Clinical trial NCT03493386
Conditions: Anaemia
Keywords: Japan Crossover Daprodustat Bioequivalence Pharmacokinetics
Sponsor: GlaxoSmithKline
Start date: 2018-04-24; Completion date: 2018-06-09
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is two-way crossover study to compare pharmacokinetic (PK) of daprodustat 2 milligram (mg) versus 4 mg tablets and food effect on the PK of daprodustat following single oral doses in healthy Japanese male subjects. This study will be conducted in two parts. Part 1 is the bioequivalence part in which subjects will receive single dose of 2 tablets of 2 mg daprodustat and single dose of 1 tablet of 4 mg daprodustat in crossover manner. Part 2 is Food effect part. In this part, subjects will receive single dose of 4 mg daprodustat tablet in fasting and fed state in a crossover manner. There will 5-day wash-out period between each intervention period. There will be approximately 52 subjects in Part 1 and 12 subjects in Part 2. The study will last for 6 weeks.

Detailed description:

Arms: arm 1: Subjects will be randomized to receive single dose of two tablets of 2 mg daprodustat in Period 1 and in Period 2 subjects will receive single dose of 4 mg daprodustat. There will be a wash-out period of 5 days between the Periods. arm 2: Subjects will be randomized to receive single dose of 4 mg daprodustat in Period 1 and in Period 2 subjects will receive single dose of two tablets of 2 mg daprodustat. There will be a wash-out period of 5 days between the Periods. arm 3: Subjects will be randomized to receive single dose of 4 mg daprodustat in fed state during Period 1 and in Period 2 subjects will receive single dose of 4 mg daprodustat in fasted state. There will be a wash-out period of 5 days between the Periods. arm 4: Subjects will be randomized to receive single dose of 4 mg daprodustat in fasted state during period 1 and in Period 2 subjects will receive single dose of 4 mg daprodustat in fed state. There will be a wash-out period of 5 days between the Periods.
Interventions: intervention 1: Daprodustat 2 mg tablet intervention 2: Daprodustat 4 mg tablet
Intervention descriptions: intervention 1: Daprodustat is available as 2 mg tablet. Subjects will receive daprodustat orally as tablet. A single dose of 2 tablets of 2 mg daprodustat will be administered in a fasted state during Part 1 of the study. intervention 2: Daprodustat is available as 4 mg tablet. Subjects will receive daprodustat orally as tablet. A single dose of 4 mg daprodustat will be administered in a fasted state during Part 1 and in fed and fasted state in Part 2 of the study.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE 
Protocol Title: A single centre, single dose, open-label, randomised, 2-way crossover 
study in healthy Japanese male subjects to evaluate the bioequivalence of daprodustat 
tablets (2 mg tablet vs. 4 mg tablet) (Part 1) and the food effect on the 
pharmacokinetics of daprodustat (Part 2). 
Protocol Number: 207727 
Compound Number: 
GSK1278863 
Study Phase: Phase I 
Short Title: Daprodustat bioequivalence and food effect study 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline K.K. (GSK) 
8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052  
Japan 
Medical Monitor Name and Contact Information  
GlaxoSmithKline K.K. (GSK) 
8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052  
Japan 
Regulatory Agency Identifying Number(s): Not applicable 
Approval Date: 12-Mar-2018 
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 
PPD


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SPONSOR SIGNATORY: 
 
 
Kosuke Kozaiwa, VP  
Head of Japan Medical Affairs, Head of Medicines 
Development, Japan Development & Medical Affairs, 
GlaxoSmithKline K.K. 
 
