-inferiority 
can be statistically demonstrated with a minimum between-group difference of -0.582 g/dL.  
 
9.2.2. 
Sample Size Sensitivity 
The power is shown according to treatment difference and standard deviation in Table 13.  
 
Table 13    Power Sensitivity (100 Subjects Evaluated, Noninferiority Margin of -1.0, 
One-Sided Significance Level of 2.5%) 
Treatment 
difference 
Standard deviation 
1.25 
1.5 
1.75 
0 
100.0% 
99.7% 
98.0% 
-0.1 
99.9% 
98.8% 
95.1% 
-0.2 
99.5% 
96.4% 
89.6% 
-0.3 
97.6% 
90.7% 
80.4% 
 
9.2.3. 
Sample Size Re-estimation or Adjustment 
No sample size re-estimation is planned for this study.  
 
9.3. 
 Data Analysis Considerations 
9.3.1. 
Analysis Populations 
• 
All Screening Population 
The All Screening Population consists of all subjects who are given subject number and whose data 
are collected, including demographics at screening. 
 
• 
Intention-To-Treat (ITT) Population 
The ITT Population consists of all subjects who are given a randomization number regardless of 
whether they actually receive study treatment and whose Hgb assessment was performed at baseline 
and at least one scheduled post-baseline visit. Subjects will be analyzed according to randomized 
treatment. This population will be the primary population for an assessment of non-inferiority. 
 
• 
modified ITT (mITT) Population 


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The mITT Population consists of all ITT subjects who have at least one Hgb measurement during the 
efficacy evaluation period. Subjects will be analyzed according to randomized treatment. This 
population will be the primary population for an assessment of superiority.  
 
• 
Per-Protocol (PP) Population 
The PP Population consists of all mITT subjects who are not major protocol violators. Details will be 
defined in the RAP. This population will be used for efficacy sensitivity analyses.  
 
• 
Safety Population 
The Safety Population consists of subjects who receive at least one dose of study treatment. Subjects 
will be analyzed according to the treatment received. This population will be used for safety analyses.  
 
• 
PK Population 
The PK Population consists of all daprodustat -treated subjects from whom PK samples are collected 
and analyzed.  
 
Additional populations may be defined in the RAP. 
 
9.3.2. 
Interim Analysis 
No interim analysis is planned.  
 
9.3.3. 
Adjustment for Multiplicity 
Adjustment for multiplicity will be applied to maintain an overall type I error rate of 5%. After a 
preliminary assessment, the primary endpoint will be evaluated to demonstrate the non-inferiority at a 
one-sided significance level of 2.5% (i.e. two-sided significance level of 5%). Only when the primary 
endpoint achieves non-inferiority, statistical testing will progress to the principal secondary endpoint 
with a focus on superiority. Since the process will follow step-down manner, a multiplicity adjustment 
will not be needed according to a closed test procedure, similarly two-sided significance level of 5% 
will be used.  
Other secondary endpoints, which will be evaluated on a complementary or exploratory basis, will be 
compared at a two-sided significance level of 5% without multiplicity adjustment.  
 
9.4. 
Key Elements of Analysis Plan 
9.4.1. 
Primary Efficacy Analysis 
The primary endpoint, which is the mean Hgb during the primary efficacy evaluation period, will be 
analyzed to demonstrate the non-inferiority of daprodustat to darbepoetin alfa in HD subjects.  
MMRM will be used to estimate the mean Hgb during the primary efficacy evaluation period and its 
95% CI by treatment groups. This model includes treatment groups, baseline Hgb, assessment visits, 
interaction terms between treatment groups and assessment visits, as well as interaction terms between 
baseline Hgb and assessment visit. As a preliminary assessment, it will be confirmed if the lower and 
upper limit of 95% CI for mean Hgb during the primary efficacy evaluation period in daprodustat 
group would be in target range (10.0- 12.0 g/dL) at first. This confirmation will be established if the 
lower and upper limit of 95% CI for the mean Hgb in daprodustat group based on observed Hgb 


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would lie fully within target range (10.0-12.0 g/dL). In addition, the point estimate and 95% CI for the 
treatment difference (daprodustat - darbepoetin alfa) in the mean Hgb during the primary efficacy 
evaluation period will be estimated. Non-inferiority will be established if the lower limit of the 95% 
CI is greater than -1.0 g/dL. Even if the 95% CI for the difference is completely negative (i.e. lies fully 
within the range -1.0 to <0 g/dL) non-inferiority would still be concluded on condition that the mean 
Hgb estimated in the daprodustat group is within the target range. 
The primary efficacy population will be the ITT Population, and the analysis will be repeated in the 
mITT and PP Population to evaluate the robustness of the conclusion. Following sensitivity analyses 
will be conducted to assess robustness of study result.  
• 
If there are Hgb considered to be impacted by blood transfusion or marketed rhEPO/ESAs, 
sensitivity analysis excluding the Hgb values from the analyses of primary endpoint will be 
conducted. 
• 
Analysis of covariance (ANCOVA) will be conducted as sensitivity analysis to MMRM. This 
model includes treatment group and baseline Hgb. The analysis population will be mITT 
population and the similar analysis will be repeated in the PP population. 
• 
A tipping point analysis based on multiple imputation will be conducted as sensitivity analysis to 
missing data assumption. This analysis explores a point where non-inferiority is not confirmed 
(tipping point) by changing assumption to missing data and repeating imputation. The analysis 
population will be ITT population and the similar analysis will be repeated in the mITT and PP 
population. 
Further details of sensitivity analyses will be provided in the RAP. 
 
9.4.2. 
Principal Secondary Efficacy Analysis 
The principal secondary endpoint, which is the proportion of subjects whose mean Hgb during the 
primary efficacy evaluation period is within the target range, will be analyzed to demonstrate the 
superiority of daprodustat to darbepoetin alfa in HD subjects.  
In the mITT Population, a logistic regression model including treatment group and baseline Hgb as 
covariates will be used to estimate the point estimate and 95% CI for the odds ratio (daprodustat/ 
darbepoetin alfa). This analysis will be performed to demonstrate the superiority at a two-sided 
significance level of 5%, conditional on the primary endpoint achieving noninferiority.  Superiority 
will be established if the lower limit of the 95% CI for odds ratio is greater than 1.0. 
 
9.4.3. 
Other Secondary Efficacy Analyses 
Among the secondary efficacy endpoints, the time (%) in Hgb target range during the primary efficacy 
evaluation period , and proportion of subjects who have an Hgb increase of more than 2 g/dL over any 
4 weeks, the point estimates and 95% CIs for the treatment difference (or odds ratio) in HD subjects 
will be calculated. Other secondary efficacy and exploratory endpoints will be summarized by each 
treatment group.  
 
9.4.4. 
Safety Analyses 
In principle, safety data will be summarized by each treatment group in the Safety Population.  
 


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9.4.4.1. 
Exposure 
Exposure information will be listed for all subjects. The duration of treatment (number of days) and 
cumulative dose will be tabulated. In addition, distribution of the dose level at each assessment visit 
and final dosing visit will be tabulated. Frequency of dose adjustment and duration of treatment 
interruption due to Hgb >13.0 g/dL will be summarized. 
 
9.4.4.2. 
Adverse Events 
All AEs will be categorized by the MedDRA system organ class and preferred term to tabulate the 
number and incidence. All AEs, SAEs, AEs leading to discontinuation of study treatment, and AEs of 
special interest will be summarized separately. Similar summary will be provided for study treatment-
related AEs.  
 
9.4.4.3. 
Other Safety Parameters 
For laboratory tests, vital signs and ECG, parameters and/or changes from baseline will be 
summarized using summary statistics at each assessment visit. The number and percentage of subjects 
with values of the potential clinical importance values will be tabulated. The criteria for the potential 
clinical importance will be described in the RAP. For lipid parameters (total cholesterol, LDL 
cholesterol, and HDL cholesterol), percent changes will also be tabulated. The number (%) of subjects 
who have any change in anti-hypertensive medications (type and/or dose) due to increased blood 
pressure will be tabulated. 
 
9.4.5. 
Pharmacokinetics Analyses 
For plasma concentrations of daprodustat over time, individual data will be listed, and summary 
statistics at each time point will be calculated for each dose level. For PK parameters (AUC 0-4 and 
Cmax), summary statistics will be calculated for each dose level, and scatter plots against the dose 
level will be generated.  
 
9.4.6. 
PRO Data Analysis 
Details of PRO data tabulation will be described in the RAP. 
 
 


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


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


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• 
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 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. 
 


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GSK will also provide the investigator with the full summary of the study results. The investigator is 
encouraged to share the summary results with the study subjects, as appropriate. 
 
GSK will also provide the investigator with the randomization numbers assigned to the subjects of 
his/her study site after the completion of all analyses. 
 
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. 
 
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 T, Makino H, Matsuo S, 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 LA, Barnhart HX., Inrig JK., et al. Secondary analysis of the CHOIR trial epoetin-α dose and 
achieved hemoglobin outcomes. Kidney International. 2008;74:791-8. 
Guidelines for Renal Anemia in Chronic Kidney Disease issued by the Japanese Society for Dialysis 
Therapy in 2015. Journal of Japanese Society for Dialysis Therapy. 2016;49(2):89-158 
 
MIRCERA. Product information in Europe (methoxy polyethylene glycol-epoetin beta). 2012-May. 
2012. 
 
KDIGO. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney 
International Supplement. 2012 Aug;2(4): 279-335. 
 


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12. APPENDICES 
12.1. Appendix 1: Abbreviations and Trademarks 
 
Abbreviations 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under Curve 
CKD 
Chronic Kidney Disease 
Cmax 
Maximum concentration 
CPK 
Creatine Phosphokinase 
CYP 
Cytochrome P450 
DNA 
Deoxyribonucleic Acid 
EPO 
Erythropoietin 
EQ-5D-5L 
EuroQol EuroQol 5 Dimension 5 Level Health Utility Index 
EQ-VAS 
EuroQol Visual Analogue Scale  
ESA 
Erythropoiesis-Stimulating Agent 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
hCG 
Human Chorionic Gonadotrophin 
HD 
Hemodialysis 
HDL 
High Density Lipoprotein 
HDF 
Hemodiafiltration 
Hgb 
Hemoglobin 
HIF 
Hypoxia-Inducible Factor 
HRQoL 
Health Related Quality of Life 
HRT 
Hormone Replacement Therapy 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
iPTH 
Intact Parathyroid Hormone  
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Recognition System 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein  
MCS 
Mental Component Summary  
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-to-Treat 
NYHA 
New York Heart Association 
PAH 
Pulmonary Artery Hypertension 
PCS 
Physical Component Summary 
PD 
Peritoneal Dialysis 
PHI 
Prolyl Hydroxylase Inhibitor 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PRO 
Patient Reported Outcome 
QT Interval 
Q-T Interval 


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QTc Interval 
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 
RNA 
Ribonucleic Acid 
rhEPO 
Recombinant human erythropoietin 
SAE 
Serious Adverse Event  
sPAP 
Systolic Pulmonary Artery Pressure 
SRM 
Study Reference Manual 
TIBC 
Total Iron Binding Capacity 
TSAT 
Transferrin Saturation 
UIBC 
Unsaturated iron Binding Capacity 
VAS 
Visual Analog Scale  
VEGF 
Vascular Endothelial Growth Factor 
 
Trademark Information 
Trademarks of the GlaxoSmithKline group of 
companies 
 
Trademarks not owned by the GlaxoSmithKline 
group of companies 
None 
 
Hemocue 
 
 
NespⓇ 
 
 
 
 


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12.2. Appendix 2:  Risk Assessment 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Daprodustat  
Excessive erythropoiesis (polycythemia) leading to 
thrombosis and/or tissue ischemia 
In animal studies, excessive erythropoiesis attributed to daprodustat 
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 daprodustat. 
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 
daprodustat based on achieved Hgb is 
provided in Section 6.4.1. 
• 
These risks have been identified as AEs 
of special interest and will be 
monitored instreamly by the internal 
safety review team throughout the 
study period. 
Death, MI, stroke, heart failure, thromboembolic events, 
thrombosis of vascular access at Hgb levels which are 
within the normal range (i.e. not polycythemic conditions) 
Marketed rhEPO/ESAs have been associated with an increased risk for 
death and serious cardiovascular events when used in patients with 
anemia of CKD. 
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat. 
• 
Specific eligibility criteria related to CV risk are 
outlined in Section 5.2. 
• 
Hgb will be closely monitored 
throughout the dosing period as 
outlined in the Time and Events Table 
Section 7.1. 
• 
These risks have been identified as AEs 


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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 daprodustat. 
Gender-averaged systemic exposure (AUC) at the no observed 
adverse effect levels (NOAEL) are 3.3 -fold (monkeys) and 737 
-fold (rats) above human exposure (25 mg). 
In clinical trials to date, mild-moderate GI signs and symptoms 
represent the most frequently reported adverse event, however 
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 daprodustat. 
• 
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, 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 daprodustat to mice caused minimal 
increases in circulating VEGF while significant EPO increases were 
observed. 
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations, an angiogenic factor that has been 
implicated in tumor growth, was observed at doses ranging from 10 to 
150 mg. In clinical studies up to 24 weeks duration at doses up to 
25 mg, changes in VEGF plasma concentrations were variable but 
similar relative to control. 
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.  
• 
Specific eligibility criteria related to personal history 
of malignancy are outlined in Section 5.2.. 
• 
Stopping criteria for subjects with 
treatment emergent malignancy are 
outlined in Section 5.4. 
• 
These risks have been identified as AEs 
of special interest and will be 
monitored instreamly by the internal 
safety review team throughout the 
study period. 
Pulmonary artery hypertension (PAH) 
A role for HIF-regulated pathways in the pathophysiology of PAH has been 
suggested based on well established effects of acute and chronic hypoxia in 
• 
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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): daprodustatA 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 therapy with daprodustat 5 mg or 100 mg has no 
clinically significant effect on echocardiographically estimated pulmonary 
artery systolic pressure (PASP) under either normoxic or hypoxic conditions. 
 
ECHO assessments performed in Phase 2b studies (24 weeks treatment 
duration) did not identify any clinically meaningful changes in sPAP in subjects 
not on dialysis. 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 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 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 daprodustat. 
internal safety review team throughout the study 
period. 
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. 
• 
These risks have been identified as AEs of special 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
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Small increases in cardiac troponin in 6 month rat study were 
consistent with the background finding of spontaneous rodent 
cardiomyopathy. There were no elevations observed in cardiac 
troponin in 9 month monkey study. 
Cardiomyopathy has not been associated with naturally 
occurring mutation in man which results in increased HIF 
stabilization. 
ECHO assessments performed in phase 2b studies (24 weeks treatment 
duration) did not identify any clinically meaningful changes in LVEF. 
 
Following review of clinical data received to date, this has not been identified 
as a safety concern for daprodustat. 
period. 
Proliferative retinopathy, macular edema, choroidal 
neovascularization 
Increases in local (ocular) VEGF production with retinal 
neovascularization and macular edema observed in diabetic 
retinopathy and to choroidal leakage, edema and neovascularization 
seen in age-related macular degeneration (Campochiaro, 2006). 
Administration of 60 mg/kg daprodustat to mice caused 
minimal increases in circulating VEGF while significant EPO 
increases were observed. 
No ocular abnormalities were seen in non-clinical studies of up 
to 13 weeks duration in mice and dogs, 26 weeks in rats, and 
39-weeks in monkeys.   
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations was observed at doses ranging from 10 
to 150 mg. In studies up to 24 weeks duration at doses up to 25 mg, 
changes in VEGF plasma concentrations were variable but similar 
relative to control. 
Ophthalmologic assessments performed in phase 2b studies (24 
weeks treatment duration) did not identify any clinically 
meaningful changes in proliferative retinopathy, macular 
edema, or choroidal neovascularization. 
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat. 
• 
Ophthalmology exams will be performed during 
screening, at approximately Week 12 on-study, and 
at the end of treatment. 
• 
These risks have been identified as AEs 
of special interest and will be 
monitored instreamly by the internal 
safety review team throughout the 
study period.  
• 
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 
• 
These risks have been identified as AEs of special 


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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 daprodustat. 
interest and will be monitored instreamly by the 
internal safety review team throughout the study 
period. 
Drug-drug interactions 
Co-administration of daprodustat with a strong CYP2C8 inhibitor 
increased the Cmax and AUC of daprodustat, 4- and 19-fold, 
respectively, while co-administration of a weak inhibitor increased the 
Cmax and AUC of daprodustat by 1.3- and 1.5-fold, respectively. 
Population PK analysis from completed Phase 2 studies suggests that 
co-administration of daprodustat with a moderate CYP2C8 inhibitor, 
leads to a ~ 2-fold increase in AUC, with no clinically-significant 
increase in the measured Hgb response. 
Daprodustat 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 daprodustat 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 daprodustat with moderate 
CYP2C8 inhibitors (i.e., clopidogrel, teriflunomide, 
deferasirox) should be performed with caution.  
Co-administration of daprodustat with potent BCRP inhibitors 
has the potential to increase exposure of daprodustat. Use of 
BCRP inhibitors (mostly weak) was found to result in a small 
change in metabolite exposure (20% increase in AUC). 
Daprodustat is an inhibitor of OATP1B1/1B3 in vitro, with IC50 
values of 6 µM and 11 µM, respectively. A clinical drug 
interaction study between 25mg daprodustat with either a 
CYP2C8 substrate or an OATP1B1/1B3 substrate showed that 
there is no PK interaction at this dose of daprodustat. 
Co-administration of daprodustat with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and inducers 
(e.g., rifampin/rifampicin) is not permitted as 
outlined in Section 6.11.2. 
Co-administration of daprodustat with 
moderate CYP2C8 inhibitors (i.e., clopidogrel, 
teriflunomide, deferasirox) should be 
performed with caution.  
Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in 
Section 6.11. 
• 
Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and Events 
Table Section 7.1. 
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat based 
on achieved Hgb is provided in Section 6.4.1. 
Safety data will be monitored instreamly by 
the internal safety review team throughout the 
study period. 
Other 
ESA risks (Control) 
See risks outlined in table for daprodustat for Excessive erythropoiesis 
The same mitigation strategies have been indentified 


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Potential Risk of Clinical Significance 
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(polycythemia) leading to thrombosis and/or tissue ischemia; Risk of 
MI, stroke, thromboembolic events, thrombosis of vascular access; and 
risk of cancer-related mortality and tumor progression. 
 
Uncontrolled hypertension. 
 
Pure red cell aplasia 
 
Hepatic function disorder with increase of ALT and Gamma-
glutamyltransferase, and jaundice have been reported as adverse 
drug reactions according to the prescribing information of 
darbepoetin alfa. 
in acoordance with the mitigation strategies for 
daprodustat  
Monitor instreamly blood pressure throughout 
the study as scheduled in Table 10. 
Specific eligibility criteria related to personal 
history of pure red cell aplasia are outlined in 
Section 5.2. 
Liver function will be monitored throughout 
the dosing period as outlined in the Time and 
Events Table provided in Section 7.1. 
 
References 
Campochiaro PA and the First ARVO/Pfizer Institute Working Group. Ocular versus Extraocular Neovascularization: Mirror Images or Vague Resemblances. 
Invest Ophthalmol & Vis Sci. 2006;47:462-74. 
 
Formenti F, Beer PA, Croft QP, 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):2001-11. 
 
Muz B, Khan MN, Kiriakidis S, et al. Hypoxia.The role of hypoxia and HIF-dependent signalling events in rheumatoid arthritis. Arthritis Research & 
Therapy. 2009;11:201. 
 
Smith TG, Brooks JT, Balanos GM, et al. Mutation of von Hippel-Lindau Tumour Suppressor and Human Cardiopulmonary Physiology . PLoS Med. 
2006;3:1178-86. 
 
Westra J, Molema G and Kallenberg CG. Hypoxia-Inducible Factor-1 as Regulator of Angiogenesis in Rheumatoid Arthritis - Therapeutic Implications.  
Current Medicinal Chemistry 2010;17(3):254-63.  


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


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


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12.5. Appendix 5: Liver Safety Required Actions and Follow up Assessments 
Phase III-IV liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance). 
 
Phase III-IV liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event 
ALT-absolute 
ALT ≥ 8xULN 
ALT Increase 
ALT ≥ 5xULN but <8xULN  persists for ≥2 weeks 
ALT ≥ 3xULN but <5xULN  persists for ≥4 weeks 
Bilirubin1, 2 
ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin)  
INR2  
ALT ≥ 3xULN and INR>1.5, if INR measured 
Cannot 
Monitor 
ALT ≥ 5xULN but <8xULN and cannot be monitored weekly for ≥2 weeks 
ALT ≥ 3xULN but <5xULN and cannot be monitored weekly for ≥4 weeks 
Symptomatic3 
ALT  ≥ 3xULN associated with symptoms (new or worsening) believed to be related to  
liver injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping Event 
Actions 
Follow Up Assessments 
• 
Immediately discontinue study treatment  
• 
Report the event to GSK within 24 hours 
• 
Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2 
• 
Perform liver event follow up assessments  
• 
Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below) 
• 
Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted  
• 
If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments  
• 
 
MONITORING: 
For bilirubin or INR criteria:  
• 
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
• 
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 adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). 
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT ≥ 3xULN and bilirubin ≥ 2xULN.  
2. 
All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) or ALT ≥ 3xULN and INR>1.5, if 
INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold 
value stated will not apply to subjects receiving anticoagulants 
3. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)    
4. 
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody or Hepatitis E RNA 
5. 
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the 
SRM.   
 
 
Phase III-IV liver chemistry increased monitoring criteria with continued therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
 
ALT ≥5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks. 
OR 
• 
Notify the GSK medical monitor within 24 hours 
of learning of the abnormality to discuss subject 
safety.  
• 
Subject can continue study treatment   
• 
Subject must return weekly for repeat liver 


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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. 
 
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. 
 
References 
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of Acetaminophen-Protein Adductsin 
Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos. 2009;37:1779-84. 
 
 
 


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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. 


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


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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 
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 
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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. 
• 
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 (or subinvestiagtor) will mark a check against ‘reviewed’ box in the lower part 
of the eCRF page within 72 hours after reporting of SAE to ensure that the causality of AE has 
been reviewed. 
• 
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 daprodustat. To achieve this 
objective, the relationship between genetic variants and the followings may be investigated. 
• 
Response to medicine, including daprodustat, ESA, other study medicines or any concomitant 
medicines; 
• 
Nephrogenic anemia and related conditions susceptibility, severity, and progression  
• 
 
Genetic data may be generated while the study is underway or following completion of the study.  
Genetic evaluations may include focused candidate gene approaches and/or examination of a large 
number of genetic variants throughout the genome (whole genome analyses). Genetic analyses which 
will be conducted for this study will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data from multiple 
clinical studies related to daprodustat to investigate these research objectives. 
 
Appropriate descriptive and/or statistical analysis methods will be used. A detailed description of any 
planned analyses will be documented in a Reporting and Analysis Plan (RAP) prior to initiation of the 
analysis. Planned analyses and results of genetic investigations will be reported either as part of the 
clinical RAP and study report, or in a separate genetics RAP and report, as appropriate. 
 
Study Population 
Any subject who is enrolled in the study can participate in the genetic research. Any subject who has 
received an allogeneic bone marrow transplant must be excluded from the genetic research. 
 
Study Assessments and Procedures 
A key component of successful genetic research is the collection of samples during clinical studies. 
Collection of samples, even when no a priori hypothesis has been identified, may enable future 
genetic analyses to be conducted, align with the purpose of the genetic research, to help understand 
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• 
A 6 mL blood sample will be taken for 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. Aspects. Med. 2012;33:467-86. 


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


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


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12.9. Appendix 9: Protocol Changes 
12.9.1. 
Amendment 1 － 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. 
 
Exclusion Criteria 
Original Text: 
8. 
Liver disease (if any of the following occurs): 
• 
ALT > 2 x upper limit of normal (ULN) 


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• 
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. 
 
 
6.11.2. 
Prohibited Medications and Non-Drug Therapies 
Original Text: 
None 
 
Revised Text: 
Use of the following drug; during the treatment period: 
• 
Erythropoietin (e.g., epoetin/ darbepoetin alfa/ epoetin beta pegol) 
 
Note: excluding darbepoetin alfa (brand name: Nesp) supplied by GSK. 
 
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 procedure. 
 
 
7.4.2. 
Adverse Events of Special Interest 
Original Text: 
• 
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 


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• 
Death, myocardial infarction (MI), stroke, venous thromboembolism, thrombosis of vascular 
access 
• 
Cardiomyopathy 
• 
Pulmonary artery hypertension (PAH) 
• 
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 (PAH) 
• 
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. 
 


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12.9.2. 
Amendment 2 － 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 PHI201754 
Analysis 
Original Text: 
As a preliminary assessment, it will be confirmed if the mean Hgb in daprodustat group would lie 
fully within target range (10.0-12.0 g/dL) at first. 
 
Revised Text: 
As a preliminary assessment, it will be confirmed if the lower and upper limit of 95% CI for mean 
Hgb during the primary efficacy evaluation period in daprodustat group would lie fully within target 
range (10.0-12.0 g/dL) at first. 
 
Reason: 
To adjust description. 
 
 
1 
PROTOCOL SYNOPSIS FOR STUDY PHI201754 
Analysis 
Original Text: 
None 
 
Revised Text: 
Following sensitivity analyses will be conducted to assess robustness of study result.  
• 
If there are Hgb considered to be impacted by blood transfusion or marketed rhEPO/ESAs, 
sensitivity analysis excluding the Hgb values from the analyses of primary endpoint will be 
conducted. 
• 
Analysis of covariance (ANCOVA) will be conducted as sensitivity analysis to MMRM. This 
model includes treatment group and baseline Hgb. The analysis population will be mITT 
population and the similar analysis will be repeated in the PP population. 
• 
A tipping point analysis based on multiple imputation will be conducted as sensitivity analysis to 
missing data assumption. This analysis explores a point where non-inferiority is not confirmed 
(tipping point) by changing assumption to missing data and repeating imputation. The analysis 
population will be ITT population and the similar analysis will be repeated in the mITT and PP 
population. 
 
Reason: 
To add sensitivity analyses for primary efficacy analyses and to adjust description. 
 
 


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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 the definition of screening failures. 
 
 
5.4. 
Permanent discontinuation of study treatment and study withdrawal 
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) 
 
Reason: 
To clarify discontinuation criteria (prohibited medication). 
 
6.9. 
Treatment of Study Treatment Overdose 
Original Text: 
None 
 
Revised Text: 
For the purposes of this study, an overdose of daprodustat is defined as any dose greater than the 
highest daily dose included in the protocol. 
 
Reason: 
To clarify the definition of overdose of daprodustat. 
 
 
7.4.2. 
Adverse Events of Special Interest 
Original Text: 
• 
Death, myocardial infarction, stroke, congestive heart failure, venous thromboembolism, 
thrombosis of vascular access 
 
Revised Text: 


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• 
Death, myocardial infarction, stroke, heart failure, thromboembolic events, thrombosis of 
vascular access 
 
Reason: 
To update AESI. 
 
9.1. 
Hypotheses 
Original Text: 
As a preliminary assessment, it will be confirmed whether the mean Hgb during the primary efficacy 
evaluation period in daprodustat group would be in target range (10.0-12.0 g/dL) at first. 
 
Revised Text: 
As a preliminary assessment, it will be confirmed whether the lower and upper limit of 95% CI for 
mean Hgb during the primary efficacy evaluation period in daprodustat group would be within target 
range (10.0-12.0 g/dL) at first. 
 