Date 
 


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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY .......................................................................................... 6 
1.1. 
Synopsis ....................................................................................................... 6 
1.2. 
Schedule of Activities (SoA) .......................................................................... 8 
2. 
INTRODUCTION .................................................................................................... 11 
2.1. 
Study Rationale .......................................................................................... 11 
2.2. 
Background ................................................................................................ 11 
2.3. 
Benefit/Risk Assessment ............................................................................ 12 
2.3.1. 
Risk Assessment ......................................................................... 13 
2.3.2. 
Benefit Assessment ..................................................................... 19 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 19 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 19 
4. 
STUDY DESIGN .................................................................................................... 19 
4.1. 
Overall Design ............................................................................................ 19 
4.2. 
Scientific Rationale for Study Design .......................................................... 21 
4.3. 
Justification for Dose .................................................................................. 21 
4.4. 
End of Study Definition ............................................................................... 21 
5. 
STUDY POPULATION ........................................................................................... 21 
5.1. 
Inclusion Criteria ......................................................................................... 22 
5.2. 
Exclusion Criteria ........................................................................................ 22 
5.3. 
Lifestyle Considerations .............................................................................. 24 
5.3.1. 
Meals and Dietary Restrictions .................................................... 24 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 25 
5.3.3. 
Activity ......................................................................................... 25 
5.4. 
Screen Failures........................................................................................... 25 
6. 
STUDY INTERVENTION ........................................................................................ 25 
6.1. 
Study Intervention(s) Administered ............................................................. 26 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 26 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 27 
6.4. 
Study Intervention Compliance ................................................................... 27 
6.5. 
Concomitant Therapy.................................................................................. 27 
6.6. 
Dose Modification ....................................................................................... 27 
6.7. 
Intervention after the End of the Study ........................................................ 28 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 28 
7.1. 
Discontinuation of Study Intervention .......................................................... 28 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 28 
7.1.2. 
QTc Stopping Criteria .................................................................. 29 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 29 
7.3. 
Lost to Follow Up ........................................................................................ 29 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 30 
8.1. 
Efficacy Assessments ................................................................................. 30 
8.2. 
Safety Assessments ................................................................................... 30 


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8.2.1. 
Physical Examinations ................................................................. 31 
8.2.2. 
Vital Signs .................................................................................... 31 
8.2.3. 
Electrocardiograms ...................................................................... 31 
8.2.4. 
Clinical Safety Laboratory Assessments ...................................... 31 
8.3. 
Adverse Events and Serious Adverse Events ............................................. 31 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 32 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 32 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 32 
8.3.4. 
Adverse Events of Special Interest (AESI) ................................... 32 
8.3.5. 
Regulatory Reporting Requirements for SAEs ............................. 33 
8.4. 
Treatment of Overdose ............................................................................... 33 
8.5. 
Pharmacokinetics ....................................................................................... 34 
8.6. 
Pharmacodynamics .................................................................................... 34 
8.7. 
Genetics ..................................................................................................... 34 
8.8. 
Biomarkers ................................................................................................. 34 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics .................................................................................................. 34 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 34 
9.1. 
Statistical Hypotheses................................................................................. 34 
9.2. 
Sample Size Determination ........................................................................ 35 
9.2.1. 
Sample Size Sensitivity ................................................................ 36 
9.2.2. 
Sample Size Re-estimation or Adjustment ................................... 36 
9.3. 
Populations for Analyses ............................................................................ 36 
9.4. 
Statistical Analyses ..................................................................................... 36 
9.4.1. 
Pharmacokinetic Analyses ........................................................... 36 
9.4.2. 
Safety Analyses ........................................................................... 38 
9.5. 
Interim Analyses ......................................................................................... 38 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 39 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 39 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 39 
10.1.2. 
Financial Disclosure ..................................................................... 39 
10.1.3. 
Informed Consent Process .......................................................... 39 
10.1.4. 
Data Protection ............................................................................ 40 
10.1.5. 
Dissemination of Clinical Study Data ........................................... 40 
10.1.6. 
Data Quality Assurance ............................................................... 41 
10.1.7. 
Source Documents ...................................................................... 41 
10.1.8. 
Study and Site Closure ................................................................ 42 
10.1.9. 
Publication Policy ......................................................................... 42 
10.2. Appendix 2: Clinical Laboratory Tests ......................................................... 43 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 45 
10.3.1. 
Definition of AE ............................................................................ 45 
10.3.2. 
Definition of SAE .......................................................................... 46 
10.3.3. 
Recording and Follow-Up of AE and SAE .................................... 47 
10.3.4. 
Reporting of SAE to GSK ............................................................. 48 
10.4. Appendix 4: Liver Safety Required Actions and Follow-up 
Assessments .............................................................................................. 50 