Reason: 
To adjust description. 
 
 
9.3.3. 
Adjustment for Multiplicity 
Original Text: 
Since the process will follow step-down manner, a multiplicity adjustment for significance level of 5% 
will not be needed according to a closed test procedure.  
Other secondary endpoints, which will be evaluated on a complementary or exploratory basis, will be 
compared at a significance level of 5% without multiplicity adjustment. 
 
Revised Text: 
Since the process will follow step-down manner, a multiplicity adjustment will not be needed 
according to a closed test procedure, similarly two-sided significance level of 5% will be used.  
Other secondary endpoints, which will be evaluated on a complementary or exploratory basis, will be 
compared at a two-sided significance level of 5% without multiplicity adjustment. 
 
Reason: 
To adjust description. 
 
 
9.4.1. 
Primary Efficacy Analysis 
Original Text: 
None 
 
Revised Text: 
Following sensitivity analyses will be conducted to assess robustness of study result.  


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• 
If there are Hgb considered to be impacted by blood transfusion or marketed rhEPO/ESAs, 
sensitivity analysis excluding the Hgb values from the analyses of primary endpoint will be 
conducted. 
• 
Analysis of covariance (ANCOVA) will be conducted as sensitivity analysis to MMRM. This 
model includes treatment group and baseline Hgb. The analysis population will be mITT 
population and the similar analysis will be repeated in the PP population. 
• 
A tipping point analysis based on multiple imputation will be conducted as sensitivity analysis to 
missing data assumption. This analysis explores a point where non-inferiority is not confirmed 
(tipping point) by changing assumption to missing data and repeating imputation. The analysis 
population will be ITT population and the similar analysis will be repeated in the mITT and PP 
population. 
 
Reason: 
To add sensitivity analyses for primary efficacy analyses. 
 
 
12.1. 
Appendix 1: Abbreviations and Trademarks 
Trademark Information 
Trademarks not owned by the GlaxoSmithKline group of companies 
Original Text: 
None 
 
Revised Text: 
NespⓇ 
 
Reason: 
To adjust description. 
 
 
12.2. 
Appendix 2: Risk Assessment 
Potential Risk of Clinical Significance 
Original Text: 
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: 
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 summary of clinical significant potential risk. 
 
 


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12.2. 
Appendix 2: Risk Assessment 
Potential Risk of Clinical Significance 
Pulmonary artery hypertension (PAH) 
Summary of Data/Rationale for Risk 
Original Text: 
Results from a clinical study of acute hypoxic challenge in healthy volunteers demonstrated that short-
term therapy with daprodustat 5 mg or 10 mg has no clinically significant effect on 
echocardiographically estimated pulmonary artery systolic pressure (PASP) under either normoxic or 
hypoxic conditions. 
 
Revised Text: 
Results from a clinical study of acute hypoxic challenge in healthy volunteers demonstrated that short-
term therapy with daprodustat 5 mg or 100 mg has no clinically significant effect on 
echocardiographically estimated pulmonary artery systolic pressure (PASP) under either normoxic or 
hypoxic conditions. 
 
Reason: 
To correct erroneous description. 
 
 
12.2. 
Appendix 2: Risk Assessment 
Potential Risk of Clinical Significance 
ESA risks (Control) 
Summary of Data/Rationale for Risk 
Original Text: 
See risks outlined in table for daprodustat for Excessive erythropoiesis (polycythemia) leading to 
thrombosis and/or tissue ischemia; Risk of MI, stroke, venous thromboembolism, thrombosis of 
vascular access; and risk of cancer-related mortality and tumor progression. 
 
Revised Text: 
See risks outlined in table for daprodustat for Excessive erythropoiesis (polycythemia) leading to 
thrombosis and/or tissue ischemia; Risk of MI, stroke, thromboembolic events, thrombosis of vascular 
access; and risk of cancer-related mortality and tumor progression. 
 
Reason: 
To update summary of data/rationale for risk. 
 
 

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
201754
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 201754
A 52-week, Phase III, double-blind, active-controlled, 
parallel-group, multi-center study to evaluate efficacy and 
safety of daprodustat compared to darbepoetin alfa in 
Japanese hemodialysis-dependent subjects with anemia 
associated with chronic kidney disease who are currently 
ESA users
Compound Number 
:
GSK1278863
Effective Date 
:
06-AUG-2018
Description:

This RAP is an amendment version 1.

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 201754.

This RAP is intended to describe the final analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval Method
NA
NA
Biostatistics Group 2, Biomedical Data 
Sciences Japan
NA
NA
Associate Manager, Biostatistics Group 2, 
Biomedical Data Sciences Japan
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorized copying or use of this information is prohibited.
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The GlaxoSmithKline group of companies
201754
2
RAP Team Approvals:
Approver
Date
Approval 
Method
02-Aug-2018
Pharma TMF
Lead Programmer; Statistical Programming & 
Reporting Group, Biomedical Data Sciences Japan
02-Aug-2018
Pharma TMF
Clinical Investigation Leader; Infectious 
Disease/Future Pipelines Discovery Office, 
Medicines Development
02-Aug-2018
Pharma TMF
Operational Science Lead; Clinical Operations Dept
02-Aug-2018
Pharma TMF
Data Quality Lead; Data Practice Group 2, 
Biomedical Data Sciences Japan
05-Aug-2018
Pharma TMF
Medical Writer; Medical Writing Office, Medicines 
Development
02-Aug-2018
Pharma TMF
Principal PK Analyst; Clinical Pharmacology Office
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval 
Method
06-Aug-2018
Pharma TMF
Lead Authors Line Manager; Biostatistics Group 2, 
Biomedical Data Sciences Japan
06-Aug-2018
Pharma TMF
Lead Programmers Line Manager; Statistical 
Programming & Reporting Group, Biomedical Data 
Sciences Japan
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................7
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................11
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Interim Analyses .........................................................................................12
3.2.
Final Analyses ............................................................................................12
4.
ANALYSIS POPULATIONS ...................................................................................13
4.1.
Protocol Deviations.....................................................................................14
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................15
5.1.
Study Treatment & Sub-group Display Descriptors.....................................15
5.2.
Baseline Definitions ....................................................................................15
5.3.
Multicenter Studies .....................................................................................16
5.4.
Examination of Covariates, Other Strata and Subgroups............................16
5.4.1.
Covariates and Other Strata ........................................................16
5.4.2.
Examination of Subgroups...........................................................16
5.5.
Multiple Comparisons and Multiplicity .........................................................17
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................17
6.
STUDY POPULATION ANALYSES .......................................................................18
6.1.
Overview of Planned Study Population Analyses........................................18
6.2.
Planned Summary Display Details..............................................................19
7.
EFFICACY ANALYSES..........................................................................................23
7.1.
Primary Efficacy Analyses ..........................................................................23
7.1.1.
Endpoint / Variables.....................................................................23
7.1.2.
Summary Measure ......................................................................23
7.1.3.
Population of Interest...................................................................24
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................24
7.1.5.
Statistical Analyses / Methods .....................................................25
7.1.5.1.
Statistical Methodology Specification..........................25
7.1.6.
Sensitivity and Supportive Analyses ............................................27
7.1.6.1.
Evaluable Hgb............................................................28
7.1.6.2.
Analysis of Covariance (ANCOVA).............................28
7.1.6.3.
Tipping Point Analysis ................................................29
7.2.
Principal Secondary Efficacy Analyses .......................................................32
7.2.1.
Endpoint / Variables.....................................................................32
7.2.2.
Summary Measure ......................................................................32
7.2.3.
Population of Interest...................................................................32
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................32
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7.2.5.
Statistical Analyses / Methods .....................................................33
7.2.5.1.
Statistical Methodology Specification..........................33
7.3.
Secondary Efficacy Analyses......................................................................35
7.3.1.
Endpoint / Variables.....................................................................35
7.3.2.
Summary Measure ......................................................................36
7.3.3.
Population of Interest...................................................................38
7.3.4.
Strategy for Intercurrent (Post-Randomization) Events ................38
7.3.5.
Statistical Analyses / Methods .....................................................38
7.4.
Exploratory Efficacy Analyses.....................................................................39
7.4.1.
Endpoint / Variables.....................................................................39
7.4.2.
Summary Measure ......................................................................39
7.4.3.
Population of Interest...................................................................41
7.4.4.
Strategy for Intercurrent (Post-Randomization) Events ................41
7.4.5.
Statistical Analyses / Methods .....................................................41
7.4.5.1.
Statistical Methodology Specification..........................42
8.
SAFETY ANALYSES .............................................................................................44
8.1.
Adverse Events Analyses ...........................................................................44
8.1.1.
Planned Adverse Events Analyses Displays ................................45
8.2.
Adverse Events of Special Interest Analyses..............................................47
8.2.1.
Planned Adverse Events of Special Interest Analyses 
Displays.......................................................................................47
8.3.
Clinical Laboratory Analyses.......................................................................47
8.3.1.
Planned Clinical Laboratory Analyses Displays ...........................49
8.4.
Other Safety Analyses ................................................................................50
8.4.1.
Planned Other Safety Analyses Displays.....................................50
9.
PATIENT REPORTED OUTCOME ANALYSES.....................................................51
9.1.
Endpoint / Variables....................................................................................51
9.2.
Summary Measure .....................................................................................52
9.3.
Population of Interest..................................................................................52
9.4.
Strategy for Intercurrent (Post-Randomization) Events ...............................52
9.5.
Statistical Analyses / Methods ....................................................................53
9.5.1.
Statistical Methodology Specification...........................................53
10. PHARMACOKINETIC ANALYSES.........................................................................54
10.1.
Pharmacokinetic Analyses..........................................................................54
10.1.1.
Endpoint / Variables.....................................................................54
10.1.1.1.
Drug Concentration Measures....................................54
10.1.1.2.
Derived Pharmacokinetic Parameters.........................54
10.1.2.
Summary Measure ......................................................................55
10.1.3.
Population of Interest...................................................................55
10.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................56
11. POPULATION PHARMACOKINETIC (POPPK) ANALYSES..................................57
12. PHARMACODYNAMIC ANALYSES.......................................................................57
13. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................57
14. REFERENCES.......................................................................................................58
15. APPENDICES........................................................................................................59
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15.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................59
15.1.1.
Exclusions from Per Protocol Population .....................................59
15.2.
Appendix 2: Schedule of Activities ..............................................................60
15.2.1.
Protocol Defined Schedule of Events...........................................60
15.3.
Appendix 3: Assessment Windows .............................................................63
15.3.1.
Definitions of Assessment Windows for Analyses........................63
15.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................64
15.4.1.
Study Phases ..............................................................................64
15.4.1.1.
Study Phases for Hgb Data ........................................64
15.4.1.2.
Study Phases for AE Data..........................................64
15.4.1.3.
Study Phases for Concomitant Medication .................64
15.5.
Appendix 5: Data Display Standards & Handling Conventions....................66
15.5.1.
Reporting Process .......................................................................66
15.5.2.
Reporting Standards....................................................................66
15.5.3.
Reporting Standards for Pharmacokinetic....................................67
15.6.
Appendix 6: Derived and Transformed Data ...............................................68
15.6.1.
General........................................................................................68
15.6.2.
Study Population..........................................................................69
15.6.3.
Efficacy........................................................................................73
15.6.4.
Safety ..........................................................................................78
15.6.5.
Pharmacokinetic ..........................................................................79
15.6.6.
Exploratory Endpoint ...................................................................79
15.6.7.
Patient Reported Outcome ..........................................................81
15.7.
Appendix 7: Reporting Standards for Missing Data.....................................83
15.7.1.
Premature Withdrawals................................................................83
15.7.2.
Handling of Missing Data.............................................................83
15.7.2.1.
Handling of Missing and Partial Dates ........................83
15.8.
Appendix 8: Values of Potential Clinical Importance ...................................84
15.8.1.
Laboratory Values........................................................................84
15.8.2.
Vital Signs....................................................................................85
15.9.
Appendix 9: Abbreviations & Trade Marks ..................................................86
15.9.1.
Abbreviations...............................................................................86
15.9.2.
Trademarks .................................................................................87
15.10. Appendix 10: List of Data Displays..............................................................88
15.10.1. Data Display Numbering..............................................................88
15.10.2. Mock Example Shell Referencing ................................................88
15.10.3. Table of Contents for Headline Results Deliverable.....................89
15.10.4. Table of Contents for SAC Deliverable ........................................91
15.10.4.1. Study Population Tables.............................................91
15.10.4.2. Efficacy Tables...........................................................93
15.10.4.3. Efficacy Figures..........................................................98
15.10.4.4. Safety Tables ...........................................................102
15.10.4.5. Safety Figures ..........................................................106
15.10.4.6. Patient Reported Outcome Tables............................107
15.10.4.7. Pharmacokinetic Tables ...........................................108
15.10.4.8. Pharmacokinetic Figures ..........................................109
15.10.4.9. ICH Listings..............................................................111
15.10.4.10.Other Listings...........................................................114
15.10.4.11.Patient Profile Listings..............................................117
15.11. Appendix 11: Example Mock Shells for Data Displays ..............................118
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16. REVISION HISTORY ...........................................................................................119
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 2015N266251_02:
Revision Chronology:
Final_V1
28-Feb-2018
Original
Amendment_Final_V1
06-Aug-2018
Amendment 1
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
9.3.3
Adjustment for Multiplicity
Adjustment for multiplicity will be 
applied to maintain an overall type I 
error rate of 5%. After a preliminary 
assessment, the primary endpoint 
will be evaluated to demonstrate the 
non-inferiority at a one-sided 
significance level of 2.5% (i.e. two-
sided significance level of 5%).
5.5
Multiple Comparisons and 
Multiplicity
Adjustment for multiplicity will be 
applied to maintain an overall type I 
error rate of 2.5% (one-sided). After 
a preliminary assessment, the 
primary endpoint will be evaluated to 
demonstrate the non-inferiority at a 
one-sided significance level of 2.5%.
An overall type I error rate 
() of 2.5% is a one-sided 
nature of the non-inferiority 
test, which is the primary 
analysis for this study. This 
can be applicable to the 
following superiority test to 
maintain =2.5%. This is 
equivalent to two-sided 
significance level of 5%.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To demonstrate non-inferiority of 
daprodustat to darbepoetin alfa based 
on hemoglobin (Hgb)

Mean Hgb during the primary efficacy evaluation period 
(Weeks 40 to 52)
Principal Secondary Objectives
Principal Secondary Endpoints

To demonstrate superiority of 
daprodustat to darbepoetin alfa in 
terms of achievement/maintenance of 
target Hgb

Number (%) of subjects with mean Hgb in the target 
range (10.0-12.0 g/dL) during the primary efficacy 
evaluation period (Weeks 40 to 52)
Secondary Objectives
Secondary Endpoints

To evaluate the appropriateness of 
the starting dose of daprodustat

Change from baseline on Hgb at Week 4 (Hgb increase 
rate)
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Objectives
Endpoints

Number (%) of subjects by Hgb change from baseline 
category at Week 4

To evaluate dose adjustment scheme
of daprodustat

Distribution of the dose level

Duration of treatment interruption due to Hgb >13 g/dL

Frequency of dose adjustments

To evaluate the overall Hgb control of 
daprodustat using darbepoetin alfa as 
control

Hgb and change from baseline at each assessment

Number (%) of subjects who have an Hgb level within the 
target range (10.0–12.0 g/dL) at each assessment visit

Time (%) in Hgb target range (10.0–12.0 g/dL) during the 
primary efficacy evaluation period (Weeks 40 to 52)

Number (%) of subjects who have an Hgb level of less 
than 7.5 g/dL

Number (%) of subjects who have an Hgb increase of 
more than 2 g/dL over any 4 weeks 

Number (%) of subjects who have an Hgb level of more 
than 13.0 g/dL and number of episodes

To evaluate the PK of daprodustat

AUC and Cmax of plasma daprodustat
Exploratory Objectives
Exploratory Endpoints

To evaluate the effect in iron use of 
daprodustat using darbepoetin alfa as 
control

Dose of IV iron during the study period and the primary 
efficacy evaluation period (Weeks 40 to 52) 

Number (%) of subjects who use IV iron during the study 
period and primary efficacy evaluation period (Weeks 40 
to 52)

To evaluate the effect on iron 
metabolism of daprodustat using
darbepoetin alfa as control

Change from baseline in ferritin

Change from baseline in transferrin saturation (TSAT) 
from baseline

Change from baseline in hepcidin

Change from baseline in serum iron

Change from baseline in total iron binding capacity (TIBC)
Patient Reported Outcome
Patient Reported Outcome Endpoints

To evaluate the effect on health-
related QoL (HR-QoL) of daprodustat 
using darbepoetin alfa as control
SF-36

Changes from baseline in SF-36 HR-QoL scores 
[Physical Component Summary (PCS), Mental 
Component Summary (MCS), and 8 subscales] at Week 
12, 28, and 52 
EuroQol Health Utility Index (EQ-5D-5L / EQ-VAS)

Change from baseline in EQ-5D-5L score at Week 12, 28, 
and 52
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Objectives
Endpoints

Change from baseline in EQ-5D-5L Visual Analog Scale 
(VAS) at Week 12, 28, and 52
Safety Objectives
Safety Endpoints

To evaluate the safety and tolerability 
of daprodustat using darbepoetin alfa 
as control

Incidence and severity of adverse events (AEs) and 
serious adverse events (SAEs), including AEs 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
Design
Features

This is a Phase III, double-blind (double-dummy), active-controlled, parallel-group, 
multi-center study designed to evaluate the efficacy (non-inferiority) and safety of 
daprodustat, when administered for 52 weeks, compared to darbepoetin alfa in 
approximately 270 Japanese hemodialysis-dependent (HD) subjects with anemia 
associated with chronic kidney disease who are currently ESA users.

This study consists of a 2~4-week screening phase, a 52-week treatment phase 
[including the primary efficacy evaluation period (Weeks 40 to 52)], and a 2-week 
follow-up phase following the treatment phase.
Dosing
Daprodustat

HD subjects randomized to the daprodustat group will start oral treatment with 
daprodustat at the starting dose of 4 mg once daily (from Day 1) and remain on the 
same regimen until the day of Week 4. 

From Weeks 4 to 52, interruption of treatment or dose adjustments will be made within 
the maintenance dose range of 1 – 24 mg according to the dose adjustment algorithm 
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.

HD subjects randomized to the darbepoetin alfa group will receive oral daprodustat 
matching placebo in the same manner.
Darbepoetin alfa

HD subjects randomized to the darbepoetin alfa group will start intravenous treatment 
with darbepoetin alfa at the starting dose according to the dose convention which 
replaces prior ESA with darbepoetin alfa at the corresponding dose once weekly (from 
Day 1) as described in the protocol.

From Week 2 to 52, dose interruptions or adjustments will be performed within the 
maintenance dose range of 10 – 60 g according to the dose adjustment algorithm so 
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Overview of Study Design and Key Features
that the HemoCue value measured every other week will achieve or remain within the 
target range (10.0 – 12.0 g/dL). Dose adjustments will be made once every 2 weeks.

HD subjects randomized to the daprodustat group will receive intravenous 
darbepoetin alfa matching placebo in the same manner.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

The randomization schedule will be generated by GlaxoSmithKline (GSK) using the 
randomization system (Randall NG). 

Subjects will be randomized centrally in a 1:1 ratio to one of the two groups, 
daprodustat group or darbepoetin alfa group, according to the randomization 
schedule.
Interim 
Analysis

No interim analysis is planned.
2.4.
Statistical Hypotheses / Statistical Analyses
The primary objective of the study is to demonstrate the non-inferiority of daprodustat to 
darbepoetin alfa based on mean Hgb during the primary efficacy evaluation period 
(Weeks 40 to 52) in HD subjects.
As a preliminary assessment, it will be confirmed whether the mean Hgb during the 
primary efficacy evaluation period in daprodustat group would be in target range (10.0-
12.0 g/dL) at first. And then the following non-inferiority statistical hypotheses are to be 
tested at a one-sided significance level of 2.5%:
•
H0: Treatment difference in mean Hgb during the primary efficacy evaluation 
period, between treatment arms (daprodustat – darbepoetin alfa), is -1.0 g/dL or less.
•
H1: Treatment difference in mean Hgb during the primary efficacy evaluation 
period, between treatment arms (daprodustat – darbepoetin alfa), is greater than -
1.0 g/dL.
Only when the primary endpoint achieves non-inferiority, statistical testing will progress 
to the principal secondary endpoint with a focus on superiority according to the step-
down procedure. More specifically, the superiority of daprodustat to darbepoetin alfa in 
terms of target Hgb control in HD subjects is to be demonstrated at a one-sided 
significance level of 2.5% by testing the following statistical hypotheses:
•
H0: The proportion of subjects whose mean Hgb during the primary efficacy 
evaluation period is within the target range (10.0-12.0 g/dL) is equal between the 
treatment groups.
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•
H1: The proportion of subjects whose mean Hgb during the primary efficacy 
evaluation period is within the target range (10.0-12.0 g/dL) is different between the 
treatment groups.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis is planned.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
The study has completed with the last subject’s last study visit.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
Container number lists have been distributed by a CD-ROM from the external 
vendor (who is the owner for creating the original container number lists) just after 
unblinding.
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Screening 

Consists of all subjects who are given subject number and 
are collected data at screening

Study Population
Enrolled

Consists of subjects in 'All Screening' except for screen 
failures (who never passed screening even if rescreened)

Study Population 
(some displays for 
EudraCT)
Randomized 

Consists of all subjects who are given randomization 
number regardless of whether they actually receive study 
treatment

Study Population
Safety

Consists of all subjects who receive at least one dose of 
study treatment. 

Subjects will be analyzed according to the treatment 
received [1]

This population will be used for safety analyses.

Study Population

Safety
Intent-To-
Treat (ITT)

Consists of all Randomized subjects who have a baseline 
and at least one post baseline schedule Hgb assessment 
[2]

Subjects will be analyzed according to randomized 
treatment. 

This population will be the primary population for an 
assessment of non-inferiority.

Study Population

Efficacy
modified ITT 
(mITT)

Consists of all ITT subjects who have at least one Hgb 
measurement during the evaluation period. 

Subjects will be analyzed according to randomized 
treatment. 

This population will be the primary population for an 
assessment of superiority.

Study Population

Efficacy
Per-Protocol 
(PP)

Consists of all mITT subjects who are not major protocol 
violators.

This population will be used for efficacy sensitivity analyses.

Protocol deviations that would exclude subjects from the PP 
population are defined in Section 4.1 (Protocol Deviations) 
and Appendix 1: Protocol Deviation Management and 
Definitions for Per Protocol Population).

Efficacy
Pharmacokine
tic (PK)

Consists of all daprodustat -treated subjects from whom PK 
samples are collected and analyzed.

PK
NOTES:
•
Basically, enrolled population will be the same as randomized population because a subject is going to be given 
randomized number as soon as passed screening.
•
Refer to Appendix 10: List of Data Displays which details the population used for each display
[1]: Only subjects receiving incorrect randomized treatment for the duration of their study participation will be analyzed 
according to the treatment received. Otherwise, subjects will be analyzed according to the treatment to which they 
were randomized. Refer to Appendix 10: List of Data Displays which details the population used for each display.
[2] See Appendix 3 for the Hgb assessment to be used for analyses 
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Figure 1
Analysis Populations
NOTES: 
[1]: Subjects who never passed screening even if rescreened
[2]: Subjects who are not given randomization number
[3]: Subjects who never receive study treatment
[4]: Subjects who do not have Hgb measurement at both baseline and at least one scheduled visits following the 
baseline
[5]: Subjects who have no Hgb measurement during the efficacy evaluation period
[6]: Subjects who are major protocol violators (See Section 4.1 and Appendix 1)
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study the 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarized and listed.
Important deviations which resulted in exclusion from the analysis population will also 
be summarized and listed (Please refer to Appendix 1: Protocol Deviation Management 
and Definitions for Per Protocol Population).
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan (PDMP).
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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.
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.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
D1
Daprodustat
Daprodustat
1
D2
Darbepoetin alfa
Darbepoetin alfa
2
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
Daprodustat vs Darbepoetin Alfa
5.2.
Baseline Definitions
The baseline Hgb value will be the value from the Day 1 visit. If missing at Day 1 visit, 
the baseline will be set to missing.
For all other endpoints, the baseline value will be the latest pre-dose assessment with a 
non-missing value. This is generally expected to be the pre-dose value from the Day 1 
visit, except for ECG. For ECG, screening assessment will be used as a baseline. The 
baseline value of vital signs at pre- and post-dialysis will be defined separately. If 
missing at Day 1 visit, screening assessment or other pre-dose assessment may be used as 
baseline. If baseline data is missing (i.e. Day 1, screening, and pre-dose assessment is all 
missing), no derivation will be performed and baseline will be set to missing.
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
Change from Baseline
For 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
1.
Log-transform the data at both the baseline and the specified 
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Definition
Reporting Details
For TSAT, Hepcidin, and 
Lipid Parameters
timepoint
2.
Calculate a change from baseline using the log-transformed 
data for each subject
3.
Calculate the mean, and 95% CI and standard error (SE) of the 
log-transformed data
4.
Exponentially back-transform to the original scale 
5.
Subtract 1, then multiply everything by 100%
So, geometric mean for percent change from baseline 
= {exp(Mean [ln(Post-Dose Visit Value) – ln(Baseline)]) – 1 }x 100
Coefficient of variation will be calculated as
CV% = [exp(Var in loge scale)-1 ]1/2 x 100
where 'Var in loge scale' represents variance of percent change from 
baseline in loge scale.
5.3.
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 for analysis.
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
The list of covariates will be used in statistical analyses. Additional covariates and other 
strata of clinical interest may also be considered.
Category
Details
Strata
Not applicable
Covariates
For primary efficacy analyses:

Mixed model for repeated measurements (MMRM) including covariates of treatment
group, baseline Hgb, visit, treatment-by-visit interaction, and baseline Hgb-by-visit 
interaction will be used.
For principal secondary efficacy analyses:

Logistic regression model including treatment group and baseline Hgb as covariates 
will be used.
5.4.2.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and statistical analyses.
Additional subgroups of clinical interest may also be considered.
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Subgroup
Categories 
Age (year)
< 65, >=65
Sex
Female, Male
Prior ESA dose (IU/week) [1][2]
<4,500, >=4,500 and <6,000, >=6,000
Prior ESA type
Epoetin, Epoetin beta pegol, Darbepoetin alfa
ERI (IU/kg/week/g/dL) [2][3]
By tertile
Period of Time on Dialysis (year)
< 5, >= 5 and < 10, >= 10
Baseline Iron Use [4]
Yes, No
Baseline Weight (kg) 
< 55, >=55
Baseline BMI (kg/m2)
<20, >=20 
History of Diabetes [5]
Yes, No
NOTES:

BMI = Body Mass Index

See Section 15.6.1 for the subgroup derivations
[1] Standardized dose on epoetin IV (IU/week) will be used.
[2] Additional thresholds might be added in order to divide the population equally as appropriate.
[3] See Section 15.6.2 for definition
[4] Subjects who used ferric citrate (trade name: Riona) will also be included in Baseline Iron Use group. This 
category will be used only for iron analyses. See Section 15.6.6.
[5] Past or current history of diabetes
5.5.
Multiple Comparisons and Multiplicity
Adjustment for multiplicity will be applied to maintain an overall type I error rate of 
2.5% (one-sided). After a preliminary assessment, the primary endpoint will be evaluated 
to demonstrate the non-inferiority at a one-sided significance level of 2.5%. Only when 
the primary endpoint achieves non-inferiority, statistical testing will progress to the 
principal secondary endpoint with a focus on superiority. Since the process will follow 
step-down manner, a multiplicity adjustment for one-sided significance level of 2.5% will 
not be needed according to a closed test procedure.
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
15.3
Appendix 3: Assessment Windows
15.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
15.5
Appendix 5: Data Display Standards & Handling Conventions
15.6
Appendix 6: Derived and Transformed Data
15.7
Appendix 7: Reporting Standards for Missing Data
15.8
Appendix 8: Values of Potential Clinical Importance
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the specified population.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, population analyzed, demographic and baseline characteristics, prior and 
concomitant medications, and exposure and treatment compliance will be based on GSK 
Core Data Standards. Analyses of dialysis will also be included. Details of the planned 
displays are presented in Appendix 10: List of Data Displays.
Endpoint / Parameter / Display Type
Population
Data Displays Generated
Table
Figure
Listing
Subject’s Disposition
Subject Status and Reason for Study Withdrawal
Randomized
Y
Reasons for Study Withdrawal
Randomized
Y
Treatment Status and Reasons for Discontinuation of 
Study Treatment
Safety
Y
Y
Screening Status and Reasons for Screen Failure
All Screening
Y
Y
Subjects Enrolled by Country and Site ID
Enrolled
Y
Subjects for Whom the Treatment Blind was Broken
Randomized
Y
Planned and Actual Treatments
Safety
Y
Protocol Deviations
Important Protocol Deviations
Randomized
Y
Y
Subjects with Inclusion/Exclusion Criteria Deviations
Randomized
Y
Y
Populations Analyzed
Study Populations
Randomized
Y
Exclusion from the Per Protocol Population
mITT
Y
Y
Subjects Excluded from Any Population
Randomized
Y
Demographic and Baseline Characteristics
Demographic Characteristics
ITT/Safety
Y
Y
Other Baseline Characteristics [1]
Safety
Y
Prior ESA
ITT/Safety
Y
Y
Age Ranges
Enrolled
Y
Race and Racial Combinations
Safety
Y
Y [2]
Family History for CV Risk Factors
Safety
Y
Y
Substance Use (History of Tobacco Use, Alcohol 
Intake)
Safety
Y
Y
Dialysis
Baseline Mode of Dialysis
Safety
Y
Y
Subjects with Change in Hemodialysis
Safety
Y
Baseline Mode of Vascular Access
Safety
Y
Y
Subjects with Vascular Therapeutic Procedures during 
the study period
Safety
Y
Subjects with Vascular Access Intervention / Revision
Safety
Y
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Endpoint / Parameter / Display Type
Population
Data Displays Generated
Table
Figure
Listing
Medical Conditions and Concomitant Medications
Current/Past Medical Conditions
Safety
Y
Y
Concomitant Medications [3]
Safety
Y
Y
Other Concomitant Medications (ESA, Iron, and Anti-
Hypertensive Medications)
Safety
Y [4]
Y
Blood Products and Blood Supportive Care Products
Safety
Y
Y
Exposure and Treatment Compliance
Exposure to Study Treatment
Safety
Y
Y
Treatment Compliance
Safety
Y
Y
NOTES :

Y = Yes display generated.
[1] As a separate listing, include prior ESA type, standardized prior ESA dose, ERI, period of time on dialysis, iron 
use, and diabetes.
[2] Listing of race.
[3] Concomitant medications in pre-therapy, on-therapy, and post-therapy period will be summarized separately.
[4] On-therapy ESA, on-therapy iron, and on-therapy anti-hypertensive medications will be provided.
6.2.
Planned Summary Display Details
Subjects who have multiple subject numbers (i.e. rescreened subjects) will be analyzed as 
unique subjects based on the latest screening results (see Section 15.6.1 and Section
15.6.2).
The definition of subgroup is described in Section 5.4.2.