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10.5. Appendix 5: Country-specific requirements ................................................. 52 
10.6. Appendix 6: Abbreviations and Trademarks ................................................ 55 
11. REFERENCES ....................................................................................................... 58 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A single centre, single dose, open-label, randomised, 2-way crossover 
study in healthy Japanese male subjects to evaluate the bioequivalence of daprodustat 
tablets (2 mg tablet vs. 4 mg tablet) (Part 1) and the food effect on the pharmacokinetics 
of daprodustat (Part 2). 
Short Title: Daprodustat bioequivalence and food effect study 
Rationale: 
This study is composed of two parts. Part 1 aims to evaluate the bioequivalence of 
daprodustat tablets (2 mg tablet vs. 4 mg tablet), and Part 2 aims to evaluate the food 
effect on the pharmacokinetics (PK) of daprodustat. 
Objectives and Endpoints: 
Objective 
Endpoint 
Primary 
Part 1 
• To determine the bioequivalence of 
daprodustat 2 mg tablet vs. 4 mg tablet in 
healthy Japanese male subjects. 
Part 2 
• To investigate the food effect on PK of 
daprodustat following a single dose of 
daprodustat in the fed and fasted state in 
healthy Japanese male subjects. 
Parts 1 and 2 
• Plasma PK parameters for daprodustat: 
AUC(0-t), Cmax, and the other 
parameters [AUC(0-inf), Tmax, 
t1/2, %AUCex, CL/F, Vz/F, kel and MRT] 
Secondary 
Parts 1 and 2 
• To assess the safety and tolerability of 
single dose of daprodustat following 
administration of daprodustat in healthy 
Japanese male subjects. 
Parts 1 and 2 
• Safety: Adverse events (AEs), clinical 
laboratory tests, vital signs (blood 
pressure, pulse and body temperature), 
and 12-lead electrocardiogram (ECG) 
parameters. 
 
Overall Design: 
This study consists of two parts; Part 1 is a single centre, single dose, open-label, 
randomised, 2-way crossover study in healthy Japanese male subjects. Part 2 is a single 


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centre, single dose in the fed and fasted state, open-label, randomised, 2-way crossover 
study in healthy Japanese male subjects.  
In both parts (Part 1 and Part 2), healthy subjects will have a screening visit within 30 
days prior to the first dose of study intervention, two intervention periods, and re-visit 7 
(±1) days after the second dose for follow-up. All subjects will be administered 
daprodustat as a single oral dose, with assessments conducted for up to 24 hours post-
dose. Subjects will be housed in the clinical research unit from Day -1 through Day 2 of 
each period. At least 5-day wash-out period will occur between each intervention period. 
Disclosure Statement: This is an open-label, 2 parts, 2-way crossover study. 
Number of Participants: 
Sufficient participants will be randomised such that approximately 52 and 12 (a total of 
64 participants) evaluable participants complete the study of Part 1 and Part 2, 
respectively. The definition of the study complete is described in the section 4.4. 
If participants prematurely discontinue the study, additional replacement participants may 
be recruited and assigned to the same treatment sequence at the discretion of the Sponsor 
in consultation with the investigator. 
If PK parameters are not within the bioequivalence acceptance criterion because of an 
insufficient number of participants, one add-on participant study can be performed using 
not less than half the number of participants with the same methodology as the initial 
study according to the “Guideline for bioequivalence studies for different strengths of 
oral solid dosage forms [MHLW, 2012]” (Japanese BE guideline). 
Intervention Groups and Duration: 
Subjects will be divided into the study of Parts 1 and 2, and will be randomized to one of 
two groups (Part 1: A or B, Part 2: C or D) in the following table;  
Part 1 (Bioequivalence part) 
• Daprodustat 2 mg tablet x 2, single dose, in the fasted state 
• Daprodustat 4 mg tablet x 1, single dose, in the fasted state 
Group 
n 
Period 1 
Period 2 
A 
26 
2 mg tablet x 2 
4 mg tablet x 1 
B 
26 
4 mg tablet x 1 
2 mg tablet x 2 
 
Part 2 (Food effect part) 
• Daprodustat 4 mg tablet, single dose, in the fed state 
• Daprodustat 4 mg tablet, single dose, in the fasted state 


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Group 
n 
Period 1 
Period 2 
C 
6 
4 mg tablet x 1 (fed) 
4 mg tablet x 1 (fasted) 
D 
6 
4 mg tablet x 1 (fasted) 
4 mg tablet x 1 (fed) 
 
Blood sampling for PK analysis will be performed prior to dosing and until 24 hours 
post-dose following each dose. The duration of each subject’s participation will be 
approximately 6 weeks from screening to the follow-up. 
Data Monitoring Committee: No 
1.2. 
Schedule of Activities (SoA) 
Time and Events Table for both Part 1 and Part 2 of the study. 
 


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Procedure 
Scree
ning1 
Intervention period (Period 1-2) 
Follow-
up 7 
Day 
-1 
Day 1 
Day 2 
Pre-dose 
0 h 
0.5 h 
1 h 
1.5 h 
2 h 
2.5 h 
3 h 
4 h 
6 h 
8 h 
12 h 
24 h 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/Medical history 
X 
Height, Weight, Body mass index (BMI) 
X 
Urine drug screen 
X 
Serology test2 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
Vital signs3 
X 
X 
X 
X 
X 
Clinical laboratory test4 
X 
X 
X 
X 
Study intervention dosing5 
X 
PK blood sampling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE6/Serious adverse events (SAE)6 
<======================================================================================================> 
Concomitant medication review 
<======================================================================================================> 
Admission to unit 
X 
Discharge 
X 
Outpatient visit 
X 
X 
1: Within 30 days prior to Day 1 of Period 1. 
2: Serology tests for syphilis [RPR & TP], Human immunodeficiency virus (HIV) antigen/antibody, Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV) antibody and Human T-
cell lymphotropic virus type 1 (HTLV-1) antibody. 
3: Body temperature (axillary), systolic and diastolic blood pressure and pulse (supine). 
4: Haematology, clinical chemistry and urinalysis. 
5: Subjects will remain in a sitting or semi-supine position for approximately 4 hours if possible after dosing on Day 1. In Part 2, study subjects who are in fed state should take a 
standard meal as recommended for chronic kidney disease (CKD) by the Japanese Society of Nephrology in Japan [Jpn J Nephrol, 2014] in 20 minutes or less and the drug product 
should be administered 30 minutes after the end of the meal. 
6: AEs and SAEs will be collected from the start of intervention until the follow-up visit at the time points specified. However, any SAEs assessed as related to study participation (e.g., 
study treatment, protocol-mandated procedures, or invasive tests) will be recorded from the time a subject consents to participate in the study. 
7: 7(±1) days post-dose of Period 2. 
 


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• 
The timing and number of planned study assessments, including safety, or PK assessments may be altered during the course of 
the study based on newly available data (e.g. to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring.  
• 
Any changes in the timing or addition of time points for any planned study assessments as the result of emerging PK data from 
this study must be documented and approved by the relevant study team member and then archived in the sponsor and site study 
files, but will not constitute a protocol amendment. The Institutional Review Board (IRB) will be informed of any safety issues 
that constitute a substantial amendment and require alteration of the safety monitoring scheme or amendment of the informed 
consent form (ICF). The changes will be approved by the IRB before implementation.


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2. 
INTRODUCTION 
Daprodustat (GSK1278863) is a prolyl hydroxylase inhibitor that stimulates 
erythropoiesis in a manner similar to the natural response to hypoxia, whereby inhibition 
of hypoxia inducible factor (HIF) prolyl-4-hydroxylases (PHD1, PHD2, PHD3) by 
daprodustat ultimately results in increased levels of HIF-responsive genes. Daprodustat is 
currently under development in oral dose as an emerging new class of agent for treatment 
of anaemia associated with chronic kidney disease (CKD). 
2.1. 
Study Rationale 
Daprodustat is formulated as immediate release tablets with dose strengths of 1 mg, 2 mg, 
4 mg and 6 mg. For the commercial formulation coloured film coats will be used for the 
1 mg, 2 mg and 6 mg tablets and white film coat will be remained for 4 mg tablet for the 
Japanese market. The dissolution profiles of these tablets have been evaluated according 
to the Japanese BE guideline, and the dissolution test results across strengths 
demonstrated equivalence with the exception of the 2 mg vs 4 mg test using water. The 
result of the 2 mg vs 4 mg dissolution test using water was considered due to properties 
of the drug substance and the drug products of daprodustat. Considering the 
administration manner for the renal anaemia patients in Japan, the risk that water has any 
effects following administration of daprodustat in humans is low. This study is planned 
according to Japanese Guideline as follows: 
Part 1 
The purpose of Part 1 is to evaluate the bioequivalence between daprodustat tablet 
strengths (2 mg vs. 4 mg) in healthy Japanese male subjects according to the Japanese BE 
guideline. 
Part 2 
The purpose of Part 2 is to evaluate the food effect on the PK of daprodustat in healthy 
Japanese male subjects with reference to Japanese Notification for Clinical 
Pharmacokinetic Studies of Pharmaceuticals [MHLW, 2001]. This part will assess the PK 
of a single oral dose of daprodustat under fasted state and following a standard meal with 
reference to the Dietary recommendations for chronic kidney disease in Japan [Jpn J 
Nephrol, 2014]. 
2.2. 
Background 
As of June 2017, more than 1700 patients and healthy subjects have received daprodustat 
in domestic and overseas clinical trials. For Japanese subjects, a global Phase I study 
including 19 Japanese subjects (dose: 10 - 100 mg single dose) and three Phase II studies 
which are domestic and multinational (dose: up to 12 mg daily including 163 Japanese 
patients) have completed, and three Phase III studies (dose: 1 - 24 mg daily) are ongoing. 
Administration of daprodustat in development with a high fat/calorie breakfast led to a 
1.0 hr delay in Tmax and 29% decrease in Cmax, and an 8% decrease in AUC in healthy 