Subject Disposition
Subject Status and Reason for Study Withdrawal
The number and percentage of subjects completing the study (see Appendix 7) or 
withdrawing early from the study will be summarized overall and by reason for 
withdrawal by treatment group and total. Reasons for withdrawal of subjects will be 
listed.
Treatment Status and Reasons for Discontinuation of Study Treatment
The number and percentage of subjects completing the treatment or discontinuing the 
treatment during the study will be summarized overall and by reason (and subreason) by 
treatment group and total.
Screening Status and Reasons for Screen Failure
The number and percentage of subjects who passed screening (i.e. enrolled) and who 
failed screening and were therefore not entered into the study will be summarized
regardless of treatment group. Note that the reasons for rescreen subjects who initially 
failed but subsequently enrolled are not included in the display (see Section 15.6.2).
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Subjects Enrolled by Country and Site ID
The number and percentage of subjects by Country, Site ID and Investigator name will be 
summarized by treatment group and total.

Protocol Deviations
Important Protocol Deviations
The number and percentage of subjects who had important protocol deviations defined in 
PDMP will be summarized by treatment group and total.
Subjects with Inclusion/Exclusion Criteria Deviations
The number and percentage of subjects, who were randomized into the trial, but deviated 
from the inclusion or exclusion criteria, will be summarized, further classifying 
inclusion/exclusion deviations by treatment group and total.

Population Analyzed
Study Populations
The number and percentage of subjects in each analysis population (defined in Section 4) 
will be summarized by treatment group and total.
Exclusion from Per Protocol Population
The number of the exclusions from the PP population and the exclusion categories (See 
Appendix 1) will be summarized by treatment group and total.

Demographic and Baseline Characteristics
Demographic Characteristics
The number and percentage of subjects or summary statistics will be provided by 
treatment group and total for the demographic and baseline characteristics: Sex, Age 
(years), Age Group (years), Ethnicity, Race detail, Height, Weight, and Body Mass Index. 
Age Group (years) will be categorized into 3 ('18', '19-64', '65'). Separate summaries 
for ITT and Safety population will be produced.
Prior ESA
For overall prior ESA, the weekly dose (standardized by IU/week), erythropoietin 
resistance index (ERI), and the number and percentage of subjects’ dosing route
(intravenous or subcutaneous) will be summarized by treatment group and total. These 
will be produced by type of prior ESA dose (epoetin, epoetin beta pegol, and darbepoetin 
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alfa). See Section 15.6.2 for standardized weekly dose and ERI. Separate summaries for
ITT and Safety population will be produced.
Age Ranges
The number and percentage of subjects within each age range category will be provided
by treatment group and total. Age range will be categorized into: 18-64 years, 65-84 
years, 85 years.
Race and Racial Combinations
Summaries of race and racial combinations will be provided by treatment group and total. 
Family History for CV Risk Factors
A summary of family (first degree relatives) history for CV risk factors will be provided
by treatment group and total.
Substance Use (History of Tobacco Use, Alcohol Intake)
A summary of substance use will be provided by treatment group and total.

Medical Conditions and Concomitant Medications
Current/Past Medical Conditions
The number and percentage of subjects with current and past medical conditions recorded 
in eCRF will be provided by treatment group and total.
Concomitant Medications
The number and percentage of subjects reporting the use of each concomitant medication 
will be summarized by treatment group and total by anatomical therapeutic chemical 
(ATC) Level 1, and Ingredient. Summaries for pre-therapy, on-therapy, and post-therapy
medication will be provided separately. See Section 15.4.1.2 for the study phases.
Other Concomitant Medications (On-Therapy ESA, Iron, and Anti-Hypertensive 
Medications)
The similar summary as above will be provided by treatment group and total focusing on 
on-therapy ESA, on-therapy iron medication, and on-therapy anti-hypertensive 
medications. See Section 15.4.1.2 for the study phases.
Blood Products and Blood Supportive Care Products (On-Therapy)
The number and percentage of subjects who use blood products and/or blood supportive 
care products will be provided by treatment group and total. The details for the use will 
also be summarized.
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
Dialysis
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 by treatment
group and total. The period of time on dialysis (years) will be summarized using mean, 
standard deviation, median, minimum, and maximum.
Baseline Mode of Vascular Access
The number and percentage of subjects with each baseline mode of vascular access will
be provided by treatment group and total. Previous vascular access will be summarized in 
the same manner.

Exposure and Treatment Compliance
Exposure to Study Treatment
Full details of exposure definition are presented in Section 15.6.2.
Time on study treatment (days), subject daily dose (for daprodustat) or weekly dose (for 
darbepoetin alfa), and cumulative dose will be summarized using the number of subjects 
exposed, mean, standard deviation, median, minimum, and maximum. Time on study 
treatment will be categorized in different time periods (< 3 months, 3 months to 6 months, 
>6 months to 12 months, >12 months; 1 month = 30.4375 days) and the number and 
percentage of subjects exposed will be displayed for each category.
Treatment Compliance
Full details of treatment compliance definition are presented in Section 15.6.2.
The number and percentage of subjects within each category will be summarized by 
treatment and total for up to Week 4, Week 40 to 52, and overall. The categories will be 
classified into under compliant, compliant, over compliant. Note that this is a double-
dummy study but a summary will be made for the active treatment and a listing will 
contain both active and placebo compliance.
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7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
Endpoint / Parameter/ 
Display Type
Populatio
n
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Mean Hgb Based on Observed Hgb During the Primary Efficacy Evaluation Period
(i.e. Individual Mean of Hgb at Week 40, 44, 48, and 52)
(Preliminary assessment)
Observed Case 
mITT population 
mITT
Y
Model based Mean Hgb During the Primary Efficacy Evaluation Period
(Primary)
MMRM
ITT
Y
Y
MMRM
mITT/PP
Y
Y
MMRM
By Subgroup
ITT
Y
Y[1]
MMRM
Evaluable Hgb
ITT
Y
Y
Analysis of Covariance 
(ANCOVA)
mITT/PP
Y
ANCOVA
By Subgroup
mITT
Y
Y[1]
Tipping Point Analysis
ITT/mITT/
PP
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Forest Plots
7.1.2.
Summary Measure
Mean Hgb based on observed Hgb during the primary efficacy evaluation period
The values will be summarized using mean, standard deviation, 95% CI, minimum, P25, 
median, P75, and maximum by treatment group.
Analysis of mean Hgb during the primary efficacy evaluation period
For ITT population, model-based mean Hgb will be estimated using a statistical model 
(Section 7.1.5). The point estimates of model-based mean Hgb for each treatment will be
presented with standard error and 95% CI. For non-inferiority assessment at a one-sided 
significance level of 2.5%, the estimate of treatment difference, its 95% CI, and a non-
inferiority p-value will be provided. Analysis will be repeated by the mITT and PP
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populations in the same manner. The subgroup analysis based on the ITT population will 
also be produced using tables and a forest plot. (See Section 7.1.5 for the detail)
Sensitivity/Supplementary analysis for mean Hgb during the primary efficacy evaluation 
period

Evaluable Hgb (Section 7.1.6.1 for the statistical analysis specifications)
Supplementary analysis using evaluable Hgb (See Section 15.6.3) based on the ITT 
population will be performed in the same manner as primary efficacy analysis using a 
mixed model for repeated measures.

ANCOVA (Section 7.1.6.2 for the statistical analysis specifications)
Supplementary analysis using ANCOVA based on the mITT population will be 
summarized in the same manner as the primary efficacy analysis with the use of a 
mixed model for repeated measures. Analysis will be repeated for the PP population.
The subgroup analysis based on the mITT population will also be produced using 
tables and a forest plot.

Tipping Point Analysis (Section 7.1.6.3 for the statistical analysis specifications)
Tipping point sensitivity analysis based on the ITT population will be summarized 
using combined treatment differences, the associated 95% CIs and non-inferiority p-
values by delta adjustments. Graphical display will be provided as a heatmap that 
represents non-inferiority p-values obtained from the test conducted for each delta 
adjustment. The horizontal and vertical axes indicate values of delta for daprodustat 
and darbepoetin alfa respectively. The color grids which highlight non-inferiority 
success or not will also be displayed.
7.1.3.
Population of Interest 
The primary efficacy analyses will be based on the ITT population, unless otherwise 
specified.
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Intercurrent events
Strategy
Study withdrawal
The following hypothetical scenario is considered;
what would have happened if the event did not occur. 
The primary analyses using MMRM assume missing 
at random mechanism, that is the observations of 
missing depend on just observed values, not on 
unobserved values. 
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Intercurrent events
Strategy
Prohibited medications 
(except for commercial ESA 
medications)
Basically, the occurrence of the event is taken to be 
irrelevant. Subjects with long-term use of prohibited 
medications will be excluded from the PP population.
Blood transfusion and/or
commercial ESA medication
In primary analyses, the occurrence of the event is 
taken to be irrelevant. 
Intermittent missing
The following hypothetical scenario is considered to 
assess what would have happened if the event did not 
occur. The hypothesis is that an intermittent missing 
would occur at at-random manner, that is the 
observations of the missing depend on just observed 
values, not on unobserved values.
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints/variables defined in Section 7.1.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and
listed.
As a preliminary assessment, it will be confirmed whether the mean Hgb during the 
primary efficacy evaluation period in the daprodustat group would be in the target range 
(10.0-12.0 g/dL) at first. This confirmation will be established if the lower and upper 
limit of 95% CI for the mean Hgb based on observed Hgb during the primary efficacy 
evaluation period in daprodustat group would lie fully within the target range. After the 
stated confirmation, non-inferiority will be assessed at a one-sided significance level of 
2.5%.
7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Mean Hgb during the primary efficacy evaluation period (Week 40 to 52)
Model Specification

Analyses will be conducted by MMRM as follows:
Hgbik = β0 + βbaseline *Baselinei + βj + βk + βjk + βbaseline*j * Baselinei + εik
    Hgbi, week: Hgb measurement for subject i at visit k
    β0: Intercept
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   βbaseline: baseline Hgb effect
    Baselinei: Hgb measurement for subject i 
    βj: treatment effect (j= daprodustat, darbepoetin alfa)
    βk: visit effect (k = Week 4, Week 8, …, Week 52)
    βjk: treatment-by-visit interaction
    βbaseline*j: baseline-by-visit interaction
    εik: random error for subject i at visit k
    i: subject (i = 1, 2, …, N)
   N: number of subjects included in the analysis

The model parameters will be estimated using Restricted Maximum Likelihood 
(method=REML) with the Newton-Raphson algorithm. 

The Kenward-Roger method for calculating the denominator degrees of freedom will be used.

The variance-covariance structures for repeated measures within the individual subject will be 
unstructured (type=UN). 

LS means for treatment j at visit k will be calculated as follows.
jk = β0 + βbaseline * μbaseline + βj+ βk + βjk + βbaseline*k * μbaseline
    jk: LS mean for treatment j at visit k
    baseline: mean for baseline Hgb

Model based mean Hgb during the primary efficacy evaluation period for treatment j will be 
calculated as follows
j*evaluation = (μj*Week 40 + μj*Week 44 + μj*Week 48 + μj*Week 52)/4
= β0 + βbaseline * μbaseline + βj+ (βWeek 40 + βWeek 44 + βWeek 48 + βWeek 52)/4 + (βj*Week 40 + βj*Week 44 + 
βj*Week 48 + βj*Week 52)/4 + (βbaseline*Week 40 + βbaseline*Week 44 + βbaseline*Week 48 + βbaseline*Week 52) *
μbaseline/4

The treatment difference for model based mean Hgb during the primary efficacy evaluation 
period will be calculated as follows
daprodustat*evaluation - darbepoetin alfa*evaluation = βdaprodustat - βdarbepoetin alfa + (βdaprodustat*Week 40 + 
βdaprodustat*Week 44 + βdaprodustat*Week 48 + βdaprodustat*Week 52)/4 - (βdarbepoetin alfa*Week 40 + βdarbepoetin alfa 
*Week 44 + βdarbepoetin alfa *Week 48 + βdarbepoetin alfa *Week 52)/4

P-value for non-inferiority test will be based on the following t test statistic (Mascha, 2011):
t = (daprodustat*evaluation - darbepoetin alfa*evaluation - )/s
: non-inferiority margin (= -1.0 g/dL)
s: standard error of treatment difference
The non-inferiority p-value is the probability of observing a larger value of t in a t distribution 
with degrees of freedom of the estimate of treatment difference based on the Kenward-Roger 
method.
Model Checking & Diagnostics

In case there is a problem with convergence of the unstructured (type=UN) variance-
covariance, the following strategy will be examined.
1.
Use Fisher’s scoring algorithm for the estimation method.
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2.
Set Heterogeneous Toeplitz (type=TOEPH) structure for variance-covariance 
structure.
3.
In the event of that this model still fails to converge, alternative correlation structures 
may be considered such as type=CSH or CS.
Model Results Presentation

The point estimates of LS mean Hgb during the primary efficacy evaluation period for each 
treatment will be presented with the associated standard errors and 95% CIs. For non-
inferiority assessment at a one-sided significance level of 2.5%, the estimate of the treatment 
difference, standard error, its 95% CI, and a non-inferiority p-value will be provided.

Non-inferiority will be established if the lower limit of the 95% CI for the treatment difference 
(daprodustat - darbepoetin alfa) of the mean Hgb during the primary efficacy evaluation period 
is greater than -1.0 g/dL (i.e., a p-value is smaller than 0.025).
Subgroup Analyses

Treatment differences (daprodustat - darbepoetin alfa) of the mean Hgb during the primary 
efficacy evaluation period, standard errors, and the associated 95% CIs will be provided by 
each subgroup (See Section 5.4.2).

The subgroup analyses will be based on the ITT population.

The same statistical analysis method (using MMRM described as above) will be applied to 
estimate the mean Hgb during the primary efficacy evaluation period for each subgroup. If 
there is a problem with convergence for a certain subgroup, the result of the subgroup will not 
be displayed.

Graphical summaries for the treatment differences of the mean Hgb during the primary efficacy 
evaluation period and the associated 95% CIs will be produced using a forest plot.
7.1.6.
Sensitivity and Supportive Analyses
To assess the robustness of the primary efficacy results, the primary efficacy analyses 
will be repeated using following sensitivity and supplementary approaches:

mITT/PP Population; the primary efficacy analyses will be repeated for the mITT 
and PP populations as the supplementary analysis.

Evaluable Hgb; if there are Hgb considered to be impacted by blood transfusion or 
marketed rhEPO/ESAs, supplementary analysis excluding the Hgb values from the 
analyses of primary endpoint will be conducted.

Analysis of covariance (ANCOVA); it will be conducted as supplementary analysis 
to MMRM. This model includes treatment group and baseline Hgb. The analysis 
population will be the mITT population and the analysis will be repeated in the PP 
population.

Tipping point analysis; based on multiple imputation it will be conducted as 
sensitivity and supplementary analysis to missing data assumption. This analysis 
explores points where non-inferiority is not confirmed (tipping points) by changing 
assumption to missing data and repeating imputations. The analysis population will 
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be the ITT population and the analysis will be repeated in the mITT and PP 
populations.
7.1.6.1.
Evaluable Hgb
The analyses will be based on the ITT population, unless otherwise specified. In a 
strategy for intercurrent event of blood transfusion and commercial ESA medication, the 
following hypothetical scenario is considered to assess what would have happened if the 
event did not occur. Non-evaluable Hgb (described in 15.6.3), which is caused by this 
event, will be treated as missing, and will be analyzed based on missing at random 
assumption (the observations of missing depend on just observed values, not on 
unobserved values).
Model Specification

Evaluable Hgb defined in Section 15.6.3 will be used for the analysis. Non-evaluable Hgb will 
be treated as missing.

Analyses will be conducted by MMRM. See Section 7.1.5.1 for the detail.
Model Results Presentation

The point estimates of adjusted mean Hgb during the primary efficacy evaluation period for 
each treatment will be presented with the associated standard errors and 95% CIs. The 
treatment difference, standard error, its 95% CI, and the non-inferiority p-value (described in 
Section 7.1.5.1, Model Specification) will also be presented.
7.1.6.2.
Analysis of Covariance (ANCOVA)
The analyses will be based on the mITT and PP populations, unless otherwise specified.
In a strategy for intercurrent event of study withdrawal, a subject who has the event 
before Week 40 will not be included in analyses. If a subject has the event on or after 
Week 40, the event is taken to be irrelevant to the mean Hgb during primary efficacy 
evaluation period (i.e., observed values will be used for the analysis).
Model Specification

A subject must have at least one Hgb measurement during the primary efficacy evaluation 
period (Week 40 to Week 52) to be included in this analysis.

Analyses will be conducted by an ANCOVA model as follows:
mean(Hgbi) = β0 + βbaseline *Baselinei + βj + ε
    mean(Hgbi) = (Hgbi,Week 40 + Hgbi,Week 44 + Hgbi,Week 48 + Hgbi,Week 52)/4:
    mean Hgb during the primary efficacy evaluation period for subject i
    β0: Intercept
    βbaseline: baseline Hgb effect
    Baselinei: Hgb measurement for subject i 
    βj: treatment effect (j= daprodustat, darbepoetin alfa)
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   ε: random error
    i: subject (i = 1, 2, …, N)
    N: number of subjects included in the analysis

LS means for treatment j will be calculated as follows:
j = β0 + βbaseline * μbaseline + βj
    j: LS mean for treatment j
    baseline: mean for baseline Hgb

The treatment difference for mean Hgb during the primary efficacy evaluation period will be 
calculated as follows:
daprodustat - darbepoetin alfa = βdaprodustat – βdarbepoetin alfa

P-value for non-inferiority test will be based on the following t test statistic (Mascha, 2011):
t = (daprodustat - darbepoetin alfa - )/s
   : non-inferiority margin (= -1.0 g/dL)
   s: standard error of treatment difference
The non-inferiority p-value is the probability of observing a larger value of t in a t distribution 
with degrees of freedom of residual 
Model Checking & Diagnostics

Not applicable
Model Results Presentation

The point estimates of adjusted mean Hgb for each treatment will be presented with the 
associated standard errors and 95% CIs. The treatment difference, standard error, its 95% CI, 
and a non-inferiority p-value (described in Section 7.1.5.1, Model Specification) will also be 
presented.
Subgroup Analyses

The subgroup analyses will be based on the modified ITT population.

The same statistical analysis method (using ANCOVA described as above) will be applied to 
estimate the mean Hgb during the primary efficacy evaluation period for each subgroup.

Graphical summaries for the treatment differences of the mean Hgb during the primary efficacy 
evaluation period and the associated 95% CIs will be produced using a forest plot.
7.1.6.3.
Tipping Point Analysis
The analyses will be based on the ITT population, unless otherwise specified.
Tipping point sensitivity analyses will be conducted under a range of missing data 
assumptions to determine how extreme assumptions need to be for non-inferiority 
conclusions to change. Assumptions about missing Hgb values on the daprodustat and 
darbepoetin alfa arm will vary independently, and will include scenarios where subjects 
with missing data on daprodustat have worse outcomes than subjects with missing data 
on darbepoetin alfa. If the tipping point scenario is clinically plausible, the conclusion 
under missing at random may be questionable.
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In a strategy for intercurrent event of study withdrawal, a hypothetical scenario is 
considered to assess what would have happened if the event did not occur. For this 
hypothesis, the missing data due to this event would occur at not-at-random manner, that 
is the observations of missing depend on unobserved values, which will be mimicked 
with delta-adjustment analysis in this study.
Model Specification

A tipping point is the critical point that reverses the study conclusion (i.e., non-inferiority test). 

Tipping point analysis for this study takes following steps:
1.
multiple imputation
2.
delta adjustment
3.
analyses for each imputed complete dataset.
4.
making combined results
As a reference, programming codes for tipping point analysis are described by Yang, 2014 as 
%midata macro in the appendix.
1.
Multiple Imputation Strategy

Imputations will be conducted by a multiple imputation method using the SAS PROC MI 
procedure.

The number of imputations will be set to 200.

The seed for reproducibility is set to 201754.

Initially, to obtain a monotone missing dataset from a non-monotone missing dataset, the 
imputation for intermittent missing values will be done using MCMC by treatment.

After obtaining the dataset with only the monotone missing patterns, imputation based on MAR 
assumption can be performed by treatment in a sequential manner. Assume that repeated 
measures variables Y1,…, Yn are included in the imputation model (linear regression model 
with a covariate of baseline Hgb). The Y1 is imputed first based on the covariate, then Y2 would
be imputed using the covariate and Y1, and so on for each variable until Yn is imputed using 
the covariate and Y1,…,Yn-1.
2.
Delta () Adjustment Strategy

Based on MAR assumption (=0), monotone missing data that occured before Week 52 will be 
imputed as shown above. To mimic missing not at random manner, sequentially increasing 
will be added to imputed values where represents a change in Hgb over 4-week interval. No 
adjustments will be done for intermittent missing values.

Sequentially increasing adjustment is to add n*value on the imputed value of nth 
monotone missing data. The longer the period of time with monotone missing, the larger 
value will be added. Suppose a subject who has withdrawn at Week 40 visit, in other 
words, this subject has monotone missing data from Week 44 to Week 52. Imputations are 
conducted on missing data of Week 44, 48, and 52 and then is added to an imputed 
value on Week 44, 2on Week 48, and 3on Week 52.

Initially, the values will be explored for both arms and will range from -4.0 to 4.0 g/dL with a 
1.0 g/dL increment. Once the “rough” tipping point is found with the large increment 
(=1.0 g/dL), the exploration will be done with smaller increments to find the more precise
tipping points. Low and high cutoffs at Hgb values of 7.0 g/dL and 14.0 g/dL will be utilized on 
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delta-adjusted imputed values. To reduce computationally intensive iterations, the further 
worsening scenarios beyond a range from -4.0 to 4.0 g/dL will not be examined. 
3.
Analysis Strategy for Each Imputed Complete Dataset

The analysis using a MMRM (described in Section 7.1.5.1) will be applied and will be repeated 
for each imputed complete dataset. The calculation of the denominator degrees of freedom 
may be simplified (e.g., between-within degrees of freedom) for the imputed complete dataset. 
The mean differences between the mean Hgb during the primary efficacy evaluation will be 
estimated for each imputed complete dataset.
4.
Combine results of m datasets

For each pair of deltas (one independently assigned delta for each treatment arm), Rubin’s 
rules (Rubin, 1987) will be used to combine results of all imputed datasets using SAS PROC 
MIANALYZE procedure. As a result, for each pair of delta values, a single estimated treatment 
difference and its standard error will be produced, with which a one-sided non-inferiority p-
value can be calculated using non-adjusted degree of freedom. 
Model Checking & Diagnostics

For the model checking & diagnostics of MMRM analyses, see the Section 7.1.5.1
Model Results Presentation

Graphics depicting treatment difference and non-inferiority p-value surfaces will be produced 
using an enhanced tipping point approach (Liublinska, 2014); A colored heat map that 
illustrates the gradual change of non-inferiority p-values will be produced.

In a display, colored grids highlight delta combinations that result in rejecting the null 
hypothesis (i.e., non-inferiority established).
Sensitivity and Supplementary Analyses

The analysis will be repeated for the mITT and PP populations.
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7.2.
Principal Secondary Efficacy Analyses
7.2.1.
Endpoint / Variables
[Endpoint / 
Parameter/ Display 
Type]
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Number (%) of Subjects with Mean Hgb in Target Range During the Primary Efficacy Evaluation 
Period
(Principal Secondary)
Logistic Regression
mITT Population
Y
Logistic Regression
ITT Population
Y
Logistic Regression
PP Population
Y
Logistic Regression
mITT Population
By Subgroup
Y
Y[1]
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Forest plots
7.2.2.
Summary Measure
Number (%) of subjects with mean Hgb in target range during the primary efficacy 
evaluation period
The number and percentage of responders, who are subjects with observed mean Hgb 
within the target range during the primary efficacy evaluation period, will be 
summarized. Odds ratio will be estimated by using a logistic regression and provided 
along with its 95% CI and a superiority one-sided p-value. Analysis will be repeated for 
the ITT and PP populations in the same manner. The subgroup analysis based on the 
mITT population will also be produced using tables and a forest plot.
7.2.3.
Population of Interest
The principal secondary efficacy analyses will be based on the mITT population, unless 
otherwise specified.
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events
Intercurrent events
Strategy
Study withdrawal
The occurrence of the event is taken to be a 
component of response to treatment. If a subject has 
no available Hgb data during Week 40 to 52 due to 
early withdrawal, the subject is deemed as a non-
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Intercurrent events
Strategy
responder. If a subject has at least one available Hgb 
data during Week 40 to 52, a response to treatment 
will be defined by whether the mean Hgb during Week 
40 to 52 using observed Hgb values within target 
range.
Prohibited medications 
(except for commercial ESA 
medications)
Basically, the occurrence of the event is taken to be 
irrelevant. Subjects with long-term use of prohibited 
medications will be excluded from the PP population.
Blood transfusion and/or
commercial ESA medication
The occurrence of the event is taken to be irrelevant.
Intermittent missing
The occurrence of the event is taken to be irrelevant.
7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.3.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.2.5.1.
Statistical Methodology Specification
Endpoint / Variables

Number (%) of subjects with mean Hgb in the target range (10.0-12.0 g/dL) during the primary 
efficacy evaluation period (Week 40 to 52)
Model Specification

The percentage of subjects with observed mean Hgb during the primary efficacy evaluation 
period within the target range will be derived from the average of observed Hgb values during 
the primary efficacy evaluation period for individuals. 

Analyses will be conducted by a logistic regression model as follows:
logit() = β0 + βbaseline *Baselinei + βj + ε
    i: treatment success (mean(Hgbi) is within the target range or not)
    β0: Intercept
    βbaseline: baseline Hgb effect
    Baselinei: Hgb measurement for subject i 
    βj: treatment effect (j= daprodustat, darbepoetin alfa)
    ε: random error 
    i: subject (i = 1, 2, …, N)
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   N: number of subjects included in the analysis

The mean Hgb during the primary efficacy evaluation period will be calculated for each
individual and confirmed if the values are in the target range or not. Therefore, subjects who 
have at least one Hgb measurement during the evaluation period will be included in this 
analysis. A subject who has missing data of the mean Hgb during the primary evaluation 
period due to intercurrent events will be regarded as a non-responder.

The odds ratio (daprodustat/darbepoetin alfa) will be obtained as follows:
OR = exp(βdaprodustat – βdarbepoetin alfa)
The odds ratio, the Wald-type 95% CI and a superiority one-sided p-value based on a z-score 
will be provided together.
Model Checking & Diagnostics

If the logistic regression cannot be applicable due to all responders or all non-responders, the 
odds ratio and the associated statistics will not be provided.
Model Results Presentation

The superiority assessment will be performed only if the primary endpoint achieved non-
inferiority.

The number and percentage of subjects with observed mean Hgb during the primary efficacy 
evaluation period within the target range (10.0-12.0 g/dL) will be presented by treatment group. 
If available, the odds ratio (daprodustat/darbepoetin alfa), the associate 95% CI, and a 
superiority one-sided p-value will also be provided, otherwise ‘NC’(not calculated) will be 
provided for odds ratios and the associated statistics.

Superiority will be established if the lower limit of the 95% CI for the odds ratio is greater than 
1.0 (i.e., a p-value is smaller than 0.025).
Subgroup Analyses

The subgroup analyses will be based on the mITT population by each subgroup (See
Section 5.4.2).

The statistical analysis method uses the same logistic model, unless the logistic model is not 
applicable due to all responders or all non-responders.

Graphical summaries for odds ratios and the associated 95% CIs will be produced using a 
forest plot. If the logistic model is not applicable, ‘NC’(not calculated) label will be provided.
Sensitivity and Supplementary Analyses

The mITT Population will be used for this logistic analysis, and the supplementary analysis 
using same logistic model will be repeated in the ITT and PP Population to evaluate the 
robustness of the conclusion. In the ITT population, subjects who have no available Hgb after
Week 40 will be considered as non-responder.

The logistic regression will be performed by a set of pre-specified subgroups (Section 5.4.2). 
These subgroup analyses are considered exploratory to assess for consistency with the overall 
results.
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7.3.
Secondary Efficacy Analyses
7.3.1.
Endpoint / Variables
[Endpoint / Parameter/ Display Type]
Absolute
Stats Analysis
Summary
Individual
T
F
T
F
F
L
Hgb
Hgb (g/dL) at each assessment visit
Y
Y
Y
Hgb (g/dL) at each assessment visit
by prior ESA type, prior ESA dose, and ERI
Y
Change from baseline in Hgb (g/dL) at each 
assessment visit 
Y
Y
Change from baseline in Hgb (g/dL) at each 
assessment visit 
by prior ESA type, prior ESA dose, and ERI
Y
Number (%) of subjects by Hgb change from baseline 
category at Week 4 [1] [2]
Y
Number (%) of subjects by Hgb change from baseline 
category at Week 4 [1] [2]
by prior ESA type, prior ESA dose, and ERI
Y
Number (%) of subjects with Hgb level within the target 
range at each assessment visit [3]
Y
Y
Time (%) in Hgb target range during the primary 
efficacy evaluation period [4]
Y
Y
Number (%) of subjects who have an Hgb level of less 
than 7.5 g/dL [5]
Y
Y
Number (%) of subjects who have an Hgb increase of 
more than 2.0 g/dL over any 4 weeks
Y
Y
Number (%) of subjects who have an Hgb level of more 
than 13.0 g/dL and number of episodes [5] 
Y
Y
Hemocue Hgb
Y
Scatter Plot of Hgb Assessments: Central Laboratory 
vs. HemoCue
Y
Dose adjustment [6]
Dose (mg or g) at each assessment visit / final visit
Y
Y
Dose (mg or g) at each assessment visit / final visit
by prior ESA type, prior ESA dose, and ERI
Y
Number (%) of subjects with each dose at each 
assessment visit
Y
Y
Number (%) of subjects with each dose at each 
assessment visit
by prior ESA type, prior ESA dose, and ERI
Y
Y
Duration (days) of treatment interruption due to Hgb 
>13.0 g/dL [1] [5]
Y
Y
Dose adjustment [1]
Y
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[Endpoint / Parameter/ Display Type]
Absolute
Stats Analysis
Summary
Individual
T
F
T
F
F
L
Subject Profiles
Hgb and Dose over Time
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] A summary will be produced for only daprodustat group 
[2] <=-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
[3] Not only within the target range, but also with above and below target range will be assessed.
[4] Rosendaal method will be used (See Section 15.6.3).
[5] On-therapy Hgb values observed at scheduled visits will be included in a summary. On-therapy Hgb values 
observed at unscheduled visits will be included if specified (See Section 7.3.2).
[6] Summaries for dose adjustment will based on HemoCue Hgb values including those of unscheduled visits.
7.3.2.
Summary Measure
Hgb at each assessment visit
The values will be summarized using mean, standard deviation, 95% CI, minimum, P25, 
median, P75, and maximum at each assessment visit by treatment group. Graphical 
summaries will be provided using mean and 95% CI over time. This will also be 
summarized by prior ESA type, prior ESA dose, and ERI subgroup.
Change from baseline at each assessment visit
The values will be summarized using mean, standard deviation, 95% CI, minimum, P25, 
median, P75, and maximum at each assessment visit by treatment group. Graphical 
summaries will be provided using mean and 95% CI over time. This will also be 
summarized by prior ESA type, prior ESA dose, and ERI subgroup.
Number (%) of subjects by Hgb change from baseline category at Week 4 - daprodustat
The number and percentage of subjects within each category will be provided only for 
daprodustat group and the categories will be classified into 6 (i.e., -2, >-2 to -1, >-1 to 0, 
>0 to 1, >1 to 2, >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. This will also be summarized by prior ESA 
type, prior ESA dose, and ERI subgroup.
Number (%) of subjects with Hgb within the target range at each assessment visit
The number and percentage of subjects with Hgb within, above and below the target 
range will be summarized at each assessment visit by treatment group. Graphical 
summaries over time will also be produced.
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Time (%) in the Hgb target range during the primary efficacy evaluation period
The time (weeks and percentage) within/above/below the target range will be
summarized by treatment group using mean, standard deviation, minimum, P25, median, 
P75, and maximum. Treatment differences (daprodustat – darbepoetin alfa) and the 
associated 95% CIs for the time (weeks and percentage) within the target range will also 
be provided. See Section 15.6.3 for details.
Number (%) of subjects who have an Hgb level of less than 7.5 g/dL
The number and percentage of subjects who have an Hgb level of less than 7.5 g/dL 
during the treatment period will be summarized by treatment group. On-therapy Hgb 
values observed in both scheduled and unscheduled visits will be included in the 
summary.
Number (%) of subjects who have an Hgb increase of more than 2.0 g/dL over any 4 
weeks
The number and percentage of subjects who have an Hgb increase of more than 2.0 g/dL 
over any 4 weeks during the treatment period will be summarized by treatment group. 
The odds ratio (daprodustat/darbepoetin alfa) will also be provided with its 95% CI. On-
therapy Hgb values will be used for the summary. See Section 15.6.3 for details.
Number (%) of subjects who have an Hgb level of more than 13.0 g/dL and number of 
episodes
The number and percentage of subjects who have an Hgb level of more than 13.0 g/dL
during the treatment period and number of episodes will be summarized by treatment 
group. On-therapy Hgb values observed in both scheduled and unscheduled visits will be 
included in the summary.
Scatter plot of Hgb assessments: Central Laboratory vs. HemoCue
A scatter plot of Hgb values measured by Central Laboratory versus Hgb values 
measured by Hemocue will be produced along with Pearson’s correlation coefficient. 
Regardless of visit and treatment group, all available pairs of Hgb (i.e. non-missing 
values in both from central laboratory and from the corresponding HemoCue 
measurement) will be used.

Dose adjustment
The dose adjustment algorithm is described in Section 15.6.3, based on HemoCue Hgb 
values.
Dose at each assessment visit/ final visit
Dose at each assessment visit and final visit will be summarized using mean, standard 
deviation, minimum, P25, median, P75, mode, and maximum at each assessment visit by 
treatment. The final visit will be the last visit of treatment exposure for each subject.
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Mean dose during Week 40 to 52 will also be summarized and includes subjects who has 
at least one exposure record during Week 40 to 52. This will also be summarized by prior 
ESA type, prior ESA dose, and ERI subgroup.
Number (%) of subjects with each dose at each assessment visit
The number and percentage of subjects with each dose (mg or g) will be provided by 
treatment. Graphical summaries of histogram will be provided with the number of 
subjects in each dose by treatment. Dose categories will be classified into 10; N/A (not 
administered), 0 mg (treatment interruption), 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 12 mg, 18 
mg, and 24 mg for daprodustat and classified into 9; N/A, 0 g, 10 g, 15 g, 20 g, 
30 g, 40 g, 60 g for darbepoetin alfa. This will also be summarized by prior ESA type, 
prior ESA dose, and ERI subgroup.
Duration (days) of treatment interruption due to Hgb >13.0 g/dL - daprodustat
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 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. On-therapy Hgb values observed in both 
scheduled and unscheduled visits will be counted in the summary.
Dose adjustment - daprodustat
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, …, ten, eleven, and twelve or more; these categories may be refined)
during the whole treatment period and Week 40 to 52, respectively. For the timing of 
dose adjustments, the number and percentage of subjects with dose adjustments by each 
assessment visit will be provided.
7.3.3.
Population of Interest
The secondary efficacy analyses will be based on the ITT population, unless otherwise 
specified.
7.3.4.
Strategy for Intercurrent (Post-Randomization) Events
Any intercurrent events are taken to be irrelevant for secondary endpoints. The secondary 
endpoints will be summarized based on available and observed data. 
7.3.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
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Unless otherwise specified, endpoints / variables defined in Section 7.3.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.4.
Exploratory Efficacy Analyses
7.4.1.
Endpoint / Variables
[Endpoint / Parameter/ Display Type]
Absolute
Stats Analysis
Summary
Individual
T
F
T
F
F
L
Iron Use
Dose of IV iron (mg) during the treatment period and 
the primary efficacy evaluation period (Week 40 to 52)
Y
Dose of IV iron (mg) during the treatment period and 
the primary efficacy evaluation period (Week 40 to 52)
  by Baseline Iron Use
Y
Number (%) of subjects who use iron during the 
treatment period and the primary efficacy evaluation 
period (Week 40 to 52)
Y
Number (%) of subjects who use iron during the 
treatment period and the primary efficacy evaluation 
period (Week 40 to 52)
  by Baseline Iron Use
Y
Iron Parameters (ferritin, TSAT, hepcidin, serum iron, and TIBC)
Raw observed value at each assessment visit
Y
Y
Y
Raw observed value at each assessment visit
  by Baseline Iron Use
Y
Y
Change from baseline at each assessment visit
Y
Y
Y
Change from baseline at each assessment visit
  by Baseline Iron Use
Y
Y
Y
Other
Scatter plot of change from baseline in Hgb at Week 4 
vs. covariates of interest – Daprodustat
Y
Scatter plot of mean dose during Week 40 to 52 vs. 
covariates of interest – Daprodustat
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.
7.4.2.
Summary Measure

Iron Use
Dose of IV iron (mg) during the treatment period and the primary efficacy evaluation 
period
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Monthly average IV iron dose by quarter (See Section 15.6.6) will be summarized using 
mean, standard deviation, minimum, P25, median, P75, and maximum. Quarter 1 (Day 1 
to Week 12), Quarter 2 (Week 12 to Week 24), Quarter 3 (Week 24 to Week 40), 
Quarter 4 (Week 40 to Week 52), and whole treatment period will be used and the 
Quarter 4 represents the primary efficacy evaluation period. This will also be summarized 
by baseline iron use defined in Section 5.4.2.
Number (%) of subjects who use iron during the treatment period and the primary 
efficacy evaluation period
The number and percentage of subjects who use iron during the treatment period and the 
primary efficacy evaluation period will be summarized separately. These will also be 
summarized by baseline iron use defined in Section 5.4.2.

Iron Parameter (ferritin, TSAT, hepcidin, serum iron, and TIBC)
Based on literature review the distributions of TSAT and hepcidin are skewed and require 
a log-transformation (See Section 5.2).
Raw observed value at each assessment visit
Ferritin, serum iron, and TIBC values will be summarized by treatment group using mean, 
standard deviation, 95% CI, minimum, P25, median, P75, and maximum at each 
assessment visit. TSAT and hepcidin values will be summarized by treatment group
using geometric mean, standard error, coefficient of variation, and 95% CI based on log-
transformed parameters, median, minimum, and maximum based on original scale at each 
assessment visit. These will also be summarized by baseline iron group. Graphical 
summaries will also be provided for each iron parameter.
Change from baseline at each assessment visit
Change from baseline in Ferritin, serum iron, and TIBC values will be summarized by 
treatment group using mean, standard deviation, 95% CI, minimum, P25, median, P75, 
and maximum at each assessment visit. Percent Change from baseline in TSAT and 
hepcidin values (Section 5.2) will be summarized by treatment group using geometric 
mean, coefficient of variation, and 95% CI based on log-transformed parameters, 
minimum, median, and maximum based on original scale at each assessment visit.
Treatment differences (daprodustat – darbepoetin alfa) and the associated 95% CIs for 
change from baseline will be provided at each assessment (See Section 7.4.5.1). For 
ferritin, serum iron, and TIBC change from baseline, graphical summaries will be 
provided by treatment group using the adjusted means and the associated 95% CIs over 
time. For TSAT and hepcidin percent change from baseline, graphical summaries will be 
provided using adjusted geometric means percent change from baseline and the 
associated 95% CIs over time. These will also be summarized by baseline iron group.
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
Other
Scatter plot of change from baseline in Hgb at Week 4 vs. covariates of interest
Scatter plot of change from baseline in Hgb at Week 4 versus following covariates of 
interest, body weight, baseline Hgb, prior ESA dose will be produced only for 
daprodustat. See Section 15.6.3 for the detailed derivations.
Scatter plot of mean dose during Week 40 to 52 vs. covariates of interest
Scatter plot of mean dose during Week 40 to 52 versus following covariates of interest, 
body weight, baseline Hgb, prior ESA dose will be produced only for daprodustat. See 
Section 15.6.3 for the detailed derivations.
7.4.3.
Population of Interest
The exploratory efficacy analyses will be based on the ITT population, unless otherwise 
specified.
7.4.4.
Strategy for Intercurrent (Post-Randomization) Events
Any intercurrent events are taken to be irrelevant for exploratory endpoints and the 
exploratory endpoints will be summarized based on available and observed data.
Analysis of change from baseline in the respective iron parameter at each assessment 
visit will follow the strategy below.
Intercurrent events
Strategy
Study withdrawal / 
Intermittent missing
The following hypothetical scenario is considered to 
assess what would have happened if the event did not 
occur. Analysis using MMRM assume missing at 
random mechanism, that is the observations of missing 
depend on just observed values, not on unobserved 
values. 
7.4.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables presented in Section 7.4.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed.
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7.4.5.1.
Statistical Methodology Specification
Endpoint / Variables

Change from baseline in the respective iron parameter at each assessment visit
Model Specification

Analyses will be repeated for each iron parameter (ferritin/TSAT/hepcidin/serum iron/TIBC)
using MMRM as follows:
Ironik = β0 + βbaseline *Baselinei + βj + βk + βjk + βbaseline*j * Baselinei + εik
    Ironi, week: each iron measurement for subject i at visit k
    β0: Intercept
    βbaseline: baseline effect of each iron parameter
    Baselinei: the baseline value of each iron parameter for subject i 
    βj: treatment effect (j= daprodustat, darbepoetin alfa)
    βk: visit effect (k = Week 4, Week 16, Week 28, Week 40, Week 52)
    βjk: treatment-by-visit interaction
    βbaseline*j: baseline-by-visit interaction
    εik: random error for subject i at visit k
    i: subject (i = 1, 2, …, N)
    N: number of subjects included in the analysis

The model parameters will be estimated using Restricted Maximum Likelihood 
(method=REML) with the Newton-Raphson algorithm. 

The Kenward-Roger method for calculating the denominator degrees of freedom will be used.

The variance-covariance structures for repeated measures within the individual subject will be 
unstructured (type=UN). 

LS means for treatment j at visit k will be calculated as follows for each iron parameter as 
adjusted mean change from baseline.
jk = β0 + βbaseline * μbaseline + βj+ βk + βjk + βbaseline*k * μbaseline
    jk: LS mean for treatment j at visit k
    baseline: mean for the baseline value of each iron parameter

The treatment difference at visit k for model based mean change from baseline will be 
calculated as follows for each iron parameter as adjusted treatment difference
daprodustat*k - darbepoetin alfa*k = βdaprodustat - βdarbepoetin alfa + βdaprodustat*k- βdarbepoetin alfa*k

Note that log-transformed values will be used for TSAT and hepcidin in the MMRM analysis. 
The LS means for treatment j at visit k and the adjusted treatment difference at visit k will be 
exponentially back-transformed to the original scale and provided as follows:
Adjusted geometric mean percent change from baseline = 100*(exp(jk) – 1)
Adjusted ratio for percent change from baseline = exp(daprodustat*k - darbepoetin alfa*k)
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Model Checking & Diagnostics

In case there is a problem with convergence of the unstructured (type=UN) variance-
covariance, the following strategy will be examined.
1.
Use Fisher’s scoring algorithm for the estimation method.
2.
Set Heterogeneous Toeplitz (type=TOEPH) structure for variance-covariance 
structure.
3.
In the event of that this model still fails to converge, alternative correlation structures 
may be considered such as type=CSH or CS.
Model Results Presentation

For ferritin, serum iron, and TIBC, the adjusted mean change from baseline will be presented 
with the associated 95% CIs by treatment at each assessment visit. The adjusted treatment 
difference (daprodustat – darbepoetin alfa) for change from baseline will also be presented 
with the associated 95% CI at each assessment visit.

For TSAT and hepcidin, the adjusted geometric mean percent change from baseline will be 
presented with the associated 95% CIs by treatment at each assessment visit. The adjusted 
ratio (daprodustat / darbepoetin alfa) for percent change from baseline will also be presented 
with the associated 95% CI at each assessment visit.
Subgroup Analyses

For all of the respective iron parameter, the above analysis will be repeated by baseline iron 
use subgroup (See Section 5.4.2) in the same manner.

The subgroup analyses will be based on the ITT population.

If there is a problem with convergence for a subgroup, the result of the subgroup will not be 
displayed.
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8.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), serious adverse 
events (SAEs), and other significant AEs will be based on GSK Core Data Standards. 
The details of the planned displays are provided in Appendix 10: List of Data Displays.
Medical device incidents fulfilling the definition of an AE/SAE will follow the same 
processes for collecting AE and SAE information and will not be summarized 
particularly.
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
On-Therapy AEs by SOC and PT
Y
Y
On-Therapy AEs by SOC and PT and Maximum Intensity
Y
On-Therapy AEs by SOC and PT by onset 
Y
On-Therapy AEs up to Week 4 by SOC and PT
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 and Maximum Intensity
Y
On-Therapy Drug-Related AEs up to Week 4 by SOC and PT
Y
On-Therapy Drug-Related AEs up to Week 4 by SOC and PT and Maximum 
Intensity
Y
Post-Therapy Drug-Related AEs by SOC and PT
Y
Post-Therapy Drug-Related AEs by SOC and PT and Maximum Intensity
Y
On-Therapy Common (>= 2 %) AEs by Overall Frequency
Y
Y [1]
On-Therapy Common (>= 5 %) Non-Serious AEs by SOC and PT (Subjects & 
No. of Occurrences)
Y
On-Therapy Non-Serious Drug-Related AEs 
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT & Verbatim Text
Y
Serious and Other Significant AEs 
Fatal Serious AEs
Y
Non-Fatal Serious AEs
Y
On-Therapy Serious AEs
Y
Post-Therapy Serious AEs
Y
On-Therapy Serious Drug-Related AEs
Y
Serious AEs in Screening Period [2]
Y
Reasons for Considering as a Serious AE
Y
On-Therapy Serious AEs by SOC and PT (Subjects & No. of Occurrences)
Y
AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study 
Y
Y
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Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Treatment by SOC and PT
CV Events
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Plot of common AEs and relative risk will be generated by treatment.
[2] Listing will be based on All Screening Population.
8.1.1.
Planned Adverse Events Analyses Displays

Adverse Events
AEs by SOC and PT
The number and percentage of subjects reporting at least one AE will be provided by 
treatment group. These events will be summarized by primary system organ class and 
preferred term. On-therapy AEs, on-therapy AEs up to Week 4, and post-therapy AEs 
will be summarized separately.
On-therapy AEs by onset (<=Week 4, >Week 4 to <=Week 16, >Week 16 to <=Week 28, 
>Week 28 to <=Week 40, >Week 40) will also be summarized separately. The number of 
subjects reporting the first occurrence of each AE will be provided by onset time by 
primary system organ class and preferred term.
AEs by SOC and PT and Maximum Intensity
AEs will be summarized by treatment group; by maximum intensity (not applicable, mild, 
moderate, severe) by primary system organ class and preferred term. Subjects who 
experience the same event several times with different intensities will only be counted 
with the maximum intensity in the order of (not applicable < mild < moderate < severe).
On-therapy AEs, on-therapy AEs up to Week 4, and post-therapy AEs will be 
summarized separately.
Drug-Related AEs by SOC and PT
The number and percentage of subjects reporting at least one drug-related AE will be 
provided by treatment group. These events will be summarized by primary system organ 
class and preferred term. On-therapy AEs, on-therapy AEs up to Week 4, and post-
therapy AEs will be summarized separately.
Drug-Related AEs by SOC and PT and Maximum Intensity
Drug-related AEs will be summarized by treatment group; by maximum intensity (not 
applicable, mild, moderate, severe) by primary system organ class and preferred term. 
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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, up to Week 4, and post-therapy AEs will be summarized 
separately.
On-Therapy Common (>= 2%) AEs by Overall Frequency
The number and percentage of subjects with on-therapy common (>= 2% in any 
treatment group) adverse events by overall frequency will be provided by treatment group. 
These events will be summarized by preferred term.
A graph will be produced which displays both AE incidence rates and relative risks.
On-Therapy Common (>= 5%) Non-Serious AEs by SOC and PT (Subjects & No. of 
Occurrences)
The number and percentage of subjects reporting at least one on-therapy common (>= 5%
in any treatment group) non-serious AE will be provided by treatment group. The number 
of on-therapy non-serious AE occurrences will also be provided. These events will be 
summarized by primary system organ class and preferred term.
On-Therapy Non-Serious Drug-Related AEs
The number and percentage of subjects with on-therapy non-serious drug-related AEs 
will be summarized by preferred term. 

Serious and Other Significant AEs
Serious AEs
The number and percentage of subjects reporting at least one Serious AE will be provided 
by treatment group. These events will be summarized by primary system organ class and 
preferred term. On- and post-therapy serious AEs will be summarized separately.
On-Therapy Serious Drug-Related AEs
The number and percentage of subjects with on-therapy serious drug-related AEs will be 
summarized by preferred term. 
On-Therapy Serious AEs by SOC and PT (Subjects & No. of Occurrences)
The number and percentage of subjects reporting at least one on-therapy serious AE will 
be provided by treatment group. The number of on-therapy serious AE occurrences will 
also be provided. These events will be summarized by primary system organ class and 
preferred term.
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AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study Treatment 
by SOC and PT
The number and percentage of subjects reporting an on-therapy AE leading to 
discontinuation of study treatment will be summarized by treatment group. These events 
will be summarized by primary system organ class and preferred term.
8.2.
Adverse Events of Special Interest Analyses
A comprehensive list based on clinical review will be used to identify each type of event.
AEs of special interest will be manually-selected before unblinding at patient-level (i.e. 
following case-by-case review by members of the Safety Review Team (SRT) including 
representatives from the local Japan team) and not at preferred term level. The details of 
the planned displays are provided in Appendix 10: List of Data Displays.
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
AEs of special interest [1]
On-Therapy AEs of special interest
Y
Y
Post-therapy AEs of special interest
Y
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Refer to Section 15.6.4
8.2.1.
Planned Adverse Events of Special Interest Analyses Displays

AEs of Special Interest (AESIs)
AEs of Special Interest
The number and percentage of subjects reporting at least one AESI will be provided by 
treatment group. These events will be summarized by each AESI term (See 
Section 15.6.4). On-therapy and post-therapy AESIs will be summarized separately.
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry/ Hematology/Other 
Laboratory tests, and liver function tests will be based on GSK Core Data Standards. The 
details of the planned displays are in Appendix 10: List of Data Displays.
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Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Chemistry
Chemistry Values by Visit 
Y
Y
Y
Percent Change from Baseline in Lipid Parameters [1]
(total cholesterol, LDL cholesterol, HDL cholesterol, and 
LDL/HDL cholesterol ratio) by Visit
Y
Y
Y
Worst Case Chemistry Results Relative to Normal Range 
Post-Baseline Relative to Baseline 
Y
Worst Case Chemistry Results Relative to PCI Criteria 
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
Iron Parameters
Iron Values by Visit [2]
Y
Y
Y
Worst Case Iron Results Relative to Normal Range Post-
Baseline Relative to Baseline 
Y
Worst Case Iron Results Relative to PCI Criteria Post-
Baseline Relative to Baseline 
Y
Other Laboratory Tests [3]
Other Laboratory Values by Visit
Y
Y
Y
Worst Case Other Laboratory Results Relative to Normal 
Range Post-Baseline Relative to Baseline
Y
Worst Case Other Laboratory Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Hepatobiliary Laboratory Abnormalities
Y
Medical Conditions for Subjects with Liver Stopping Events
Y
Substance Use for Subjects with Liver Stopping Events
Y
Scatter Plot of Maximum vs. Baseline for ALT
Y
Scatter Plot of Maximum ALT vs Maximum Total Bilirubin
Y
All Laboratory
All Laboratory Data for Subjects with any Value of 
Potential Clinical Concern/PCI
Y
Laboratory Values of PCI
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Lipid parameters will be log-transformed and the percent change from baseline will be reported.
[2] Transferrin and UIBC will be included for this summary and other iron parameters will be provided as efficacy 
endpoints.
[3] Only iPTH will be collected as other laboratory tests.
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8.3.1.
Planned Clinical Laboratory Analyses Displays
LDL/HDL cholesterol ratio will be derived from LDL and HDL cholesterol (see Section 
15.6.4), and handled as one of chemistry laboratory tests and lipid parameters.