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South Asian subjects resident in India (Study PHI113634). These data suggest that 
daprodustat may be administered without regard to food. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
daprodustat is provided in the Investigator’s Brochure (IB). 
2.3. 
Benefit/Risk Assessment 
Summaries of findings from both clinical and non-clinical studies conducted with 
daprodustat can be found in the daprodustat IB and IB supplement(s), if applicable. 
 


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2.3.1. 
Risk Assessment 
The potential risks of clinical significance including adverse events of special interest (AESI)(Section 8.3.4), and the mitigation strategies 
for this protocol taking into account the results of completed clinical and non-clinical studies with daprodustat, are outlined in the table 
below. These sentences are included in the interests of transparency. However, the risks of following events after the single lower dose 
(up to 4 mg) administration in this study are considered very low. 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) [Daprodustat] 
Excessive erythropoiesis (polycythaemia) 
leading to thrombosis and/or tissue ischaemia 
In animal studies, excessive erythropoiesis (haemoglobin (Hgb) 
/haematocrit (Hct) > upper limit normal) attributed to daprodustat was 
associated with vascular congestion, inflammation, microthrombi, and 
tissue ischaemia in a number of organs. 
Phase II dose-ranging studies, and associated statistical and dose 
response modelling has informed Phase III dose rationale, starting doses, 
dose steps, and dose adjustment scheme to optimize Hgb management. 
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat at clinically relevant doses. 
 
Specific eligibility criteria related to 
requirements for entry Hgb are detailed in 
Exclusion Criteria. 
 
Hgb will be closely monitored throughout the 
dosing period as outlined in the SoA (Section 
1.2). 
 
Specific guidance for discontinuation of 
daprodustat based on Hgb is provided in 
Section 7.1. 
 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 
Death, Myocardial infarction (MI), stroke, heart 
failure, thromboembolic events, thrombosis of 
vascular access at Hgb levels which are within 
the normal range (i.e. not polycythaemic 
conditions) 
Marketed recombinant human erythropoietin (rhEPO) and its analogues 
have been associated with an increased risk for death and serious 
cardiovascular (CV) events when used in patients with anaemia of CKD. 
In non-clinical studies conducted to date, not observed at tolerated doses 
when Hgb/Hct within normal range for species. 
The clinical data received to date are insufficient to conclude or refute this 
risk. 
 
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 SoA (Section 
1.2).  
 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 
Oesophageal and gastric erosions (e.g. upper 
gastrointestinal (GI) bleeding, severe abdominal 
pain, upper GI perforations)  
In animal studies, undesirable GI effects including emesis, abnormal 
faeces and/or decreased food consumption/body weight loss and stomach 
erosions/ulcers with haemorrhage were observed with daprodustat. 
In rats, stomach erosions were observed with intravenous and oral 
administration of daprodustat. 
Stomach erosions/ulcers also reported in rats with some marketed rhEPO 
 
Suspected GI bleeding or significant symptoms 
consistent with erosions or ulcers should be 
investigated diagnostically (i.e. endoscopic 
examination) as clinically warranted. 
 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
and its analogues. 
In clinical trials to date with daprodustat, mild-moderate GI signs and 
symptoms represent the most frequently reported AE, 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. 
Cancer-related mortality and tumour progression 
and recurrence 
In clinical trials, use of rhEPO and its analogues 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 vascular endothelial growth factor (VEGF) while significant 
erythropoietin (EPO) increases were observed. There were no test article-
related neoplastic findings in 2-year rat (oral daprodustat) or mouse 
(daprodustat + subcutaneous injection of the 3 major human metabolites; 
M2, M3 and M13) carcinogenicity studies. 
In clinical studies conducted to date, administration of daprodustat has 
been associated with: 
Once daily administration: 
 
In 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. 
 
Systemic EPO concentrations within the physiologic range. 
Three times weekly administration: 
In studies up to 4 weeks duration at doses of 10 to 30 mg: 
 
Dose dependent increases in plasma VEGF and EPO concentrations 
were observed. 
 