Chemistry/Hematology/Iron Parameter/Other Laboratory Tests
Clinical Laboratory Values by Visit
The values will be summarized using mean, standard deviation, median, minimum, and 
maximum at each assessment visit and baseline by treatment group. Chemistry, 
hematology, iron parameter, and other laboratory values will be summarized separately.
Percent Change from Baseline in Lipid Parameters
Lipid parameters (including LDL/HDL cholesterol ratio) will be log-transformed and the 
percent change from baseline will be reported. The percent change from baseline in each 
lipid parameter, including baseline values, will be summarized using geometric mean, 
95% CI, minimum, median, and maximum at each assessment visit by treatment group. 
In baseline values, the coefficient of variation will also be provided.
Clinical Laboratory Changes from Baseline by Visit
The values will be summarized using mean, standard deviation, median, minimum, and 
maximum at each assessment visit. Change from baseline in chemistry (excluding 
LDL/HDL cholesterol ratio), hematology, iron parameter, and other laboratory will be 
summarized separately.
Worst Case Laboratory Results Relative to Normal Range/PCI Criteria Post-Baseline 
Relative to Baseline 
The number of subjects with worst case laboratory results relative to normal 
range/potential clinical importance (PCI) criteria which are post-baseline relative to 
baseline, including unscheduled assessments, will be summarized by test and category by 
treatment group. Summaries for normal range and PCI will be provided separately. The 
categories for normal range are: To Low, To Normal or No Change, To High; the 
categories for PCI criteria are: To Low, To w/in Range or No Change, To High. The 
categorization is determined by comparing the baseline category to the worst case post-
baseline category. PCI criteria is described in Appendix 8.

Hepatobiliary (Liver)
Details of liver chemistry stopping criteria are described in the protocol.
Liver monitoring/stopping events will be summarized by treatment group. 
Hepatobiliary laboratory abnormalities will be summarized by treatment group. 
A scatter plot of maximum on-therapy ALT values versus baseline ALT values will be 
produced if larger data permit.
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A scatter plot of maximum total bilirubin (xULN) versus maximum ALT (xULN) values 
on-therapy will be produced if larger data permit.
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10: List of Data Displays.
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
ECG
ECG Findings 
Y
Y
ECG Values by Visit
Y
Y
Abnormal ECG Findings
Y
Vital Signs
Vital Signs by Visit
Y
Y
Y
Worst Case Vital Sign Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline
Y
All Vital Signs for Subjects with Any Values of PCI
Y
Ophthalmology
Prior-Therapy Ophthalmologic Exams
Y
Y
On-Therapy Ophthalmologic Exams
Y
Y
Change in Anti-Hypertensive Medications
Number (%) of Subjects Who Have Any Change in Anti-
Hypertensive Medications During the Treatment Period
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.
8.4.1.
Planned Other Safety Analyses Displays

ECG
ECG findings ('normal', 'abnormal, not clinically significant', 'abnormal, clinically 
significant') will be summarized by assessment visit for each treatment group. Change 
from baseline in ECG values will be summarized using mean, standard deviation, 
minimum, median, and maximum by assessment visit for each treatment group. Findings 
without regard to visits (labelled “Worst Case Post-Baseline”, only the worst case finding 
for each subject) will also be provided. All ECG measures (heart rate, PR interval, QRS 
duration, QT [uncorrected] interval and QTcB [calculated], result of ECG) will be 
included in listings.
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
Vital Signs
Vital sign values will be summarized using mean, standard deviation, minimum, median, 
and maximum by assessment visit for each treatment group. Separate summary statistics 
of 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 5.2). 
The number of subjects with worst case vital sign results relative to PCI criteria which 
are post-baseline relative to baseline, including unscheduled assessments, will also be 
summarized by test and category by treatment group. The categories for PCI criteria are: 
To Low, To w/in Range or No Change, To High. The categorization is determined by 
comparing the baseline category to the worst case post-baseline category.

Ophthalmology Exams
The responses to each question and any questions will be summarized using number and 
percentage at each assessment visit by treatment group. The response will be classified 
into 'Yes' and 'No'. A summary of ophthalmology exams at screening and at on-therapy 
will be produced separately. The number and percentage of subjects with worst case 
after-screening ophthalmology exams (i.e., the response is ‘Yes’ at least once during 
whole treatment period, including unscheduled visits) will also be summarized by each 
question by treatment group.

Change in Anti-Hypertensive Medications
The number and percentage of subjects who have any change at least once in anti-
hypertensive medications (type and/or dose) due to increased blood pressure during 
whole treatment period will be summarized by treatment group.
9.
PATIENT REPORTED OUTCOME ANALYSES
9.1.
Endpoint / Variables
Endpoint / Parameter/ Display Type
Absolute
Stats Analysis
Summary
Individual
T
F
T
F
F
L
Patient Reported Outcome
SF-36 HR-QoL Scores (PCS, MCS, 8 
subscales)
Y
Y
Changes from Baseline in SF-36 HR-QoL 
Scores (PCS, MCS, 8 subscales)
Y
Y
EQ-5D-5L Scores
Y
Y
EQ-5D-5L Index Values
Y
Y
Changes from Baseline in EQ-5D-5L Index 
Value
Y
Y
EQ VAS
Y
Y
Changes from Baseline in EQ VAS
Y
Y
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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.
9.2.
Summary Measure
Scoring derivations are described in Section 15.6.7.
SF36 HR-QoL Scores and Changes from Baseline (PCS, MCS, 8 subscales)
The summary scores (PCS and MCS) and the domain scores (Physical Functioning [PF], 
Role-Physical [RP], Bodily Pain [BP], General Health [GH], Vitality [VT], Social 
Functioning [SF], Role-Emotional [RE], and Mental Health [MH]) will be summarized 
using mean, standard deviation, median, minimum, and maximum at each assessment 
visit by treatment group. For changes from baseline, the adjusted treatment difference and 
the 95% CIs will also be provided (See Section 15.6.7).
EQ-5D-5L / EQ VAS Scores and Changes from Baseline in EQ-5D-5L Index Value / EQ 
VAS
The number and percentage of subjects with each score within each category will be 
displayed at each assessment visit by treatment group. EQ-5D-5L index values and EQ 
VAS scores will be provided using mean, standard deviation, median, minimum, and 
maximum at each assessment visit by treatment group. For changes from baseline, the 
adjusted treatment difference and the 95% CIs will also be provided (See Section 15.6.7).
9.3.
Population of Interest
The analyses will be based on the ITT population, unless otherwise specified.
9.4.
Strategy for Intercurrent (Post-Randomization) Events
Any intercurrent events are taken to be irrelevant for the endpoints and the endpoints will 
be summarized based on available and observed data.
Analysis of change from baseline in the respective QoL parameter at each assessment 
visit will follow the strategy below.
Intercurrent events
Strategy
Study withdrawal / 
Intermittent missing
The following hypothetical scenario is considered to 
assess what would have happened if the event did not 
occur. Analysis using MMRM assume missing at 
random mechanism, that is the observations of missing 
depend on just observed values, not on unobserved 
values. 
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9.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.3.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed.
9.5.1.
Statistical Methodology Specification
Endpoint / Variables

Change from baseline in the respective QoL parameter at each assessment visit
Model Specification

Analyses will be repeated for each QoL parameter (SF-36 HR-QoL scores/EQ-5D-5L index 
value/EQ-VAS score) using MMRM as specified in Section 7.4.5.1:

Note that the QoL parameters are no need to be log-transformed as opposed to some of the 
iron parameters.
Model Results Presentation

The adjusted mean change from baseline will be presented with the associated 95% CIs by 
treatment at each assessment visit. The adjusted treatment difference (daprodustat –
darbepoetin alfa) for change from baseline will also be presented with the associated 95% CI
at each assessment visit.
Subgroup Analyses

Not applicable
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10.
PHARMACOKINETIC ANALYSES
10.1.
Pharmacokinetic Analyses
10.1.1.
Endpoint / Variables
The details of the planned displays are presented in Appendix 10: List of Data Displays.
Endpoints
Untransformed
Log-Transformed
Summary
Individual
Summary
Individual
F
T
F
L
F
T
F
L
Plasma Concentrations of 
Daprodustat
Y [1] [2]
Y
Y [1]
Y
Derived PK Parameters
Y [3]
Y [3]
Y[3]
Y
Y[3]
Dose Normalized PK 
Parameters
Y [3]
Y [3]
Y[3]
Y
Y[3]
NOTES :

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Linear and Semi-Log plots will be created on the same display.
2.
Separate Mean (± SD) and Median plots will be generated.
3.
Individual PK parameters calculated based on less than 4-time point concentrations or any time deviated 
concentration will be omitted from summaries and figures.
10.1.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 15.5.3
Reporting Standards for Pharmacokinetic)
Concentrations of daprodustat in plasma will be listed and summarized by dose group 
and nominal time. Individual plasma concentration-time profiles and median/mean 
profiles by dose group will be plotted. Each of figures will contain one plot on the 
untransformed scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. a 
log-linear plot).
10.1.1.2.
Derived Pharmacokinetic Parameters
Derivation of pharmacokinetic parameters will be performed by, or under the direct 
auspices of, Clinical Pharmacology & Science Promotion Office, GlaxoSmithKline K.K.
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (version 6.3 or higher). All calculations of non-compartmental parameters 
will be based on actual sampling times. Pharmacokinetic parameters listed will be 
determined from the plasma daprodustat concentration-time data, as data permits.
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Parameter
Parameter Description
AUC(0-4)
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(last)) will be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the linear trapezoidal for each decremental trapezoid.
The concentration at 0 hr will be set to 0.
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
Tmax
Time to first occurrence of Cmax will be obtained directly from the concentration-time 
data.
NOTES:

Additional parameters may be included as required.

C(last) is expected to be the concentration observed at 4 hours after the most recent dose.
10.1.2.
Summary Measure
Refer to Section 15.5.3 for the display standards.

Plasma Daprodustat Concentrations
Non-transformed and log-transformed plasma concentration at every scheduled time 
point will be summarized at Week 12, Week 24, and all visits (i.e., pooled analysis of 
Week 12 and Week 24) by dose level. Non-transformed plasma concentration of 
daprodustat will be summarized using mean, 95% CI, standard deviation, median, 
minimum, and maximum. Log-transformed plasma concentration of daprodustat will be 
summarized using geometric mean, 95% CI of geometric mean, standard deviation of 
log-transformed data and between subject coefficient of variation (%CVb).

PK Parameters
Non-transformed and log-transformed PK parameters will be summarized at Week 12, 
Week 24, and all visits (i.e., pooled analysis of Week 12 and Week 24) by dose level. 
Non-transformed PK parameters of daprodustat (AUC(0-4), Cmax, and Tmax) will be 
summarized using mean, 95% CI, standard deviation, median, minimum, and maximum. 
Log-transformed PK parameters of daprodustat (AUC(0-4),  Cmax, and Tmax) will be 
summarized using geometric mean, 95% CI of geometric mean, standard deviation of 
log-transformed data and between subject coefficient of variation (%CVb).
Dose normalized PK parameters (non-transformed and log-transformed) will also be 
summarized in the same manner by dose level. In summary of dose normalized PK 
parameters, summary tables by tablet strength (non-transformed and log-transformed) 
will be provided.
10.1.3.
Population of Interest
The pharmacokinetic analyses will be based on the PK population, unless otherwise 
specified.
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10.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Any intercurrent events are taken to be irrelevant for pharmacokinetic endpoints. The 
pharmacokinetic endpoints will be summarized based on available and observed data.
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11.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
No population pharmacokinetics analyses are planned for this study, but the 
pharmacokinetic data may be used for a separate report.
12.
PHARMACODYNAMIC ANALYSES
No pharmacodynamics analyses are planned for this study, but the pharmacodynamic 
data may be used for a separate report.
13.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES
No pharmacokinetic / pharmacodynamic analyses are planned for this study, but the 
pharmacokinetic / pharmacodynamic data may be used for a separate report.
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14.
REFERENCES
Besarab A, Reyes CM, and Hornberger J. Meta-Analysis of Subcutaneous Versus 
Intravenous Epoetin in Maintenance Treatment of Anemia in Hemodialysis Patients.
American Journal of Kidney Diseases. 2002; 40 (No. 3): 439-446.
GlaxoSmithKline Document Number 2015N266251_02 Study ID 201754. A 52-week, 
Phase III, double-blind, active-controlled, parallel-group, multi-center study to evaluate 
efficacy and safety of daprodustat compared to darbepoetin alfa in Japanese 
hemodialysis-dependent subjects with anemia associated with chronic kidney disease 
who are currently ESA users. Report Date 19-Jul-2017. 
Liublinska V, Rubin DB. Sensitivity analysis for a partially missing binary outcome in a 
two-arm randomized clinical trial. Statistics in Medicine 2014; 33(24): 4170-4185.
Mascha EJ and Sessler DI. Equivalence and noninferiority testing in regression models 
and repeated-measures designs. Anesth Analg. 2011;112(3):678-87
Michael O ’Kelly and Bohdana Ratitch. Clinical Trials with Missing Data: A Guide for 
Practitioners. John Wiley & Sons Ltd. 2014.
Rosendaal FR, Cannegieter SC, Van der Meer, FJM, and Briet, E. A Method to 
Determine the Optimal Intensity of Oral Anticoagulant Therapy. Thrombosis and 
Haemostasis. 1993; 69 (3): 236–239.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons, 1987.
User’s Manual for the SF-36v2 Health Survey Third Edition, 2011.
Yang Yuan, SAS Institute Inc. Sensitivity Analysis in Multiple Imputation for Missing 
Data. Paper SAS270-2014
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15.
APPENDICES
15.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
15.1.1.
Exclusions from Per Protocol Population
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01
Informed Consent in Deviation Category
02
Eligibility Criteria Not Met in Deviation Category
03
Not Withdrawn After Developing Withdrawal Criteria in Deviation Category
04
Wrong study treatment or assignment administered in Deviation Subcategory
05
Randomization procedures (e.g. subject randomized out of order) in Deviation Subcategory
06
Less than 3 out of 4 scheduled evaluable Hgb values from the primary efficacy evaluation 
period [1]
07
Subject received prohibited medication for more than 14 days during study period [2]
08
Non-compliance with randomized medication (compliance category of under compliant or 
over compliant) [3] during the primary efficacy evaluation period, based on eCRF 
randomized medication exposure and compliance forms
NOTES:
[1] Evaluable Hgb values are described in Section 15.6.3.
[2] Prohibited mediations include strong inhibitors of CYP2C8 (e.g., gemfibrozil) and strong inducers of CYP2C8 (e.g., 
rifampin/rifampicin), not include erythropoietin (e.g., epoetin/ darbepoetin alfa/ epoetin beta pegol, excluding 
darbepoetin alfa supplied by GSK). 
[3] See Section 15.6.2; Over compliant: <80%, compliant: 80% and 120%, over compliant: >120%
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15.2.
Appendix 2: Schedule of Activities
15.2.1.
Protocol Defined Schedule of Events
Phase
Screening
Treatment
Visit
All assessments pre-dialysis, unless noted.
-4～-2 11
Day 1
2
4
6
8
10
12
14
16
18
20
22
24
26
28
Allowance range (days)
±3
-
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history, demography, height, weight 1
X
IWRS call
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study medication dispensing 2, 3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study treatment compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (before and after dialysis) 4
X
X
X
X
X
Ophthalmology 5
ECG
X
X
HemoCue Hgb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
Hgb
only
Hgb
only
X
Hgb
only
Hgb
only
X
Clinical chemistry
X
X
X
X
X
Pregnancy test (serum hCG) 6
X
X
X
X
X
Estradiol, FSH 7
X
PK 8
X
X
Ferritin, TSAT
X
X
X
X
X
Serum iron, TIBC, UIBC, serum transferrin, hepcidin
X
X
X
X
iPTH
X
X
HR-QoL (SF-36, EQ-5D-5L/ EQ-VAS)
X
X
X
Genetics sample 9
X
AE assessment 10
X 12
Concomitant Medications Review
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Phase
Treatment
Follow-up
Visit
All assessments pre-dialysis, unless noted.
30
32
34
36
38
40
42
44
46
48
50
52
Early 
withdrawal 13
2 weeks 
after Week 52 or 
early withdrawal
Allowance range (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-
±3
Informed consent
Inclusion/exclusion criteria
Medical history, demography, height, weight 1
IWRS call
X
X
X
X
X
X
X
X
X
X
X
X
X
Study medication dispensing 2, 3
X
X
X
X
X
X
X
X
X
X
X
Study treatment compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (before and after dialysis) 4
X
X
X
X
Ophthalmology 5
ECG
X
HemoCue Hgb
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
Hgb
only
Hgb
only
X
Hgb
only
Hgb
only
X
X
X
Clinical chemistry
X
X
X
X
Pregnancy test (serum hCG) 6
X
X
X
X
Estradiol, FSH 7
PK 8
Ferritin, TSAT
X
X
X
Serum iron, TIBC, UIBC, serum transferrin, hepcidin
X
X
X
iPTH
X
HR-QoL
X
X
Genetics sample 9
AE assessment 10
Concomitant Medications Review
1.
Body weight is measured after dialysis.
2.
Daprodustat/placebo will be dispensed once every 4 weeks, and darbepoetin alfa/placebo will be dispensed once every 2 weeks
3.
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. 
4.
At visits without dialysis, only one measurement of each parameter will be obtained.
5.
Ophthalmology exams should be conducted at the following time points.
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6.
Screening: anytime after consenting and prior to first dose of study medication (Day 1)
7.
Week 12: window from weeks 10-14 (inclusive)
8.
End of study: window from weeks 48-52 (inclusive)
9.
Early study medication discontinuation: withdrawal eye exam as close to the last dose as possible (the repeat exams are not required if one has been performed within the 2 
prior weeks).
10. Performed in females of childbearing potential.
11. Measured in female subjects only to determine the menopausal status (see Section 5.1 in protocol.)
12. See Table 11 in protocol.
13. Informed consent for optional Genetic research should be obtained before collecting a sample (see Section 7.6 in protocol.).
14. See Section 7.4.1.1. in protocol. The interval between screening and Day 1 should be 4 weeks in subjects treated with epoetin beta pegol every 4 weeks or darbepoetin alfa 
every 4 weeks in the prior ESA therapy.
15. Only SAEs assessed as related to study participation or a GSK product are collected.
16. For withdrawn subjects, specified assessments should be done wherever possible.
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15.3.
Appendix 3: Assessment Windows
All data will be reported according to the nominal visit date for which it was reported 
(that is, no visit windows will be applied during dataset creation). Permissible range at 
each visit was specified in time & event table (See Appendix 2). Records in the eCRF 
unscheduled visit will not be slotted to a particular time point, but remain as unscheduled 
if they are either summarized or listed unless otherwise specified.
Regarding the visits where only HemoCue Hgb is available (i.e., Week 2, Week 6,
Week 10, etc. See Appendix 2.), the Hgb values will not be used for any analyses but 
presented in the listing unless otherwise specified.
15.3.1.
Definitions of Assessment Windows for Analyses
Analysis Time Point
Definitions
Screening [1]
Data collected in Screening visit
If multiple records are present, the latest record will be used for analysis.
Day 1 [1]
Data collected in Day 1 visit
If multiple records are present, the latest record will be used for analysis.
Week 2
Data collected in Week 2 visit
Week 4
Data collected in Week 4 visit
Week 6
Data collected in Week 6 visit
…
…
Week 48
Data collected in Week 48 visit
Week 50
Data collected in Week 50 visit
Week 52
Data collected in Week 52 visit
Follow-up
Data collected in Follow-up visit
Note: 
Any unscheduled visit will not be slotted to a particular time point.
[1] For rescreened subjects, data collected in screening-pass visit (i.e., screening and day 1 visit where the subject 
has passed a screening test) will be used for analysis. They may have multiple records at Screening and/or Day 1 
visit, which associates with a screening pass visit and screening failure visit(s) (See Section 15.6.1)
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15.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
15.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
randomization date and treatment stop date.
Treatment stop date is defined in Section 15.6.1.
15.4.1.1.
Study Phases for Hgb Data
Treatment State
Definition
Pre-therapy
Date ≤ Randomization Date
On-therapy
Randomization Date < Date ≤ Treatment Stop Date + 1 day
Post-therapy
Date > Treatment Stop Date + 1 day
NOTES: 

If randomization date is missing then the assessment will be considered to be pre-therapy
15.4.1.2.
Study Phases for AE Data
On-therapy AEs will be treated as treatment emergent AEs, therefore, treatment emergent 
flag for AEs will be derived from on-therapy treatment state.
Treatment State
Definition
Pre-therapy
AE Start Date < Randomization Date
On-therapy
Randomization Date ≤ AE Start Date ≤ Treatment Stop Date + 1 day
Post-therapy
AE Start Date > Treatment Stop Date + 1 day
Duration (Days) 
AE Resolution Date – AE Onset Date + 1 day
Drug-related
If relationship is marked ‘YES’ on eCRF or value is missing.
NOTES: 

If randomization date is missing then the assessment will be considered to be pre-therapy
15.4.1.3.
Study Phases for Concomitant Medication
Treatment State
Definition
Pre-therapy
Concomitant medications that meet either following conditions will be regarded as pre-
therapy.

Concomitant Medication Start Date < Randomization Date [a, b, c, j, n]

Concomitant Medication Start Date is missing [g, h, i, m, o]

Randomization Date is missing
On-therapy
Concomitant medications that meet either following conditions will be regarded as on-
therapy.

Randomization Date ≤ Concomitant Medication Start Date ≤ Treatment Stop 
Date + 1 [d, e, k, p, q, r, s, v]

(Concomitant Medication Start Date < Randomization Date) AND (Randomization 
Date ≤ Concomitant Medication Stop Date) [b, c, n]
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Treatment State
Definition

(Concomitant Medication Start Date < Randomization Date) AND (Concomitant 
Medication Stop Date is missing) [j]

(Concomitant Medication Start Date is missing) AND (Concomitant Medication 
Stop Date Randomization Date) [h, i, o]

(Concomitant Medication Start Date is missing) AND (Concomitant Medication 
Stop Date is missing) [m]
Post-therapy
Concomitant medications that meet either following conditions will be regarded as 
post-therapy.

Concomitant Medication Stop Date > Treatment Stop Date [c, e, f, I, r, t, v]

Concomitant Medication Stop Date is missing [j, k, l, m, s, u]
NOTES: 

Data of concomitant medication includes ESA, iron, and blood products and blood supportive care products.

Alphabets in brackets after the conditions correspond to each case in following illustrations.
Illustrations of the pre-therapy, on-therapy, and post-therapy for concomitant medications 
are included below:
Pre-
therapy
On-therapy
Post-therapy
Pre-therapy
medication
On-therapy
medication
Post-therapy
medication
(a)
xx
Randomization Date
Treatment Stop Date
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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15.5.
Appendix 5: Data Display Standards & Handling 
Conventions
15.5.1.
Reporting Process
Software

The currently supported versions of SAS software and S-Plus will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Compound
: /arenv/arprod/gsk1278863/mid201754/final_01
QC Spreadsheet
: /arenv/arprod/gsk1278863/mid201754/final_01/documents
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.1.3 & ADaM IG 
Version 1.0. If the Study Data Standardization Plan (SDSP) exists for a study, ensure the CDISC 
versions are consistent.
Generation of RTF Files

RTF files will not be generated.
15.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should locate in the modular appendices as ICH or non-ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP's.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Scheduled visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) 
will be included in listings, figures, summaries and statistical analyses.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
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Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

If unscheduled visits are included, details of how summaries will be displayed will be provided in 
the RAP.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1: This does not apply to the output of 
statistical models or when the standard list is inappropriate.

For cases where the standard may not be applied, see the display details in 
Section 6 to Section 10.
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
15.5.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to
GUI_51487. 
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
The following PK parameters will be derived by the Programmer: 

Dose-Normalized PK parameters 
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to Standards for Handling NQ Impacted PK Parameters.
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Each pharmacokinetic parameter (AUC(0-4), Cmax, and Tmax) will be summarized 
using the minimum set of summary statistics (IDSL statistical display principle 
6.06.1).
For each pharmacokinetic parameter (AUC(0-4), Cmax, and Tmax), the log-
transformed parameter will be summarized using the summary statistics. The 
summary statistics are: N, n, geometric mean, 95% CI of geometric mean, standard 
deviation (SD) of log-transformed data and between subject coefficient of variation 
(CVb (%)) will be reported.
[1] CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data)
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15.6.
Appendix 6: Derived and Transformed Data
15.6.1.
General
Multiple Measurements at One Analysis Time Point

Subjects having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant PCI summary tables.

For multiple measurements at Screening and/or Day 1 visit, the screening-pass visit record will be used 
for analysis (See Appendix 3).
Study Day

Calculated as the number of days from Randomization Date:

Ref Date = Missing         → Study Day = Missing 

Ref Date < Randomization Date → Study Day = Ref Date – Randomization Date

Ref Data ≥ Randomization Date → Study Day = Ref Date – (Randomization Date) + 1
Unique Subject ID

All subjects have unique subject ID for analyses even if a subject was enrolled after rescreened. 
Tables/figures/listings will be produced based on unique subject ID.

For a rescreened subject, the unique subject ID will be derived from the first-assigned subject number 
though he or she seems to have different subject numbers in eCRF by screening assessments.
Rescreening Subjects

For rescreened subjects, data collected in screening-pass visit will be used for analysis. They may have 
multiple records at Screening and/or Day 1 visit, which associates with a screening-pass visit and 
screening failure visit(s)

Regarding a listing of SAEs in screening period, all pre-therapy SAEs captured in eCRF will be
provided including screen failure records of rescreened subjects.
Treatment Start Date

First randomized treatment start date
Treatment Stop Date - Daprodustat

Calculated as the latest randomized treatment stop date
Treatment Stop Date – Darbepoetin Alfa

Following definition will be based on “assumed” treatment stop date because the treatment stop date is 
not captured in eCRF.
Definition:

If a subject has completed the treatment period (i.e., Week 52 visit record is present), treatment stop 
date will be calculated as Week 52 visit date
o
Week 52 visit date will be based on laboratory Hgb date. HemoCue Hgb date will be used when 
laboratory Hgb date is unavailable.

If a subject has withdrawn from the treatment period (i.e., Week 52 visit record is missing), treatment 
stop date will be calculated as the latest treatment start date + 6 days (1 day before the next treatment 
start date if a subject hadn’t withdrawn)

Subjects are intended to have weekly injection of darbepoetin alfa, therefore assumed treatment 
stop date could include “+ 6 days” to mimic weekly dosing.
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Subgroup Definition

For general considerations, see Section 5.4.2.