Pre-dose concentrations of EPO and VEGF were near or below 
baseline indicating no accumulation of EPO or VEGF after three 
times weekly dosing. 
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 
7.1. 
 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 
Pulmonary artery hypertension (PAH) 
A role for HIF-regulated pathways in the pathophysiology of PAH has been 
 
Monitoring of emerging safety data by an 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
suggested based on well-established effects of acute and chronic hypoxia 
in man on the pulmonary vasculature (vasoconstriction), and by findings in 
patients with naturally occurring mutations that result in decreased HIF 
degradation [Smith, 2006; Formenti, 2011]. 
There have been no histopathologic findings suggestive of PAH in pre-
clinical safety studies (up to 13-weeks duration in dogs, up to 2-years in 
rats and mice, and up to 39-weeks in monkeys.) 
Acute hypoxic challenge (rats): Daprodustat produced increases in peak 
right ventricular pressure (PRVP) during acute hypoxia that were slightly 
higher than the vehicle control group. However, these hypoxia-induced 
PRVP changes were within the range of PRVP changes noted among 
untreated rats. 
Results from a clinical study of acute hypoxic challenge in patients 
demonstrated that short-term (5 days) therapy with daprodustat 5 mg or 
100 mg had no clinically significant effect on transthoracic 
echocardiographic estimates of pulmonary artery systolic pressure (PASP) 
under either normoxic or hypoxic conditions. 
Echocardiograph (ECHO) assessments performed in Phase IIb studies 
(24weeks treatment duration) did not identify any clinically meaningful 
changes in PASP in subjects not on dialysis. 
In haemodialysis subjects, mean absolute change from baseline in PASP 
was similar for both treatment groups; however, there was a numeric 
imbalance (GSK Total: 8 [7%]; Control 0) in subjects reaching the PASP 
potential clinical importance (PCI) (>20 mmHg increase from baseline). 
Regarding this imbalance, there were a number of confounding factors in 
the study, most notably a 4.5:1 randomization scheme and inconsistency in 
timing of ECHOs relative to dialysis day. 
Additionally, 2 of 3 subjects with resolution of PASP on safety follow-up 
ECHOs had confounding conditions that could contribute to resolution 
other than discontinuation of study drug; and there was no dose 
relationship for subjects meeting the PASP 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 
internal GSK Safety Review Team 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
identified as a safety concern for daprodustat. 
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. 
With lifetime exposure to daprodustat in a 2-year rat oral carcinogenicity 
study, an exacerbation of rat spontaneous, progressive cardiomyopathy 
(PCM)(focal myofiber degeneration/necrosis with inflammatory infiltrates) 
was observed at doses of 0.8 mg/kg/day and above, although total 
incidence and severity distribution within any daprodustat group were 
within historical control ranges. This is consistent with an equivocal 
threshold for exacerbation of spontaneous, PCM at 0.8 mg/kg/day which is 
also the threshold dose for observing increased Hct values in individual 
rats. 
Cardiomyopathy has not been associated with naturally occurring mutation 
in man which results in increased HIF stabilization. 
ECHO assessments performed in Phase IIb studies (24 weeks treatment 
duration) did not identify any clinically meaningful changes in left 
ventricular ejection fraction (LVEF). 
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.  
 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team 
Proliferative retinopathy, macular oedema, 
choroidal neovascularization 
Increases in local (ocular) VEGF production with retinal neovascularization 
and macular oedema observed in diabetic retinopathy and to choroidal 
leakage, oedema 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. 
Aside from congestion of retinal vessels and optic disc hyperaemia 
secondary to markedly increased red cell mass, no ocular abnormalities 
were observed in non-clinical studies. 
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 administered once daily and from 10 to 30 mg administered three 
times weekly. 
 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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 IIb studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes in 
proliferative retinopathy, macular oedema, or choroidal neovascularization. 
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat. 
Exacerbation of rheumatoid arthritis 
In inflamed rheumatic joints, activation of HIF-related genes secondary to 
decreased oxygen and proinflammatory cytokines has been postulated to 
contribute to the neoangiogenesis, proliferation and infiltration of 
rheumatoid synovial fibroblasts [Westra, 2010; Muz, 2009]. 
No abnormalities were 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. 
 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team 
Drug-drug interactions 
Daprodustat is a substrate of cytochrome P450 (CYP)2C8: 
Co-administration of daprodustat with a strong CYP2C8 inhibitor (i.e., 
gemfibrozil) increased the Cmax and AUC of daprodustat, 4- and 19-fold, 
respectively, while co-administration of a weak CYP2C8 inhibitor (i.e., 
trimethoprim) increased the Cmax and AUC of daprodustat by 1.3- and 
1.5-fold, respectively. Population PK analysis from completed Phase II 
studies suggests that co-administration of daprodustat with a moderate 
CYP2C8 inhibitor (i.e., clopidogrel) leads to a ~ 2-fold increase in AUC, 
with no clinically significant increase in the measured Hgb response. 
Although CYP2C8 induction studies were not performed, co-administration 
of daprodustat with an inducer of CYP2C8 (e.g. rifampin/rifampicin) may 
decrease the exposure of daprodustat. 
Even though co-administration of daprodustat with strong inhibitors and 
inducers of CYP2C8 is prohibited, inadvertent co-administration may 
occur. Due to the known time delay in enhancing erythropoiesis by 
daprodustat, co- administration with strong CYP2C8 inhibitors for up to 
14 days is not anticipated to lead to immediate marked increases in Hgb 
levels. Therefore, there is adequate time to change to alternate therapy 
that does not inhibit CYP2C8. 
Additionally, as the time for maximum induction of CYP2C8 occurs after 
 