Regarding prior ESA type and prior ESA dose, see Section 15.6.2

Period of time on dialysis (years) will be defined as follows:
o
(Randomization Date – Date of Dialysis Initiation + 1) / 365.25 

Baseline iron use = use or non-use of pre-therapy iron medications (including Riona and P-TOL, see 
Section 15.6.6) 

History of diabetes will be derived from the current history diabetes (Yes/No) in medical history records.
Time Definitions (per GSK standard principles)

1 week = 7 days

1 month = 30.4375 days

1 year = 365.25 days
15.6.2.
Study Population
Subject Disposition and Study Population
Rescreened Subjects

Screening status and reason for screening failure for a subject who has multiple subject numbers will be 
unique in the unique subject ID.
o
The screening status of a subject who failed screening but passed rescreening will be ‘enrolled’, and 
the reason for failure will not be counted.
o
The screening status of a subject who failed more than one screening and never passed will be 
‘failed’, and the reason for failure will be derived from the latest failure record.

Study population of subjects will be derived from the above unique screening status.
Demographics and Baseline Characteristics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
A date and month will be imputed as ‘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
Type of Prior ESA

For this study, prior ESA dose can be administered in several different ways, which are categorized by 
GSK drug codes as follows.
Prior ESA
Epoetin
Epoetin beta pegol
Darbepoetin alfa
CMDRGCOL
00928302
00928303
00928305
53876201
50520401

Dosing route (IV or SC) will be derived from eCRF.
Prior ESA Dose (IU/week) at Baseline

During screening, subjects may be receiving ESA in multiple ways, including epoetin IV or SC, 
darbepoetin alfa IV or SC, or epoetin beta pegol IV or SC. The dose of ESA at screening visit will be 
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Demographics and Baseline Characteristics
standardized to obtain a continuous single unit prior ESA dose in terms of epoetin IV (IU/week). The 
standardization will be carried with the following formula based on literature review:

For subjects taking epoetin IV
o
Standardized mean prior ESA dose (IU/week) = epoetin IV dose (IU/week)

For subjects taking epoetin SC
o
Standardized mean prior ESA dose (IU/week) = (161/113)*epoetin SC dose(IU/week): 
[Besarab. 2002]

For subjects taking darbepoetin alfa IV or SC
o
Standardized mean prior ESA dose (IU/week) = 250*darbepoetin alfa dose (g/week)

For subjects taking epoetin beta pegol IV or SC
o
Standardized mean prior ESA dose (IU/week) = 208*epoetin beta pegol dose (g/week)

Prior ESA dose will be calculated using a weighted mean:
o
Mean prior ESA dose (g/week or IU/week) = ([dose_w]1*[duration1] + ... + [dose_w]n*[duration]n)] / 
[[duration]1+ ... + [duration]n]
where
o
[Dose_w]n = [dose]n * [frequency]n
o
[Duration]n = [Prior ESA start date]n+1 – [prior ESA start date]n*
or
[Randomization date] – [prior ESA start date]n*
when nth record is the last prior ESA dose
*Using “[end date] – [start date] +1’ may be inappropriate because the start date may be 
identical with the end date in case the dose frequency is once daily or twice daily, etc.
Note: Frequency is defined as follows:
If subject receives prior ESA x times per week frequency = x
If subject receives prior ESA every x weeks frequency = 1/x
If subject receives prior ESA x times per month frequency = x * 7 / 30.4375
If subject receives prior ESA x times per day frequency = x * 7/duration
once daily (QD) = 1 time per day, twice daily (BID) = 2 times per day, etc…

Prior ESA dose during the period of 12 weeks prior to randomization will be used for calculation.

To obtain this, some records may be converted for calculation because some dosing records may 
include both before and after the period or may not include the period. 
o
If a start date of dosing is before 12 weeks prior to randomization (i.e., study day < -84), the start 
date will be replaced to the date of study day = -84 for the calculation.
o
This conversion makes the records before 12 weeks prior to randomization ignorable because the 
records will lose their information and weighting of duration before the period. 
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Demographics and Baseline Characteristics
Illustration of Standardized Mean Prior ESA calculation (ex: epoetin IV)
Record#
Visit
Start Date
Dose 
(IU)
Frequency. 
[unit]
Duration 
(days)
Dose_w
(IU / week)
1
Screening
06Feb2017
750
Once daily
2
750*7/2 = 
2625
2
Screening
08Feb2017
750
Once daily
2
750*7/2 = 
2625
3
Screening
10Feb2017
1500
Once daily
3
1500*7/3 = 
3500
4
Screening
13Feb2017
750
3 [times/week]
9
750*3 = 2250
-
Day 1
22Feb2017
[Randomization 
Date]
Weighted mean (IU/week)
=2578.1
Erythropoietin Resistance Index (ERI) at Baseline

Calculated as standardized mean prior ESA dose (IU/week) divided by dry weight (kg) at screening visit 
and then divided by the achieved Day 1 Hgb (g/dL).
Exposure
Blinded Dose Level

Blinded dose level of each visit will be linked with prescribed dose according to the protocol:
Dose level
0
1
2
3
4
5
6
7
8
Treatment
Prescribed Dose
Daprodustat / 
Placebo
0 mg
1 mg
2 mg
4 mg
6 mg
8 mg
12 mg
18 mg
24 mg
Darbepoetin 
Alfa / Placebo
0 g
10 g
15 g
20 g
30 g
40 g
60 g
NA
NA

In darbepoetin alfa / placebo treatment, prescribed dose will be associated with exposure records. Two 
records of exposure within a certain visit form have a certain blinded dose level. 
Prescribed Dose and Actual Dose

Prescribed dose will be derived from blinded dose level captured in eCRF.

Actual dose will be derived from container number(s) captured in eCRF. Note that unscheduled 
(additional) bottles will not be taken into account. In principle, actual dose will be the same as 
prescribed dose except for a case in which inconsistency between a prescribed dose and actual
bottle(s) occurs. If such an inconsistency occurs, it may not be possible to determine what dose was 
actually taken. In these cases, the actual dose may be changed from the prescribed dose to a more 
plausible value based on the available information (e.g., IRT data).
Extent of Exposure of Daprodustat

Subjects who were randomized but did not report a treatment start date will be categorized as having 
zero days of exposure.

Time on study treatment will be calculated based on the following formula:
Time on study treatment (days)
= [Study Treatment Stop date] – [Study Treatment Start date] + 1 day
The time on study treatment does not exclude dose interruptions.
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Exposure

Cumulative dose will be based on the formula using actual dose:
Cumulative Dose = Sum of ([Exposure Duration] x [Actual Dose]) at Each Visit
where Exposure duration = [Treatment Stop date] – [Treatment Start date] +1 day

Subject daily dose (= Cumulative Dose / Time on study treatment) is calculated for each subject using 
actual dose and the summary statistics are calculated based on the subject average daily dose.

Distribution of the dose level
Dose level will be classified into 9 categories; 0 mg (i.e. treatment interruption), 1 mg, 2 mg, 4 mg, 
6 mg, 8 mg, 12 mg, 18 mg, 24 mg according to actual dose.
Extent of Exposure of Darbepoetin Alfa

Subjects who were randomized but did not report a treatment start date will be categorized as having 
zero days of exposure.

Time on study treatment will be calculated based on the following formula:
Time on study treatment (days)
= [Study Treatment Stop date] – [Study Treatment Start date] + 1 day
The time on study treatment does not exclude dose interruptions.

Cumulative dose will be based on the formula using actual dose:
Cumulative Dose = Sum of Actual Dose at Each Visit

Subject weekly dose (= Cumulative Dose / Time on study treatment) is calculated for each subject using 
actual dose and the summary statistics are calculated based on the subject average weekly dose.

Distribution of the dose level
Dose will be classified into 7 categories; 0 g (i.e. treatment interruption), 10 g, 15 g, 20 g, 
30 g, 40 g, 60 g according to actual dose.
Treatment Compliance of Daprodustat

Treatment compliance will be calculated for daprodustat as follows:
o
Compliance (%) = [(Total # of tablets actual taken) / (Total # of tablets planned taken)] * 100
where
Total # of tablets actual taken = Sum of (Numbers of Tablets Taken at Each Visit)
Total # of tablets planned taken = Sum of [(Treatment Stop Date – Treatment Start Date + 1 day) x 
Planned # of tablet / day in Each Visit]
o
Daprodustat compliance will also be categorized based on calculated compliance:
Calculated compliance < 80%          Under Compliant
Calculated compliance 80% and 120% Compliant
Calculated compliance > 120%         Over Compliant
Where a container number is available, planned # of tablet/day is defined as follows according to the 
protocol:
o
0 mg 1 tablet/day (i.e., subjects takes placebo tablets)
o
1 mg 1 tablet/day
o
2 mg 1 tablet/day
o
4 mg 1 tablet/day
o
6 mg 1 tablet/day
o
8 mg 2 tablets/day
o
12 mg 2 tablets/day
o
18 mg 3 tablets/day
o
24 mg 4 tablets/day
where dose record is derived from prescribed dose.
Where a container number is not available (i.e., bottles not delivered to a subject), planned # of 
tablet/day will be 0 so that the treatment compliance will not be calculated.
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Exposure
Where unscheduled (additional) bottles are being captured, the total # of tablets actual taken will be 
slotted to the corresponding scheduled visit. 
Treatment Compliance of Darbepoetin Alfa

Treatment compliance of darbepoetin alfa will be based on dosing records (weekly doses are captured)
and categorized as Under Compliant, Compliant, and Over Compliant, and will be defined as follows:
o
Calculated compliance < 80%          Under Compliant
o
Calculated compliance 80% and 120% Compliant
o
Calculated compliance > 120%         Over Compliant

Calculated compliance will just be carried to derive compliance category, not provided for any displays. It 
will be carried using the following formula:
o
Calculated compliance (%) = [(Total # of dosing records with container number) / (Total # of planned 
dosing)] * 100
where
Total # of planned dosing = [Time on study treatment (days)] / 7 
where Time on study treatment (days) = Treatment Stop Date – Treatment Start date + 1
When a container number is available in a visit, subjects will receive an injection in the visit (i.e., dosing 
records may be available even when subjects don’t receive injections). 

For compliance up to Week 4, following formulae will be used:
Total # of actual dosing up to Week 4 = Sum of (Number of dosing records with container number 
before Week 4 visit)
Total # of planned dosing up to Week 4 = [Time on study treatment (days) up to Week 4] / 7 

Time on study treatment (days) up to Week 4
= [Week 4 Dosing Date] – [Treatment Start date] + 1 day
If Week 4 dosing date is missing (i.e., withdrawal before Week 4), treatment stop date will be used 
instead.

For compliance during the primary efficacy evaluation period, following formulae will be used:
Total # of actual dosing during the EP = Sum of (Number of dosing records with container number
on and after Week 40 visit).
Total # of planned dosing during the EP = [Time on study treatment (days) during the EP] / 7 

Time on study treatment (days) during the EP
= [Treatment Stop Date] – [Week 40 Dosing Date] + 1 day
If Week 40 dosing date is missing (i.e., withdrawal before Week 40), the compliance will not be 
calculated.
15.6.3.
Efficacy
Hgb Values
Central Laboratory and HemoCue Hgb Values

For reporting purposes, central laboratory Hgb values will be used, unless otherwise specified. However, 
if a central laboratory Hgb value is missing, a corresponding non-missing HemoCue Hgb value, which is 
associated with the identical subject number and visit, will be used.
Evaluable Hgb Values

It will be used for reporting sensitivity analysis results and Hgb listings.

Evaluable Hgb values will be based on on-therapy central laboratory and/or HemoCue Hgb values that 
are not taken within the 8 weeks following a transfusion or within the 8 weeks following a non-
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Hgb Values
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 be regarded as non-evaluable.
o
Blood Product Administration Date < Date ≤Blood Product Administration Date + 56 (days)
o
ESA Start Date < Date of Hgb data ≤ESA Stop Date + 56 (days)
Flowchart for Hgb Analyses

This flowchart will be applicable, unless otherwise specified 

Basically, scheduled visits between Day 1 and Week 52 will be applicable to this flowchart, but analyses 
including by-visit summaries may include other schedued visits (ie. screening and follow-up visit).
[1] Regarding partially evaluated Hgb values, the following summaries of Hgb will include unscheduled visits:

Summary of Time (weeks and %) within Hgb target range during the primary efficacy evaluation 
period

Summary of Number (%) of subjects who have an Hgb level of less than 7.5 g/dL

Summary of Number (%) of subjects who have an Hgb level of more than 13.0 g/dL and number of 
episodes
Hgb Increase of More than 2.0 g/dL over Any 4 Weeks

For this reporting purpose, Hgb values from central laboratory will be used as previously described.

A subject who has at least one record with Hgb increase of more than 2.0 g/dL over any 4 weeks will be 
counted and all episodes will be listed.

Hgb increase will be calculated for scheduled visits between Day 1 and Week 52 if available (i.e. Week 4 
Hgb - Day 1 Hgb, Week 8 Hgb - Week 4 Hgb, ...)
Illustration of calculation (example in case of Week 12 missing, until Week 24 visit)
Hgb
(g/dL)
Lab Date
Study 
Day
Visit
Hgb increase
9.1
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

Odds ratio and its 95% CI will be obtained using the same statistical model described in Section 7.2.5.

When the odds ratio is undefined, it will not be presented.
Scatter Plot of Hgb Assessments: Central Laboratory vs. HemoCue

All available pairs of Hgb (i.e. non-missing values in both from central laboratory and from the 
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Hgb Values
corresponding HemoCue measurement) will be used, regardless of treatment groups and visits. The 
figure will include a linear regression line with 95% CI band, R-squared, and Pearson’s correlation 
coefficient. 
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. Covariates of Interest

The following scatter plot figures will be produced for overall: 

Change from Baseline in Hgb at Week 4 vs. Body Weight at Screening

Change from Baseline in Hgb at Week 4 vs. Baseline Hgb

Change from Baseline in Hgb at Week 4 vs. Prior ESA Dose

Vertical axis will indicate the change from baseline in Hgb (g/dL) at Week 4, horizontal axis will indicate 
the covariates of interest; dry body weight (kg) at screening, baseline Hgb (g/dL), or prior ESA dose 
(IU/week).

Only individual plots will be provided unlike the scatter plot of Hgb assessments.
Scatter Plot of Mean Dose During Week 40 to 52 vs. Covariates of Interest

The following scatter plot figures will be produced for overall: 

Mean Dose during Week 40 to 52 vs. Body Weight at Screening

Mean Dose during Week 40 to 52 vs. Baseline Hgb

Mean Dose during Week 40 to 52 vs. Prior ESA dose

Vertical axis will indicate the mean dose (mg), horizontal axis will indicate the covariates of interest; dry 
body weight (kg) at screening, baseline Hgb (g/dL), or prior ESA dose (IU/week).

Mean dose will be calculated from the arithmetic mean using the latest 3 exposure records (i.e., for 
completers Week 40, 44, and 48), which are based on the actual doses and the scheduled visits.

Subjects who has less than 3 dosing records will be excluded from the figures.

Mean dose during Week 40 to 52 will also be summarized and listed. 

Only individual plots will be provided unlike the scatter plot of Hgb assessments.
Time in Target Range
Time (weeks and percentage) in Target Range During the Primary Efficacy Evaluation Period

For this reporting purpose, on-therapy Hgb values of central laboratory during Week 40 to Week 52, 
including unscheduled visits, will be used. However, if a central laboratory Hgb value is missing, a 
corresponding non-missing HemoCue Hgb value, which is associated with the identical subject number 
and visit, will be used.

Number of days that a subject’s Hgb is within the analysis range of 10.0-12.0 g/dL inclusive between 
Week 40 and 52, including any on-therapy Hgb values that were taken during this time period. Linear 
interpolation is used to estimate Hgb between visits, if a subject has an intermittent missing value
(Rosendaal, 1993).
Illustration of calculation
Hgb
(g/dL)
Lab Date
Visit
Ref 
Day
Hgb Shift
Total shift (%) 
within range
Time in range 
(weeks)
9.9
01AUG2017
Week 
40
0
NC
NC
NC
10.8
01SEP2017
Week 
44
31
0.9 (=10.8-
9.9)
total shift: 0.8
0.8/0.9=88.89%
(31-0)*0.8889/7
=27.56/7 (weeks)
missing
01OCT2017
Week 
48
61
NA
NA
NC
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Time in Target Range
12.4
01NOV2017
Week 
52
92
1.6 (=12.4-
10.8)
total shift: 1.2
1.2/1.6=75%
(92-31)*0.75/7
=45.75/7 (weeks)
Overall time in the target range = (27.56 + 45.75)/7 = 73.31/7 = 10.47 (weeks)
Percent time in the target range = 10.47/(92/7) = 79.68%
NC: Not calculated, NA: Not available

Hgb laboratory assessment date will be used to calculate a duration (Ref Day) between assessments.
o
Duration between assessments = [Hgb lab date] – [Hgb lab date of the previous measurement]
If a subject was withdrawn from the treatment before Week 40 so that the duration between Week 40 to 
Week 52 cannot be calculated, the subject will not be included in a summary.
Basically, the duration should be [Week 52 lab date – Week 40 lab date] unless a subject was withdrawn 
before Week 52. In this case, treatment stop date will be used instead of Week 52.

As an above example, suppose a subject has Hgb reading 9.9 g/dL on August 1st (Week 40), then 
reading if 10.8 g/dL on September 1st. The assumption is made that the week, between these scheduled 
assessments the subjects Hgb increases from 9.9 to 10.8 g/dL in a linear manner. The following steps 
are taken to calculate the time (days) the subject’s Hgb was within target range (10.0 to 12.0 g/dL).
1.
Calculate amount of Hgb shift (9.9 to 10.8 = 0.9 shift) and Hgb shift within range (0.8 out of shift is 
within range of 10.0 – 12.0)
2.
Calculate percent of total shift (%) within range (0.8/0.9 = 88.89%)
3.
Estimate the number of weeks since last visit within range (88.89% x duration between 
assessments = 88.89% x 31/7 weeks = 3.94 weeks within range)
If a subject has an intermittent missing Hgb assessment (on-therapy), the linear interpolation will be 
done by ignoring missing Hgb data.
To calculate overall time (weeks) in Hgb target range, the total days in range for each time period are 
added together and divided by 7. 
The % of time in range between Week 40 and Week 52 for a subject will be calculated by calculating 
overall time (weeks) within range and dividing by the total duration (weeks) between Week 40 to Week 
52. Similarly, the % of time above Hgb target range and % of time above and below Hgb target range will 
be calculated,
Dose Adjustment
Dose Adjustment Algorithm

Note that dose adjustment summaries will be produced only for daprodustat group.

Dose adjustment algorithm will be based on HemoCue Hgb values at scheduled visits. No Hgb values 
measured at unscheduled visits will be included.

Dose will be derived from actual dose associated with container numbers.

The following table illustrates the algorithm using analysis flags as below:
o
(FL_A): Adjustment flags will be counted if actual dose is changed from that of the previous visit.
o
(FL_B): Over 13.0 g/dL flags will be counted if HemoCue Hgb >13.0 g/dL is observed.
o
(FL_C): Interruption flags will be counted if actual dose is zero.
Treatment durations will be calculated based on the following formula:
o
Duration (days) = Treatment Stop Date – Treatment Start Date + 1 day
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Dose Adjustment
Illustration of dose adjustment algorithm (24-week case)
Visit
(Example)
Treatment 
Start date/
Stop date
Duration
HemoCue 
Hgb
(g/dL)
Dose 
(mg)
(FL_A)
(FL_B)
(FL_C)
Adjust-
ment
Over 
13 g/dL
Inter-
ruption
Day 1
01FEB2017/
01MAR2017
29
11.1
4
N
N
N
Week 4
02MAR2017/
15MAR2017
14
11.4
4
N
N
N
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
12.6
0
N
N
Y
Week 20
02JUL2017/
01AUG2017
31
11.7
1
Y
N
N
Week 24
-
-
12.3
-
-
N
-
For programmers, note that the flags are for the purposed of illustration, and are not intended to 
imply any type of requirement.
For summary tables, further details are described within the next items;
o
'Duration (days) of treatment interruption due to Hgb >13.0 g/dL'
o
'Dose adjustment'
Duration (days) of Treatment Interruption due to Hgb >13.0 g/dL
Calculation of duration of treatment interruption due to Hgb >13.0 g/dL will be based on the dose adjustment 
algorithm defined in the protocol.

Duration (days) = Sum of [Duration]n
where
[Duration]n represents exposure duration at visit n to meet the following.

Treatment interruption is made due to HemoCue Hgb over 13.0 g/dL and consecutive until 
treatment is resumed.
In the above illustration, duration = 61 (days), from Week 12 and 16 visit records.
Dose Adjustment
Calculation of frequency of dose adjustment will be based on the above algorithm.

Number of dose adjustment will be counted for each subject as follows:
o
Counts of adjustment flag = 'Y'
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15.6.4.
Safety
Adverse Events
AE up to Week 4
Cut-off date of Week 4 for individuals will be based on Week 4 visit date which is associated with the earliest 
date throughout Week 4 records (i.e., SDTM.SV.STDTC). 
AEs of Special Interest (AESIs)
AESIs are manually-selected at patient-level (i.e. following case-by-case review by members of the SRT 
including representatives from the local Japan team) and not at preferred term level.
AESI categories are classified as follows:

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis

Death, myocardial infarction, stroke, heart failure, thromboembolic events, thrombosis of vascular 
access

Cardiomyopathy

Pulmonary artery hypertension

Cancer-related mortality and tumor progression and recurrence

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization

Exacerbation of rheumatoid arthritis
Thrombosis and tissue ischemia events will be considered to be secondary to excessive erythropoiesis if 
during the window of [AE start date – 30 days, AE start date +15 days] any one of the following 3 events 
occurs:

Any Hgb value > 13 g/dL

Hgb increase > 2 g/dL over 2 weeks

Hgb increase > 4 g/dL over 4 weeks
Note: Thrombosis and tissue ischemia events that need to be considered against the above 3 Hgb events 
will be identified by the case-by-case review.
Note: HemoCue and central laboratory values will be considered separately. Unscheduled Hgb values will 
also be used in the assessment of secondary to excessive erythropoiesis if available.
Note: For the second two bullets, all Hgb values that have an assessment date within the window of [AE start 
date – 58 days, AE start date + 15 days] will be considered.
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
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Laboratory Parameters

The default convention for reporting of clinical laboratory units will be the international system of units (SI 
units).
Lipid Parameters

LDL/HDL cholesterol ratio will be derived from the following equation.
o
LDL/HDL cholesterol ratio = LDL cholesterol (mmol/L) / HDL cholesterol (mmol/L)
Log-Transformation

Lipid parameters will be log-transformed and the percent change from baseline will be reported. Based 
on literature review the distributions of hepcidin and TSAT are skewed and require a log-transformation. 
Other endpoints may also be log-transformed if deemed appropriate (See Section 5.2).
Others

For summaries of the absolute neutrophils and lymphocytes count, PCI cutoffs will be calculated by 
multiplying the percentages given for each subject by the absolute white blood count.
15.6.5.
Pharmacokinetic
General
Dose Level

Summaries by dose level and used tablet strength will be based on an actual dose associated with a 
container number. (See Section 15.6.2). Tablet strength is defined as follows:
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
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 which is actually provided to subjects will be derived from an actual dose of the visit 
(including unscheduled visit) which meets the following:
o
Treatment Start Date Date of last dose taken prior to PK sampling Treatment Stop Date 
Others

Dose normalized PK parameters will be derived from [PK parameters / actual dose (mg)].

In aggregated analyses, data collected in Week 12 and Week 24 will be aggregated.

For the PK parameters calculation, the concentration at 0 hr will be set to 0 and assign zero to NQ 
values.

Individual’s PK parameters calculated less than 4-time point concentrations or any time deviated 
(beyond 30 min of scheduled timepoints) concentrations will be omitted from summaries and figures, 
but presented in a listing.
15.6.6.
Exploratory Endpoint
Iron Endpoints
Subjects Who Used IV and Oral Iron

Number of subjects who used IV and/or oral iron will be summarized

Subjects who used IV and oral iron will be defined as follows:
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
Subjects with on-therapy IV and/or oral iron medication collected in a specific eCRF form 
(CONMEDS-IRON).

Subjects who used Riona (GSK drug code=00752601) will also be regarded as baseline iron use 
subjects in a subgroup analysis and also counted for oral iron use in this summary.

Regarding oral iron use, the number of subjects who used Riona and other than Riona will also be 
counted respectively.
IV Iron Dose by Quarter

Records of on-therapy iron medication will be used for the following calculations

Monthly average IV iron during the treatment period = Total IV iron dose (mg) during the treatment 
period / (duration in the treatment period (days) / 30.4375 days)

Monthly average IV iron by quarter = Total IV iron dose during each quarter (mg) / (duration in a quarter 
(days) / 30.4375 days).

Total IV 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 IV iron dose during each quarter (mg) = (iron dose1*frequency1*duration1) + ... + (iron 
dosen*frequencyn*durationn)
o
Duration (days) = (stop date1 - start date1 + 1) + ... + (stop daten - start daten + 1)
Frequency is defined as follows:
o
If subject receives iron dose with once daily frequency = 1
o
If subject receives iron dose with BID frequency = 2
o
If subject receives iron dose with TID frequency = 3
o
If subject receives iron dose with QID frequency = 4
o
If subject receives iron dose with every x week frequency = 1/(7*x)If subject receives 
iron dose with every x week frequency = 1/(7*x)
o
If subject receives iron dose with x times per week frequency = x/7
o
If subject receives iron dose with x times per month frequency = 1/(30.4375*x)
Total IV iron during the treatment period will be carried in the same manner.

Quarters will be defined as follows:
Start Date
End Date
Treatment 
period
Randomization Date
Treatment Stop Date
Quarter 1
Randomization Date
Treatment Start Date at Week 12 - 1 day
Quarter 2
Treatment Start Date at Week 12
Treatment Start Date at Week 24 - 1 day
Quarter 3
Treatment Start Date at Week 24
Treatment Start Date at Week 40 - 1 day
Quarter 4[1]
Treatment Start Date at Week 40
Treatment Stop Date 
NOTES:

A Quarter End Date will be replaced with treatment stop date (see Section 15.6.1) when 
treatment start date at Week 12, 24, or 40 is missing (i.e. early withdrawal before Week 12, 24, or 
40). In this case, the subsequent Quarter(s) will not be generated. 

Iron medication start/stop date will be defined newly for the analyses in addition to Quarter 
start/end date to derive amount of iron dose within a specified Quarter (analysis flags may be 
used to judge which quarters the iron records should belong to).
[1] Quarter 4 represents the primary efficacy evaluation period.

If iron medication start date < randomization date, the iron medication start date will be replaced with 
randomization date for the analysis.

If iron medication end date > Treatment Stop Date, the iron medication stop date will be replaced with 
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15.6.7.
Patient Reported Outcome
The original version of instructions and questionnaire items for the study are written in Japanese. 
In displays, the items will be translated into English version (can be found at 
http://www.qualitymetric.com for SF-36v2, EuroQol products for EQ-5D-5L).
SF-36v2
Overview of Scoring Algorithm

Scores will be calculated by Optum PRO CoRE. Refer to “User’s Manual for the SF-36v2 Health 
Survey Third Edition, 2011” for further details.

Three sets of summary scores will be calculated based on responses to each item on the SF-36:

Physical Component Summary (PCS) score

Mental Component Summary (MCS) score
Treatment Stop Date for the analysis.

If iron medication start date and stop date step over quarters, the iron medication record will be 
divided; the end date in the former 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 n
(n=1,2,3, & 4)
Quarter n Start Date ≤ Iron Medication Start Date
and
Iron Medication End Date ≤ Quarter n End Date
Quarter n & n+1 (will be divided as 
described above)
(n=1,2, & 3)
Iron Medication Start Date ≤ Quarter n End Date
and
Quarter [n+1] Start Date ≤ Iron Medication Stop Date
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 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 5.2.
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 5.2
Iron Use Subgroup

Subjects who used Riona will also be regarded as baseline iron use subjects in a subgroup analysis.

The baseline iron use will be defined as follows:
o
A subject takes a pre-therapy iron medication and/or a pre-therapy medication of the GSK drug 
code = 00752601 (FERRIC CITRATE; Riona).
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SF-36v2

Domain scores based on the following eight domains

Physical Functioning

Role-Physical (i.e., role limitations due to physical health)

Bodily Pain

General Health

Vitality

Social Functioning

Role-Emotional (i.e., role limitations due to mental/emotional health)

Mental Health
The scoring process is summarized in the following figure (Refer to Figure 5.1 in User’s Manual for the SF-
36v2 Health Survey Third Edition, 2011).
Before submitting an SF-36v2 response set for scoring, the following points will be ensured.

SF-36v2 Acute is being used for this study.

Missing values will be estimated using the Maximum Data Recovery Mode.

2009 U.S. general population will be set for scoring.
EQ-5D-5L / EQ-VAS
Scoring Algorithm

EQ-VAS scores will be summarized based on the numbers participants have written in the box.

Index values will be calculated based on responses to each item on the EQ-5D-5L:

Mobility (level 1 to 5; e.g., level 1 = “I have no problems in waling about”)

Self-Care (level 1 to 5; e.g., level 1 = “I have no problems washing or dressing myself”)

Usual Activities (level 1 to 5; e.g., level 1 = “I have no problems doing my usual activities”)

Pain / Discomfort (level 1 to 5; e.g., level 1 = “I have no pain or discomfort”)

Anxiety / Depression (level 1 to 5; e.g., level 1 = “I am not anxious or depressed”)

Based on the EQ-5D-5L profile, the index value will be carried out using “EQ-5D-
5L_Crosswalk_Index_Value_Calculator.v2” (can be downloaded from the EuroQol website). Japan 
specific value sets will be used.
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15.7.
Appendix 7: Reporting Standards for Missing Data
15.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as follows: A 
completed subject is one who has completed all periods of the study including the 
follow-up visit.

Withdrawn subjects were not replaced in the study.

All available data from subjects who were withdrawn from the study will be listed and all 
available planned data will be included in summary tables and figures, unless otherwise 
specified.
15.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report, if 
applicable.
15.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
When only the start year is provided, a '01' will be used for the day and 'Jan' will be 
used for the month
o
When only the start month and year is provided, a ‘01’ will be used for the day.
o
When only the stop year is provided, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.
o
When only the stop month and year is provided, a ‘28/29/30/31’ will be used for the 
day (dependent on the month and year). 