Co-administration of daprodustat with all 
medicine is basically not permitted as outlined 
in Section 6.5. 
 
Hgb will be closely monitored throughout the 
dosing period as outlined in the SoA (Section 
1.2). 
 
Specific guidance for discontinuation of 
daprodustat based on Hgb is provided in 
Section 7.1. 
 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
approximately 10 - 14 days of dosing with rifampin [Brodie, 2013; 
Ohnhaus, 1989], daprodustat systemic exposure will decrease over time 
which will result in a lag period before an effect on Hgb is recognized and 
is of clinical concern. 
Daprodustat is an inhibitor of CYP2C8:  
A clinical drug interaction study between 25 mg and 100 mg daprodustat 
with a CYP2C8 substrate (i.e., pioglitazone) showed that there is no PK 
interaction at these doses of daprodustat. 
Daprodustat is a substrate of breast cancer resistance protein (BCRP): 
Population PK analysis from Phase II studies suggested that while BCRP 
inhibitors were a covariate for daprodustat CL/F (8.6% lower clearance) the 
predicted change in exposure was not considered to be of clinical 
relevance. 
Daprodustat is an inhibitor of organic anion transporter polypeptide 
(OATP)1B1/1B3:  
A clinical drug interaction study between 25 mg and 100 mg daprodustat 
with an OATP1B1/1B3 substrate (i.e., rosuvastatin) showed that no PK 
interaction at this these doses of daprodustat. 
 


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2.3.2. 
Benefit Assessment 
This study is being conducted in healthy male Japanese subjects with no significant 
medical history. Subjects will not receive benefit from this study.  
2.3.3. 
Overall Benefit: Risk Conclusion 
Overall, the available data from non-clinical and clinical studies has not identified 
prohibitive risks associated with daprodustat at the exposures planned for this study.  
While there are a number of important potential risks identified for daprodustat, these 
can be addressed in clinical trials with proper subject selection, close safety 
monitoring, and specific risk characterization and mitigation. 
 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
Part 1 
• To determine the bioequivalence of 
daprodustat 2 mg tablet vs. 4 mg 
tablet in healthy Japanese male 
subjects. 
Part 2 
• To investigate the food effect on PK 
of daprodustat following a single dose 
of daprodustat in the fed and fasted 
state in healthy Japanese male 
subjects. 
 
Parts 1 and 2 
• Plasma PK parameters for 
daprodustat: AUC(0-t), Cmax, and the 
other parameters [AUC(0-inf), Tmax, 
t1/2, %AUCex, CL/F, Vz/F, kel and 
MRT]. 
 
Secondary 
Parts 1 and 2 
• To assess the safety and tolerability 
of single dose of daprodustat 
following administration of 
daprodustat in healthy Japanese 
male subjects. 
 
Parts 1 and 2 
• 
Safety: AEs, clinical laboratory tests, vital 
signs (blood pressure, pulse and body 
temperature), and 12-lead ECG 
parameters. 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This study consists of two parts; Part 1 is a single centre, single dose, open-label, 
randomised, 2-way crossover study in healthy Japanese male subjects. Part 2 is a 