The recorded partial date will be displayed in listings.
Adverse 
Events

The CRF does not allow for the possibility of partial dates.
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15.8.
Appendix 8: Values of Potential Clinical Importance
15.8.1.
Laboratory Values
Chemistry
Laboratory Parameter
Units
Clinical Concern Range
Low Flag
High Flag
Albumin (serum)
g/L
< 30 g/L
>55 g/L
Aspartate Aminotransferase
IU/L
N/A
3x ULRR
Alanine Aminotransferase
IU/L
N/A
3x ULRR
Bilirubin (total)
mol/L
N/A
2x ULRR
Calcium (albumin-adjusted)
mmol/L
< 1.87 mmol/L
> 2.56 mmol/L
Bicarbonate (total)
mmol/L
< 20 mmol/L
> 32 mmol/L
Inorganic phosphate
mmol/L
< 0.81 mmol/L
> 1.77 mmol/L
Potassium (serum)
mmol/L
> 0.5 mmol/L below 
LLRR
> 1.0 mmol/L above 
ULRR
Sodium (serum)
mmol/L
< 130 mmol/L
> 150 mmol/L
Hemotology
Laboratory Parameter
Units
Clinical Concern Range
Low Flag
High Flag
Platelet Count 
GI/L
< 80 GI/L
> 500 GI/L
WBC Count
GI/L
> 1x LLRR
>5x ULRR
   Neutrophils
GI/L
< 1.0 GI/L
N/A
   Lymphocytes
GI/L
< 0.5 GI/L
N/A
Iron Parameters
Laboratory Parameter
Units
Clinical Concern Range
Low Flag
High Flag
Ferritin
g/L
< 100 g/L
> 1200 g/L
TSAT
%
<15 %
>40 %
Other Parameters
Laboratory Parameter
Units
Clinical Concern Range
Low Flag
High Flag
iPTH
ng/L
N/A
> 9x ULRR
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15.8.2.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85 mmHg
> 180 mmHg
Diastolic Blood Pressure
mmHg
< 45 mmHg
> 110 mmHg
Heart Rate
beats/min
< 40 beats/min
> 110 beats/min
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15.9.
Appendix 9: Abbreviations & Trade Marks
15.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
ANCOVA
Analysis of Covariance
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb/ CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
Hgb
Hemoglobin
HRQoL
Health-Related Quality of Life
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
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Abbreviation
Description
SOP
Standard Operation Procedure
SRT
Safety Review Team
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TIBC
Total Iron Binding Capacity
TSAT
Transferrin Saturation
UIBC
Unsaturated Iron Binding Capacity
UN
Unstructured
VAS
Visual Analog Scale
WBC
Whole Blood Cell
15.9.2.
Trademarks
Trademarks of the GlaxoSmithKline Group 
of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
HemoCue
Optum PRO CoRE
P-TOL
Riona
SAS
S-Plus
WinNonlin
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15.10.
Appendix 10: List of Data Displays
15.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.27
Not applicable
Efficacy
2.1 to 2.58
2.1 to 2.43
Safety
3.1 to 3.50
3.1 to 3.2
Patient Reported Outcome
4.1 to 4.10
Not applicable
Pharmacokinetic
5.1 to 5.8
5.1 to 5.15
Section
Listings
ICH Listings
1 to 33
Other Listings
34 to 71
Patient Profile Listings
72 to 81
15.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Patient Reported Outcome
PRO_Fn
PRO_Tn
PRO_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
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15.10.3.
Table of Contents for Headline Results Deliverable
The numbering of displays will match with that of final statistical analysis.
Headline Results Analysis
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Headline Tables
Study Population
1.1
Randomized
ES8
Summary of Subject Status and Reason for Study Withdrawal
1.10
Safety
DM1
Summary of Demographic Characteristics - Safety
Efficacy
2.1
ITT
EFF_T1
Summary of Hgb (g/dL) by Visit
2.2
ITT
EFF_T1
Summary of Change from Baseline in Hgb (g/dL) by Visit
2.3
mITT
EFF_T2
Summary of Mean Hgb (g/dL) Based on Observed Cases During the 
Primary Efficacy Evaluation Period
2.4
ITT
EFF_T3
Analysis of Mean Hgb (g/dL) During the Primary Efficacy Evaluation Period
– ITT
2.15
mITT
EFF_T5
Analysis of Number (%) of Subjects with Mean Hgb in Target Range During 
the Primary Efficacy Evaluation Period - mITT
Safety
3.1
Safety
AE1
Summary of On-Therapy AEs by SOC and PT
3.8
Safety
AE1
Summary of On-Therapy Drug-Related AEs by SOC and PT
3.17
Safety
AE1
Summary of On-Therapy Serious AEs
3.21
Safety
AE1
Summary of On-Therapy AEs Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment by SOC and PT
3.22
Safety
SAFE_T2
Summary of On-Therapy AEs of Special Interest
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Headline Results Analysis
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
3.48
Safety
SAFE_T6
Summary of Ophthalmologic Exams at Screening
3.49
Safety
SAFE_T7
Summary of On-Therapy Ophthalmologic Exams
Headline Listings
30
Safety
SAFE_L1
Listing of Adverse Events of Special Interest
64
Safety
SAFE_L2
Listing of Ophthalmologic Exams
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15.10.4.
Table of Contents for SAC Deliverable
15.10.4.1. Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Subject’s Disposition
1.1.
Randomized
ES8
Summary of Subject Status and Reason for Study Withdrawal
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.2.
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
Y
1.3.
All Screening
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
Y
1.4.
Enrolled
NS1
Summary of Subjects Enrolled by Country and Site ID
EudraCT/clinical operations
Y
Protocol Deviations
1.5.
Randomized
DV1
Summary of Important Protocol Deviations
ICH E3
Y
1.6.
Randomized
IE1
Summary of Inclusion/Exclusion Criteria Deviations
ICH E3
Y
Population Analyzed
1.7.
Randomized
SP1
Summary of Study Populations
IDSL
Y
1.8.
mITT
SP2
Summary of Exclusions from Per Protocol Population 
IDSL
Y
Demographic and Baseline Characteristics
1.9.
ITT
DM1
Summary of Demographic Characteristics - ITT
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.10.
Safety
DM1
Summary of Demographic Characteristics – Safety
ICH E3, GSK CTR, FDAAA, EudraCT
Y
1.11.
ITT
POP_T1
Summary of Prior ESA – ITT
Y
1.12.
Safety
POP_T1
Summary of Prior ESA - Safety
Y
1.13.
Enrolled
DM11
Summary of Age Ranges
EudraCT
Y
1.14.
Safety
DM5
Summary of Race and Racial Combinations
ICH E3, GSK CTR, FDAAA, EudraCT
Y
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
1.15.
Safety
FH1
Summary of Family History for CV Risk Factors
IDSL
Y
1.16.
Safety
SU1
Summary of Substance Use (History of Tobacco Use, Alcohol 
Intake)
IDSL
Y
Dialysis
1.17.
Safety
POP_T2
Summary of Baseline Mode of Dialysis
Y
1.18.
Safety
POP_T3
Summary of Baseline Mode of Vascular Access
Y
Medical Conditions and Concomitant Medications
1.19.
Safety
MH4
Summary of Current Medical Conditions
ICH E3
Y
1.20.
Safety
MH4
Summary of Past Medical Conditions
ICH E3
Y
1.21.
Safety
CM1
Summary of Concomitant Medications (Pre-Therapy)
ICH E3
Y
1.22.
Safety
CM1
Summary of Concomitant Medications (On-Therapy)
ICH E3
Y
1.23.
Safety
CM1
Summary of Concomitant Medications (Post-Therapy)
ICH E3
Y
1.24.
Safety
CM1
Summary of Other Concomitant Medications (On-Therapy)
Y
1.25.
Safety
POP_T4
Summary of Blood Products and Blood Supportive Care 
Products (On-Therapy)
Y
Exposure and Treatment Compliance
1.26.
Safety
EX1
Summary of Exposure to Study Treatment
Y
1.27.
Safety
POP_T5
Summary of Treatment Compliance
Y
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15.10.4.2. Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
Hgb - General
2.1.
ITT
EFF_T1
Summary of Hgb (g/dL) by Visit
Y
2.2.
ITT
EFF_T1
Summary of Change from Baseline in Hgb (g/dL) by Visit
Y
Mean Hgb based on observed Hgb During the Primary Efficacy Evaluation Period
2.3.
mITT
EFF_T2
Summary of Mean Hgb (g/dL) Based on Observed Cases During 
the Primary Efficacy Evaluation Period
Y
Primary Efficacy Analyses: Model based Mean Hgb During the Primary Efficacy Evaluation Period
2.4.
ITT
EFF_T3
Analysis of Mean Hgb (g/dL) During the Primary Efficacy 
Evaluation Period – ITT
Y
2.5.
mITT
EFF_T3
Analysis of Mean Hgb (g/dL) During the Primary Efficacy 
Evaluation Period – mITT
Y
2.6.
PP
EFF_T3
Analysis of Mean Hgb (g/dL) During the Primary Efficacy 
Evaluation Period – PP
Y
2.7.
ITT
EFF_T3
Analysis of Mean Hgb (g/dL) During the Primary Efficacy 
Evaluation Period – Subgroup
Y
Sensitivity Analyses
2.8.
ITT
EFF_T3
Sensitivity Analysis of Mean Hgb (g/dL) During the Primary 
Efficacy Evaluation Period Using Evaluable Hgb
Y
2.9.
mITT
EFF_T3
Sensitivity Analysis of Mean Hgb (g/dL) During the Primary 
Efficacy Evaluation Period Using ANCOVA – mITT
Y
2.10.
PP
EFF_T3
Sensitivity Analysis of Mean Hgb (g/dL) During the Primary 
Efficacy Evaluation Period Using ANCOVA – PP
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
2.11.
mITT
EFF_T3
Sensitivity Analysis of Mean Hgb (g/dL) During the Primary 
Efficacy Evaluation Period Using ANCOVA - Subgroup
Y
2.12.
ITT
EFF_T4
Tipping Point Summary for Non-Inferiority Test (Daprodustat vs 
Darbepoetin Alfa) – ITT
Y
2.13.
mITT
EFF_T4
Tipping Point Summary for Non-Inferiority Test (Daprodustat vs 
Darbepoetin Alfa) – mITT
Y
2.14.
PP
EFF_T4
Tipping Point Summary for Non-Inferiority Test (Daprodustat vs 
Darbepoetin Alfa) - PP
Y
Number (%) of Subjects with Mean Hgb in Target Range During the Primary Efficacy Evaluation Period
2.15.
mITT
EFF_T5
Analysis of Number (%) of Subjects with Mean Hgb in Target 
Range During the Primary Efficacy Evaluation Period - mITT
Y
2.16.
PP
EFF_T5
Analysis of Number (%) of Subjects with Mean Hgb in Target 
Range During the Primary Efficacy Evaluation Period – PP
Y
2.17.
ITT
EFF_T5
Analysis of Number (%) of Subjects with Mean Hgb in Target 
Range During the Primary Efficacy Evaluation Period - ITT
Y
2.18.
mITT
EFF_T5
Analysis of Number (%) of Subjects with Mean Hgb in Target 
Range During the Primary Efficacy Evaluation Period –
Subgroup
Y
Hgb
2.19.
ITT
EFF_T6
Summary of Number (%) of Subjects by Hgb Change from 
Baseline Category at Week 4 - Daprodustat
Y
2.20.
ITT
EFF_T7
Summary of Number (%) of Subjects with Hgb within Target 
Range by Visit
Screening visit will not be included
Y
2.21.
ITT
EFF_T8
Summary of Time (%) in Hgb Target Range During the Primary 
Efficacy Evaluation Period
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
2.22.
ITT
EFF_T9
Summary of Number (%) of Subjects Who Have Hgb Level of 
Less than 7.5 g/dL
Y
2.23.
ITT
EFF_T9
Summary of Number (%) of Subjects Who Have Hgb Increase of 
More than 2.0 g/dL over Any 4 weeks
Y
2.24.
ITT
EFF_T10
Summary of Number (%) of Subjects Who Have Hgb Level of 
More than 13.0 g/dL and Number of Episodes
Y
Dose Adjustment
2.25.
ITT
EFF_T11
Summary of Dose  by Visit
Y
2.26.
ITT
EFF_T12
Summary of Number (%) of Subjects with Each Dose (/day) by 
Visit - Daprodustat 
Y
2.27.
ITT
EFF_T13
Summary of Number (%) of Subjects with Each Dose (/week) by 
Visit – Darbepoetin Alfa 
Y
2.28.
ITT
EFF_T14
Summary of Duration (days) of Treatment Interruption due to 
Hgb >13.0 g/dL – Daprodustat
Y
2.29.
ITT
EFF_T15
Summary of Dose Adjustment – Daprodustat
Y
Iron Use During the Treatment Period
2.30.
ITT
EFF_T16
Summary of IV Iron Dose (mg) During the Treatment Period
Y
2.31.
ITT
EFF_T17
Summary of Number (%) of Subjects with Iron Use During the 
Treatment Period
Y
2.32.
ITT
EFF_T16
Summary of IV Iron Dose (mg) During the Treatment Period by 
Baseline Iron Use
Y
2.33.
ITT
EFF_T17
Summary of Number (%) of Subjects with Iron Use During the 
Treatment Period by Baseline Iron Use
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
Iron Parameters (ferritin, TSAT, hepcidin, serum iron, and TIBC)
2.34.
ITT
LB1
Summary of Ferritin (ug/L) by Visit
Y
2.35.
ITT
LB1
Summary of Ferritin (ug/L) Change from Baseline by Visit
Y
2.36.
ITT
EFF_T18
Summary of Transferrin Saturation (%) by Visit
Y
2.37.
ITT
EFF_T19
Summary of Transferrin Saturation (%) Percent Change from 
Baseline by Visit
Y
2.38.
ITT
EFF_T18
Summary of Hepcidin (nmol/L) by Visit
Y
2.39.
ITT
EFF_T19
Summary of Hepcidin (nmol/L) Percent Change from Baseline 
by Visit
Y
2.40.
ITT
LB1
Summary of Serum Iron (umol/L) by Visit
Y
2.41.
ITT
LB1
Summary of Serum Iron (umol/L) Change from Baseline by Visit
Y
2.42.
ITT
LB1
Summary of Total Iron Binding Capacity (umol/L) by Visit
Y
2.43.
ITT
LB1
Summary of Total Iron Binding Capacity (umol/L) Change from 
Baseline by Visit
Y
2.44.
ITT
LB1
Summary of Ferritin (ug/L) by Visit by Baseline Iron Use
Y
2.45.
ITT
LB1
Summary of Ferritin (ug/L) Change from Baseline by Visit by 
Baseline Iron Use
Y
2.46.
ITT
EFF_T18
Summary of Transferrin Saturation (%) by Visit by Baseline Iron 
Use
Y
2.47.
ITT
EFF_T19
Summary of Transferrin Saturation (%) Percent Change from 
Baseline by Visit by Baseline Iron Use
Y
2.48.
ITT
EFF_T18
Summary of Hepcidin (nmol/L) by Visit by Baseline Iron Use
Y
2.49.
ITT
EFF_T19
Summary of Hepcidin (nmol/L) Percent Change from Baseline 
by Visit by Baseline Iron Use
Y
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
2.50.
ITT
LB1
Summary of Serum Iron (umol/L) by Visit by Baseline Iron Use
Y
2.51.
ITT
LB1
Summary of Serum Iron (umol/L) Change from Baseline by Visit
by Baseline Iron Use
Y
2.52.
ITT
LB1
Summary of Total Iron Binding Capacity (umol/L) by Visit by 
Baseline Iron Use
Y
2.53.
ITT
LB1
Summary of Total Iron Binding Capacity (umol/L) Change from 
Baseline by Visit by Baseline Iron Use
Y
Hgb – Prior ESA subgroup
2.54.
ITT
EFF_T1
Summary of Hgb (g/dL) by Visit by Prior ESA Type, Prior ESA 
Dose, and ERI
repeat Table 2.1 for prior ESA type, prior ESA 
dose, and ERI subgroup
Y
2.55.
ITT
EFF_T1
Summary of Change from Baseline in Hgb (g/dL) by Prior ESA 
Type, Prior ESA Dose, and ERI
repeat Table 2.2 for prior ESA type, prior ESA 
dose, and ERI subgroup
Y
2.56.
ITT
EFF_T5
Summary of Number (%) of Subjects by Hgb Change from 
Baseline Category at Week 4 by Prior ESA Type, Prior ESA 
Dose, and ERI - Daprodustat
repeat Table 2.16 for prior ESA type, prior 
ESA dose, and ERI subgroup for daprodustat 
group
Y
2.57.
ITT
EFF_T11
Summary of Dose (/day) by Visit by Prior ESA Type, Prior ESA 
Dose, and ERI - Daprodustat
repeat Table 2.22 for prior ESA type, prior 
ESA dose, and ERI subgroup for daprodustat 
group
Y
2.58.
ITT
EFF_T12
Summary of Number (%) of Subjects with Each Dose (/day) by 
Visit by Prior ESA Type, Prior ESA Dose, and ERI –
Daprodustat
repeat Table 2.23 for prior ESA type, prior 
ESA dose, and ERI subgroup for daprodustat 
group
Y
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15.10.4.3. Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Raw Mean Hgb
2.1.
ITT
EFF_F1
Plot of Mean Change from Baseline in Hgb (g/dL) and 95% CIs 
over Time by Treatment
Y
2.2.
ITT
EFF_F1
Plot of Mean Hgb (g/dL) and 95% CIs over Time by Treatment
Y
Model-Based Mean Hgb During the Primary Efficacy Evaluation Period
2.3.
ITT
EFF_F2
Hgb Curve over Time (with 95% Confidence Band) by Mixed 
Model for Repeated Measures by Treatment – ITT
Y
2.4.
mITT
EFF_F2
Sensitivity Hgb Curve over Time (with 95% Confidence Band) by 
Mixed Model for Repeated Measures by Treatment - mITT
Y
2.5.
PP
EFF_F2
Sensitivity Hgb Curve over Time (with 95% Confidence Band) by 
Mixed Model for Repeated Measures by Treatment - PP
Y
2.6.
ITT
EFF_F2
Sensitivity Hgb Curve over Time (with 95% Confidence Band) by 
Mixed Model for Repeated Measures by Treatment – Evaluable 
Hgb
Y
2.7.
ITT
EFF_F3
Forest Plot of Model-Adjusted Treatment Difference 
(Daprodustat vs Darbepoetin Alfa) for Mean Hgb (g/dL) During 
the Primary Efficacy Evaluation Period by Subgroup – MMRM
Y
2.8.
mITT
EFF_F3
Sensitivity Forest Plot of Model-Adjusted Treatment Difference 
(Daprodustat vs Darbepoetin Alfa) for Mean Hgb (g/dL) During 
the Primary Efficacy Evaluation Period by Subgroup - ANCOVA
Y
2.9.
ITT
EFF_F4
Tipping Point Display for Non-Inferiority Test (Daprodustat vs 
Darbepoetin Alfa) – ITT
Y
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
2.10.
ITT
EFF_F4
Tipping Point Display for Non-Inferiority Test (Daprodustat vs 
Darbepoetin Alfa) – mITT
Y
2.11.
ITT
EFF_F4
Tipping Point Display for Non-Inferiority Test (Daprodustat vs 
Darbepoetin Alfa) - PP
Y
Number (%) of Subjects with Mean Hgb in Target Range During Primary Efficacy Evaluation Period
2.12.
ITT
EFF_F5
Forest Plot of Model-Adjusted Odds Ratio (Daprodustat / 
Darbepoetin Alfa) for Proportion of Subjects with Mean Hgb in 
Target Range During the Primary Efficacy Evaluation Period by 
Subgroup
Y
Hgb
2.13.
ITT
EFF_F6
Histogram of Number (%) of Subjects with Hgb within Target 
Range over Time
Like Fig. 2.7.6.2.3.1-2 in NESP CTD 2.7.6
Screening and follow-up visit will not be 
included
Y
2.14.
ITT
EFF_F7
Scatter Plot of Hgb Assessments: Central Laboratory vs. 
HemoCue
Y
Dose Adjustment
2.15.
ITT
EFF_F8
Histogram of Dose by Visit
Y
2.16.
ITT
EFF_F8
Histogram of Dose by Visit by Prior ESA Type, Prior ESA Dose, 
and ERI
Y
Subject Listing
2.17.
ITT
EFF_F9
Subject Profiles of Hgb and Dose over Time
Provided based on active treatment group
Y
Iron Parameters
2.18.
ITT
EFF_F1
Plot of Mean Ferritin (ug/L) Change from Baseline and 95% CI 
over Time
Y
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
2.19.
ITT
EFF_F1
Plot of Geometric Mean Transferrin Saturation Percent Change 
from Baseline and 95% CI over Time
Y
2.20.
ITT
EFF_F1
Plot of Geometric Mean Hepcidin Percent Change from Baseline
and 95% CI over Time
Y
2.21.
ITT
EFF_F1
Plot of Mean Serum Iron (umol/L) Change from Baseline and 
95% CI over Time
Y
2.22.
ITT
EFF_F1
Plot of Mean Total Iron Binding Capacity (umol/L) Change from 
Baseline and 95% CI over Time
Y
2.23.
ITT
EFF_F1
Plot of Mean Ferritin (ug/L) Change from Baseline and 95% CI 
over Time by Baseline Iron Use
Y
2.24.
ITT
EFF_F1
Plot of Geometric Mean Transferrin Saturation Percent Change 
from Baseline and 95% CI over time by Baseline Iron Use
Y
2.25.
ITT
EFF_F1
Plot of Geometric Mean Hepcidin Percent Change from Baseline 
and 95% CI over Time by Baseline Iron Use
Y
2.26.
ITT
EFF_F1
Plot of Mean Serum Iron (umol/L) Change from Baseline and 
95% CI over Time by Baseline Iron Use
Y
2.27.
ITT
EFF_F1
Plot of Mean Total Iron Binding Capacity (umol/L) Change from 
Baseline and 95% CI over Time by Baseline Iron Use
Y
2.28.
ITT
EFF_F1
Plot of Mean Ferritin (ug/L) and 95% CI over Time
Y
2.29.
ITT
EFF_F1
Plot of Geometric Mean Transferrin Saturation (%) and 95% CI 
over Time
Y
2.30.
ITT
EFF_F1
Plot of Geometric Mean Hepcidin (nmol/L) and 95% CI over 
Time
Y
2.31.
ITT
EFF_F1
Plot of Mean Serum Iron (umol/L) and 95% CI over Time
Y
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
2.32.
ITT
EFF_F1
Plot of Mean Total Iron Binding Capacity (umol/L) and 95% CI 
over Time
Y
2.33.
ITT
EFF_F1
Plot of Mean Ferritin (ug/L) and 95% CI over Time by Baseline 
Iron Use
Y
2.34.
ITT
EFF_F1
Plot of Geometric Mean Transferrin Saturation (%) and 95% CI 
over time by Baseline Iron Use
Y
2.35.
ITT
EFF_F1
Plot of Geometric Mean Hepcidin (nmol/L) and 95% CI over 
Time by Baseline Iron Use
Y
2.36.
ITT
EFF_F1
Plot of Mean Serum Iron (umol/L) and 95% CI over Time by 
Baseline Iron Use
Y
2.37.
ITT
EFF_F1
Plot of Mean Total Iron Binding Capacity (umol/L) and 95% CI 
over Time by Baseline Iron Use
Y
Other
2.38.
ITT
EFF_F10
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. Body 
Weight – Daprodustat
Y
2.39.
ITT
EFF_F10
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. 
Baseline Hgb – Daprodustat
Y
2.40.
ITT
EFF_F10
Scatter Plot of Change from Baseline in Hgb at Week 4 vs. Prior 
ESA Dose – Daprodustat
Y
2.41.
ITT
EFF_F10
Scatter Plot of Mean Dose During Week 40 to 52 vs. Body 
Weight – Daprodustat
Y
2.42.
ITT
EFF_F10
Scatter Plot of Mean Dose During Week 40 to 52 vs. Baseline 
Hgb – Daprodustat
Y
2.43.
ITT
EFF_F10
Scatter Plot of Mean Dose During Week 40 to 52 vs. Prior ESA 
Dose – Daprodustat
Y
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15.10.4.4. Safety Tables
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Adverse Events (AEs)
3.1.
Safety
AE1
Summary of On-Therapy AEs by SOC and PT
ICH E3
Y
3.2.
Safety
AE5
Summary of On-Therapy AEs by SOC and PT and Maximum 
Intensity
ICH E3
Y
3.3.
Safety
AE1
Summary of On-Therapy AEs up to Week 4 by SOC and PT
Y
3.4.
Safety
AE5
Summary of On-Therapy AEs up to Week 4 by SOC and PT and 
Maximum Intensity
Y
3.5.
Safety
SAFE_T1
Summary of On-Therapy Common (>=2%) AEs by SOC and PT
by Onset
J-CTD; Not cumulative summary
Y
3.6.
Safety
AE1
Summary of Post-Therapy AEs by SOC and PT
ICH E3
Y
3.7.
Safety
AE5
Summary of Post-Therapy AEs by SOC and PT and Maximum 
Intensity
ICH E3
Y
3.8.
Safety
AE1
Summary of On-Therapy Drug-Related AEs by SOC and PT
ICH E3
Y
3.9.
Safety
AE5
Summary of On-Therapy Drug-Related AEs by SOC and PT and 
Maximum Intensity
ICH E3
Y
3.10.
Safety
AE1
Summary of On-Therapy Drug-Related AEs up to Week 4 by 
SOC and PT
Y
3.11.
Safety
AE5
Summary of On-Therapy Drug-Related AEs up to Week 4 by 
SOC and PT and Maximum Intensity
Y
3.12.
Safety
AE1
Summary of Post-Therapy Drug-Related AEs by SOC and PT
Y
3.13.
Safety
AE5
Summary of Post-Therapy Drug-Related AEs by SOC and PT 
and Maximum Intensity
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
3.14.
Safety
AE3
Summary of On-Therapy Non-Serious Drug-Related AEs
Required for Plain Language Summary
Y
3.15.
Safety
AE3
Summary of On-Therapy Common (>=2%) AEs by Overall 
Frequency
ICH E3
Y
3.16.
Safety
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
3.17.
Safety
AE1
Summary of On-Therapy Serious AEs
GSK CTR
Y
3.18.
Safety
AE1
Summary of Post-Therapy Serious AEs
GSK CTR
Y
3.19.
Safety
AE3
Summary of On-Therapy Serious Drug-Related AEs
Required for Plain Language Summary
Y
3.20.
Safety
AE16
Summary of On-Therapy Serious AEs by SOC and PT (Subjects 
& No. of Occurrences)
FDAAA, EudraCT
Y
3.21.
Safety
AE1
Summary of On-Therapy AEs Leading to Withdrawal from Study 
/ Permanent Discontinuation of Study Treatment by SOC and PT
IDSL
Y
AEs of Special Interest
3.22.
Safety
SAFE_T2
Summary of On-Therapy AEs of Special Interest
Y
3.23.
Safety
SAFE_T2
Summary of Post-Therapy AEs of Special Interest
Y
Laboratory: Chemistry
3.24.
Safety
LB1
Summary of Chemistry Values by Visit 
ICH E3
Includes Baseline values
Y
3.25.
Safety
LB1
Summary of Chemistry Changes from Baseline by Visit
ICH E3
Y
3.26.
Safety
SAFE_T3
Summary of Percent Change from Baseline in Lipid Parameters 
(Total Cholesterol, LDL Cholesterol, HDL Cholesterol, LDL/HDL 
Cholesterol Ratio) by Visit
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
3.27.
Safety
LB15
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline
ICH E3
Y
3.28.
Safety
LB17
Summary of Worst Case Chemistry Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline
ICH E3
Y
Hematology
3.29.
Safety
LB1
Summary of Hematology Values by Visit
ICH E3
Includes Baseline values
Y
3.30.
Safety
LB1
Summary of Hematology Changes from Baseline by Visit
ICH E3
Y
3.31.
Safety
LB15
Summary of Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline
ICH E3
Y
3.32.
Safety
LB17
Summary of Worst Case Hematology Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline
ICH E3
Y
Iron Parameters
3.33.
Safety
LB1
Summary of Iron Parameter by Visit
ICH E3
Includes Baseline values
Y
3.34.
Safety
LB1
Summary of Iron Parameter Changes from Baseline by Visit
ICH E3
Y
3.35.
Safety
LB15
Summary of Worst Case Iron Parameter Results Relative to 
Normal Range Post-Baseline Relative to Baseline
ICH E3
Y
3.36.
Safety
LB15
Summary of Worst Case Iron Parameter Results Relative to PCI 
Criteria Post-Baseline Relative to Baseline
ICH E3
Y
Other Laboratory Tests
3.37.
Safety
LB1
Summary of Other Laboratory Values by Visit
ICH E3
Includes Baseline values
Y
3.38.
Safety
LB1
Summary of Other Laboratory Changes from Baseline by Visit
ICH E3
Y
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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
3.39.
Safety
LB15
Summary of Worst Case Other Laboratory Results Relative to 
Normal Range Post-Baseline Relative to Baseline
ICH E3
Y
3.40.
Safety
LB17
Summary of Worst Case Other Laboratory Results Relative to 
PCI Criteria Post-Baseline Relative to Baseline
ICH E3
Y
Hepatobiliary (Liver)
3.41.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
IDSL
Y
3.42.
Safety
LIVER10
Summary of Subjects Meeting Emergent Hepatobiliary 
Laboratory Abnormality Criteria
IDSL
Y
ECG
3.43.
Safety
EG1
Summary of ECG Findings
IDSL
Y
3.44.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
Y
Vital Signs
3.45.
Safety
SAFE_T4
based on VS1
Summary of Vital Signs by Visit
Summarized by each assessment status (i.e. 
pre- and post-dialysis)
Y
3.46.
Safety
SAFE_T4
based on VS1
Summary Change from Baseline in Vital Signs by Visit
Summarized by each assessment status (i.e. 
pre- and post-dialysis)
Y
3.47.
Safety
SAFE_T5
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- and post-dialysis)
Y
Ophthalmology
3.48.
Safety
SAFE_T6
Summary of Ophthalmologic Exams at Screening
Y
3.49.
Safety
SAFE_T7
Summary of On-Therapy Ophthalmologic Exams
Y
Change in Anti-Hypertensive Medications
3.50.
Safety
SAFE_T8
Summary of Change in Anti-Hypertensive Medications Due to 
Increased Blood Pressure
Y
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15.10.4.5. Safety Figures
Safety Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Adverse Events
3.1.
Safety
AE10
Common (>=2%) On-Therapy AEs Sorted by Relative Risk
IDSL
Y
Clinical Laboratory Analyses
3.2.
Safety
SAFE_F1
Plot of Percent Change from Baseline in Lipid Parameters
(Total Cholesterol, LDL Cholesterol, HDL Cholesterol, LDL/HDL 
Cholesterol Ratio) over Time
Geometric mean and its 95% CI will be 
presented.
Y
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15.10.4.6. Patient Reported Outcome Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
SAC
Patient Reported Outcome
4.1.
ITT
SF2
Summary of SF-36 HR-QoL Scores (PCS, MCS, 8 Subscales)
including PCS and MCS
Y
4.2.
ITT
SF4
Summary of Changes from Baseline in SF-36 HR-QoL Scores
(PCS, MCS, 8 Subscales)
including PCS and MCS
Y
4.3.
ITT
PRO_T1
Summary of EQ-5D-5L Score
Y
4.4.
ITT
PRO_T2
Summary of EQ-5D-5L Index Value
Y
4.5.
ITT
PRO_T2
Summary of Changes from Baseline in EQ-5D-5L Index Value
Y
4.6.
ITT
PRO_T3
Summary of EQ Visual Analog Scale (VAS)
Y
4.7.
ITT
PRO_T3
Summary of Changes from Baseline in EQ Visual Analog Scale 
(VAS)
Y
4.8.
ITT
PRO_T4
Analysis of Changes from Baseline in SF-36 HR-QoL Scores
(PCS, MCS, 8 Subscales)
Y
4.9.
ITT
PRO_T5
Analysis of Changes from Baseline in EQ-5D-5L Index Value
Y
4.10.
ITT
PRO_T5
Analysis of Changes from Baseline in EQ Visual Analog Scale 
(VAS)
Y
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15.10.4.7. Pharmacokinetic Tables
Pharmacokinetic Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Plasma Daprodustat Concentrations
5.1.
PK
PK01
Summary of Daprodustat Plasma Concentration by Dose Level
(non-transformed)
Y
5.2.
PK
PK_T1
based on PK05
Summary of Daprodustat Plasma Concentration by Dose Level
(loge-transformed)
Y
PK parameters
5.3.
PK
PK03
Summary of Daprodustat Pharmacokinetic Parameters by Dose 
Level (non-transformed)
Y
5.4.
PK
PK05
Summary of Daprodustat Pharmacokinetic Parameters by Dose 
Level (loge-transformed)
Y
5.5.
PK
PK03
Summary of Dose Normalized Daprodustat Pharmacokinetic 
Parameters by Dose Level (non-transformed)
Y
5.6.
PK
PK05
Summary of Dose Normalized Daprodustat Pharmacokinetic 
Parameters by Dose Level (loge-transformed)
Y
5.7.
PK
PK03
Summary of Dose Normalized Daprodustat Pharmacokinetic 
Parameters by Used Tablet Strength (non-transformed)
Y
5.8.
PK
PK05
Summary of Dose Normalized Daprodustat Pharmacokinetic 
Parameters by Used Tablet Strength (loge-transformed)
Y
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15.10.4.8. Pharmacokinetic Figures
Pharmacokinetic Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Plasma Daprodustat Concentrations
5.1.
PK
PK24
Individual Daprodustat Plasma Concentration-Time Plots
(Linear and Semi-Log) (by Dose)
Y
5.2.
PK
PK17
Mean Daprodustat Plasma Concentration-Time Plots
(Linear and Semi-Log) (by Dose)
Y
5.3.
PK
PK19
Mean (+SD) Daprodustat Plasma Concentration-Time Plots
(Linear and Semi-Log) (by Dose)
Y
5.4.
PK
PK20
Median Daprodustat Plasma Concentration-Time Plots
(Linear and Semi-Log) (by Dose)
Y
PK parameters
5.5.
PK
PK_F1
Individual Plot of Daprodustat Dose Level and PK Parameters 
(AUC(0-4) and Cmax)
will provide only pooled data 
Y
5.6.
PK
PK_F2
Mean (+SD) Plot of Daprodustat Dose Level and PK Parameters 
(AUC(0-4) and Cmax)
will provide only pooled data
Y
5.7.
PK
PK_F3
Median Plot of Daprodustat Dose Level and PK Parameters 
(AUC(0-4) and Cmax)
will provide only pooled data
Y
5.8.
PK
PK_F1
Individual Plot of Daprodustat Dose Level and Dose Normalized PK 
Parameters (AUC(0-4) and Cmax)
will provide only pooled data
Y
5.9.
PK
PK_F2
Mean (+SD) Plot of Daprodustat Dose Level and Dose Normalized 
PK Parameters (AUC(0-4) and Cmax)
will provide only pooled data
Y
5.10.
PK
PK_F3
Median Plot of Daprodustat Dose Level and Dose Normalized PK 
Parameters (AUC(0-4) and Cmax)
will provide only pooled data
Y
5.11.
PK
PK_F4
Box Plot of Daprodustat Dose Level and Dose Normalized PK 
Parameters (AUC(0-4) and Cmax)
will provide only pooled data
Y
5.12.
PK
PK_F1
Individual Plot of Daprodustat Used Tablet Strength and Dose 
Normalized PK Parameters (AUC(0-4) and Cmax)
will provide only pooled data
Y
5.13.
PK
PK_F2
Mean (+SD) Plot of Daprodustat Used Tablet Strength and Dose 
will provide only pooled data
Y
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Pharmacokinetic Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Normalized PK Parameters (AUC(0-4) and Cmax)
5.14.
PK
PK_F3
Median Plot of Daprodustat Used Tablet Strength and Dose 
Normalized PK Parameters (AUC(0-4) and Cmax)
will provide only pooled data
Y
5.15.
PK
PK_F4
Box Plot of Daprodustat Used Tablet Strength and Dose Normalized 
PK Parameters (AUC(0-4) and Cmax)
will provide only pooled data
Y
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15.10.4.9. ICH Listings
ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Study Population
Subject Disposition
1.
Randomized
ES2
Listing of Reasons for Study Withdrawal
ICH E3
Y
2.
Safety
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
Y
3.
All 
Screening
ES7
Listing of Reasons for Screen Failure
CONSORT Diagram 
Y
4.
Randomized
BL1
Listing of Subjects for Whom the Treatment Blind was Broken
ICH E3
Y
5.
Safety
TA1
Listing of Planned and Actual Treatments
GSK CSR
Y
Protocol Deviations
6.
Randomized
DV2
Listing of Important Protocol Deviations
Y
7.
Randomized
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
Y
Population Analyzed
8.
Randomized
SP3
Listing of Subjects Excluded from Any Population
Subjects excluded from Safety, ITT, mITT, and 
PP will be included.
Y
9.
mITT
SP3
Listing of Subjects Excluded from Per Protocol Population
Include the exclusion categories
Y
Demographic and Baseline Characteristics
10.
Safety
DM2
Listing of Demographic Characteristics
ICH E3
Y
11.
Safety
POP_L1
Listing of Other Baseline Characteristics
Y
12.
Safety
CM2
Listing of Prior ESA
Y
13.
Safety
DM9
Listing of Race
ICH E3
Y
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ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Exposure and Treatment Compliance
14.
Safety
POP_L2
Listing of Exposure Data - Daprodustat
ICH E3
Include placebo daprodustat treatment
Y
15.
Safety
POP_L3
Listing of Exposure Data - Darbepoetin Alfa
ICH E3
Include placebo darbepoetin alfa treatment
Y
16.
Safety
POP_L4
Listing of Study Medication Compliance
ICH E3
Include compliance of placebo treatment
Y
Efficacy
Hgb
17.
ITT
EFF_L1
Listing of Hgb Data
Y
18.
ITT
EFF_L2
Listing of Subjects Who Have an Hgb Level of Less than 
7.5 g/dL
Y
19.
ITT
EFF_L2
Listing of Subjects Who Have an Hgb Increase of More than 
2.0 g/dL over Any 4 weeks
Y
20.
ITT
EFF_L2
Listing of Subjects Who Have an Hgb Level of More than 
13.0 g/dL
Y
21.
ITT
EFF_L3
Listing of Subjects with Treatment Interruption due to Hgb > 
13 g/dL
Y
Safety
Adverse Events
22.
Safety
AE8
Listing of All Adverse Events
ICH E3
Y
23.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
Y
24.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
Y
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ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Serious and Other Significant Adverse Events
25.
Safety
AE8
Listing of Fatal Serious Adverse Events
ICH E3
Y
26.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
Y
27.
All 
Screening
AE8
Listing of Serious AEs in Screening Period
Y
28.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
Y
29.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
Y
30.
Safety
SAFE_L1
Listing of Adverse Events of Special Interest
ICH E3
Displays will be produced with AESI category in 
addition of AE8 template.
Y
All Laboratory
31.
Safety
LB5
Listing of All Chemistry Data for Subjects with Any Value 
Outside of Normal Range/of PCI
ICH E3
Y
32.
Safety
LB5
Listing of All Hematology Data for Subjects with Any Value 
Outside of Normal Range/of PCI
ICH E3
Y
33.
Safety
LB5
Listing of All Other Laboratory Data for Subjects with Any Value 
Outside of Normal Range/of PCI
ICH E3
Y
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15.10.4.10. Other Listings
Other Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Study Population
Demographic and Baseline Characteristics
34.
Safety
FH4
Listing of Family Members with History of Cardiovascular Risk 
Factors
Y
35.
Safety
SU2
Listing of Substance Use History
Y
Medical Conditions and Concomitant Medication
36.
Safety
MH2
Listing of Medical Conditions
Y
37.
Safety
CM2
Listing of Concomitant Medications
Y
38.
Safety
POP_L5
Listing of ESA Concomitant Medications (On-, Post-Therapy)
Y
39.
Safety
POP_L6
Listing of Iron Concomitant Medications
Y
40.
Safety
POP_L7
Listing of Anti-Hypertensive Concomitant Medications
Y
41.
Safety
POP_L8
Listing of Blood Products and Blood Supportive Care Products
Y
Dialysis
42.
Safety
POP_L9
Listing of Baseline Mode of Dialysis
Y
43.
Safety
POP_L9
Listing of Subjects with Changes in Hemodialysis
Y
44.
Safety
POP_L10
Listing of Baseline Mode of Vascular Access
Y
45.
Safety
POP_L11
Listing of Subjects with Vascular Therapeutic Procedures
Y
46.
Safety
POP_L11
Listing of Subjects with Vascular Access Intervention / Revision
Y
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Other Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Safety
Suicidality-Related Adverse Event
47.
Safety
IDSL standard
Listing of Possible Suicidality-Related Adverse Event Data: 
Event and Description (Section 1-Section 2)
Y
48.
Safety
IDSL standard
Listing of Possible Suicidality-Related Adverse Event Data: 
Possible Cause(s) (Section 3)
Y
49.
Safety
IDSL standard
Listing of Possible Suicidality-Related Adverse Event Data: 
(Section 4)
Y
50.
Safety
IDSL standard
Listing of Possible Suicidality-Related Adverse Event Data: 
(Section 5-8)
Y
Clinical Laboratory, ECG, Vital Sign, and Ophthalmology Exam
51.
Safety
LB5
Listing of Chemistry Data
Y
52.
Safety
LB5
Listing of Hematology Data
Y
53.
Safety
LB5
Listing of Other Laboratory Data
Y
54.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
This listing is required for medical review of 
subjects with liver stopping events.
Y
55.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
This listing is required for medical review of 
subjects with liver stopping events.
Y
56.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
Y
57.
Safety
LIVER6
Listing of Liver Stopping Event Information for RUCAM Score
Y
58.
Safety
LIVER7
Listing of Liver Biopsy Details
Y
59.
Safety
LIVER8
Listing of Liver Imaging Details
Y
60.
Safety
EG3
Listing of ECG Values
Y
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Other Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
61.
Safety
EG5
Listing of ECG Findings
Delete column of ‘Clinically Significant Change 
from Baseline?’ from EG5 template
Y
62.
Safety
VS4
Listing of Vital Signs
Y
63.
Safety
VS4
Listing of All Vital Signs for Subjects with Values of PCI
Y
64.
Safety
SAFE_L2
Listing of Ophthalmologic Exams
Y
65.
Safety
SAFE_L3
Listing of Subjects Who Have Any Change in Anti-Hypertensive 
Medications
Y
Other
66.
Safety
PREG1a
Listing of Subjects Who Became Pregnant During the Study
Y
Exploratory Endpoints
67.
Safety
LB5
Listing of Iron Parameter Data
All iron parameters will be included.
Y
Patient Reported Outcome
68.
ITT
PRO_L1
Listing of SF-36v2 Summary Scores and Domain Scores
Including PCS, MCS and 8 subscales
Y
69.
ITT
PRO_L2
Listing of Individual Scores of EQ-5D-5L / VAS
Y
Pharmacokinetic Parameters
70.
PK
PK07
Listing of Daprodustat Pharmacokinetic Concentration-Time 
Data by Dose Level
Y
71.
PK
PK13
Listing of Derived Daprodustat Pharmacokinetic Parameters by 
Dose Level
Y
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15.10.4.11. Patient Profile Listings
Patient Profile Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
SAC
Safety
72.
Safety
IDSL standard
Patient Profile Listing of Arrhythmias
Y
73.
Safety
IDSL standard
Patient Profile Listing of Congestive Heart Failure
Y
74.
Safety
IDSL standard
Patient Profile Listing of Cerebrovascular Events/Stroke/ 
Transient Ischemic Attack
Y
75.
Safety
IDSL standard
Patient Profile Listing of Deep Venous Thrombosis/ Pulmonary 
Embolism
Y
76.
Safety
IDSL standard
Patient Profile Listing of Myocardial Infarction /Unstable Angina
Y
77.
Safety
IDSL standard
Patient Profile Listing of Peripheral Arterial Thrombosis 
Embolism
Y
78.
Safety
IDSL standard
Patient Profile Listing of Pulmonary Hypertension
Y
79.
Safety
IDSL standard
Patient Profile Listing of Revascularization
Y
80.
Safety
IDSL standard
Patient Profile Listing of Valvulopathy
Y
81.
Safety
IDSL standard
Patient Profile Listing of Deaths
Y
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15.11.
Appendix 11: Example Mock Shells for Data Displays
Full mock shells for data displays are developed as separate documents.
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16.
REVISION HISTORY
Note that minor wording changes are not included in below.
Reporting and Analysis Plan_201754_Amendment_Final_V1.1 [06-Aug-2018]
Section # and Name
Description of Change
Brief Rationale
4
Analysis Populations
15.3
Appendix 3: 
Assessment Windows
It has been clarified that Hgb assessments at HemoCue visits (Week 2, 6, 10, …) will not 
be included in the analysis.
Clarification
5.4.2
Examination of
Subgroups
Subgroup definitions for ERI and period of time on dialysis were refined.
It would facilitate review of subgroup results
6
Study Population
Analyses
15.10.4 Table of Contents for 
SAC Deliverable
Some modifications were made for study population displays as below:
1.
Added 2 listings; subjects excluded from any population and subjects excluded from 
per-protocol population
2.
Removed a summary of race and racial combination based on ITT population.
3.
Added a separate listing of study specific baseline characteristics
1.
It would facilitate review of results of 
populations analyzed.
2.
Safety population would be sufficient to 
be assessed
3.
It would facilitate review of results of 
baseline characteristics.
6.2
Planned Summary 
Display Details
Clarifications has been made to the way to display of exposure and treatment compliance.
Clarification
7.1
Primary Efficacy 
Analyses
15.10.4 Table of Contents for 
SAC Deliverable
Added tables of the tipping point analysis
It would facilitate review of tipping point 
results.
7.1.6.3
Tipping Point Analysis
The number of imputations was reconsidered and a text was updated.
Modifications
7.2
Principal Secondary 
Efficacy Analyses
A method to construct 95% CI and a one-sided p-value for odds ratio has been specified
in Section 7.2.5.1 Statistical Methodology Specification
Clarification
7.3
Secondary Efficacy 
Analyses
15.10.4 Table of Contents for 
SAC Deliverable
Added several Hgb summaries by prior ESA dose, prior ESA type, and ERI and a listing of 
subjects with treatment interruption due to Hgb > 13 g/dL. 
It would facilitate review of switching from 
ESA to daprodustat and treatment 
interruption due to Hgb > 13 g/dL
7.3
Secondary Efficacy 
Analyses
Text added to a summary of dose to be provided for both treatment group.
To ensure the dose results for both 
treatment group
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Reporting and Analysis Plan_201754_Amendment_Final_V1.1 [06-Aug-2018]
Section # and Name
Description of Change
Brief Rationale
7.4
Exploratory Efficacy 
Analyses
15.10.4 Table of Contents for 
SAC Deliverable
Figures of the raw observed values for each iron parameter were added.
It would facilitate review of iron parameters
results
7.4
Exploratory Efficacy 
Analyses
It has been clarified that the scatter plot figures will be created for only daprodustat group.
Clarification
7.4
Exploratory Efficacy 
Analyses
Analysis using a mixed model for repeated measures has been added for change from 
baseline in the respective iron parameter in Section 7.4.5.1 Statistical Methodology 
Specification. Also, the strategy for intercurrent events was added as appropriate.
A model-based approach would be 
effectively estimate the results of the iron 
parameters more effectively
8.1.1
Planned Adverse 
Events Analyses Displays
1.
Clarification has been made to a summary of AEs by onset, i.e., the first occurrences 
for each subject will be used for the summary.
2.
Text added to description of a summary of SAEs (subjects & No. of occurrences)
1.
Clarification according to PMDA 
requirement
2.
Correction
8.3
Clinical Laboratory 
Analyses
LDL/HDL cholesterol ratio was added as one of lipid parameters of interest.
It would facilitate review of lipid parameters 
results
8.4.1
Planned Other Safety
Analyses Displays
Update has been made to the ophthalmology exam to add the response (Y/N) to any 
questions.
Clarification
9
Patient Reported 
Outcome Analyses
Clarification has been made to the terminology of EQ-5D-5L scores and the index value.
Clarification
9
Patient Reported 
Outcome Analyses
Statistical methodology specification using a mixed model for repeated measures has 
been added for the change from baseline in the respective QoL parameter in Section 9.5.1
Statistical Methodology Specification. Also, the strategy for intercurrent events was added 
as appropriate.
A model-based approach would be 
effectively estimate the results of the QoL 
parameters more effectively
15.1.1
Exclusions from Per 
Protocol Population
It has been clarified that the exclusion criteria 07 does not include ESA medications.
Clarification
15.5.2
Reporting Standards
Text modified for a detailed description of rules to present summary statistics for 
continuous data.
To avoid internal inconsistency: the details 
of displays were also described in each 
analysis section
15.6.1
Subgroup Definition
Correction was made to the definition of period of time on dialysis. 
Correction
15.6.2
Prior ESA Dose
Correction was made to a numeric character in an illustration table.
Correction
15.6.2
Exposure
1.
Update was made to consider that additional bottles may occur in an unscheduled 
1.
Changed definitions to consider all 
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Section # and Name
Description of Change
Brief Rationale
visit. Text added to clarify that the container number(s) in an unscheduled visit will be 
counted for treatment compliance, however not counted for the actual dose.
2.
Clarification has been made to categorization of treatment compliance of daprodustat 
and a display for darbepoetin alfa.
possible records of drug accountability.
2.
Clarification
15.6.3
Evaluable Hgb Values
Text in evaluable Hgb values corrected.
Correction
15.6.3
Scatter Plot of Hgb 
Assessments
Clarification has been made to a display including the linear regression line with 95% CI 
band, R-squared, and Pearson’s correlation coefficient.
Regarding description of other exploratory scatter plot figures, text corrected appropriately.
Clarification and correction
15.6.3
Time in Target Range
Text added to clarify the general Hgb rule for the whole analysis.
Clarification
15.6.3
Dose Adjustment
1.
Modification has been made to the dose adjustment definition to use the actual dose 
instead of the prescribed dose
2.
Updates were made to the derivation for duration of treatment interruption due to Hgb 
>13.0 g/dL to follow the protocol-defined treatment interruption.
1.
Dose adjustment summaries should be 
focused on actual use in clinical 
practice.
2.
Treatment interruption based on dose 
adjustment algorithm defined in the 
protocol should be provided.
15.6.4
Safety
Text added to identify thrombosis and/or tissue ischemia events secondary to excessive 
erythropoiesis using Hgb criteria.
Hgb criteria would be useful to identify the 
secondary to excessive erythropoiesis 
events in an unbiased way.
15.6.6
Iron Endpoints
Text modified to clarify the handling of Riona and P-TOL in iron endpoints and text related 
to Riona and P-TOL removed from IV iron dose section since they are oral tablets and not 
used for IV iron.
Clinical review; Riona will be absorbed and 
affect iron evaluation so be counted as iron 
use. P-TOL contains nonabsorbable iron so 
not be counted. 
15.6.7
Patient Reported
Outcome
Product name of SF-36 scoring software was updated and the detail of scoring algorithm 
was removed. Also, text added to specify the scoring conditions.
Scoring software is currently updated and a 
newer scoring algorithm is not available at 
present therefore removed.
15.10.3 Table of Contents for 
Headline Results Deliverable
Ophthalmology and AESI results were added to the headline results deliverable.
It would facilitate review of headline results.
15.10.4 Table of Contents for 
SAC Deliverable
Some titles and programming notes were updated for clarifications. Also, the numbering of 
displays has been updated as appropriate.
Based on study team’s review of dry-run 
deliverables, team’s input has been 
reflected. 
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