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single centre, single dose in the fed and fasted state, open-label, randomised, 2-way 
crossover study in healthy Japanese male subjects.  
In both parts (Part 1 and Part 2), healthy subjects will have a screening visit within 30 
days prior to the first dose of study intervention, two intervention periods, and re-visit 
7 (±1) days after the second dose for follow-up. All subjects will be administered 
daprodustat as a single oral dose, with assessments conducted for up to 24 hours post-
dose. Subjects will be housed in the clinical research unit from Day -1 through Day 2 
of each period. At least 5-day wash-out period will occur between each intervention 
period. 
Subjects will participate in Parts 1 and 2, and receive the study intervention shown 
below; 
Part 1 (Bioequivalence part) 
• Daprodustat 2 mg tablet x 2, single dose, in the fasted state 
• Daprodustat 4 mg tablet x 1, single dose, in the fasted state 
Group 
n 
Period 1 
Period 2 
A 
26 
2 mg tablet x 2 
4 mg tablet x 1 
B 
26 
4 mg tablet x 1 
2 mg tablet x 2 
 
Part 2 (Food effect part) 
• Daprodustat 4 mg tablet, single dose, in the fed state 
• Daprodustat 4 mg tablet, single dose, in the fasted state 
Group 
n 
Period 1 
Period 2 
C 
6 
4 mg tablet x 1 (fed) 
4 mg tablet x 1 (fasted) 
D 
6 
4 mg tablet x 1 (fasted) 
4 mg tablet x 1 (fed) 
 
Blood sampling for PK analysis will be performed prior to dosing and until 24 hours 
post-dose following each dose. The duration of each subject’s participation will be 
approximately 6 weeks from screening to the follow-up. 
Number of Participants 
Sufficient participants will be randomised such that approximately 52 and 12 (a total 
of 64 subjects) evaluable participants complete the study of Part 1 and Part 2, 
respectively. The definition of the study complete is described in the section 4.4. 
If participants prematurely discontinue the study, additional replacement participants 
may be recruited and assigned to the same treatment sequence at the discretion of the 
sponsor in consultation with the investigator. 
If PK parameters are not within the bioequivalence acceptance criterion because of an 
insufficient number of participants, one add-on participant study can be performed 


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using not less than half the number of participants with the same methodology as the 
initial study according to the Japanese BE guideline. 
4.2. 
Scientific Rationale for Study Design 
This is a 2-way crossover study design to compare the PK of daprodustat tablet (2 mg 
tablet vs. 4 mg tablet) and food effect on the PK of daprodustat following single oral 
doses in healthy Japanese male subjects. Part 1 is designed according to the Japanese 
BE guideline. To investigate the food effect in the closer clinical practice, a standard 
meal as recommended by the Japanese Society of Nephorology for chronic kidney 
disease [Jpn J Nephrol, 2014] will be used in Part 2. 
A previous single-dose study in healthy male Japanese subjects (PHI115385) using an 
earlier tablet formulation confirmed that the mean t1/2 of daprodustat from 10 
to100 mg was approximately 1.0 - 2.1 hours. Therefore, in this study, subjects will be 
hospitalised for 2 days in each period and undergo the examinations for safety 
assessments. The wash out between the 2 intervention periods is set to be ≥ 5 days, 
and the follow-up visit is set to be up to 7 (±1) days post the dose in Period 2. 
4.3. 
Justification for Dose 
A study is planned for the evaluation of the bioequivalence of daprodustat tablets 
(2 mg tablet vs. 4 mg tablet) (Part 1), because the dissolution tests of these tablets in 
water failed to demonstrate equivalence. To evaluate the bioequivalence of the 
daprodustat 2 mg and 4 mg tablet strengths, a single 4 mg dose has been selected for 
PK evaluation.  
To investigate the effect of food on the PK of daprodustat (Part 2), a single 4 mg dose 
which is the starting dose in Phase III studies in Japan has been selected. 
As of June 2017, more than 1700 patients and healthy subjects have received 
daprodustat. Overall, single oral doses of up to 500 mg (100 mg for Japanese) and 
repeated dose of up to 100 mg for 14 days administered to healthy subjects have been 
generally well tolerated.  
4.4. 
End of Study Definition 
A subject is considered to have completed the study if he has completed all phases of 
the study including the last scheduled procedure shown in the SoA. 
The end of the study is defined as the date of the last visit of the last subject in the 
study. 
 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 


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5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
Age 
1. Participant must be 20 to 55 years of age inclusive, at the time of signing the 
informed consent. 
Type of Participant and Disease Characteristics 
2. Japanese participants who are overtly healthy as determined by medical 
evaluation including medical history, physical examination, laboratory tests, and 
cardiac monitoring. 
Weight 
3. Body weight  50 kg and body mass index (BMI) within the range 18.5 - 
24.9 kg/m2 (inclusive). 
Sex 
4. Male 
Informed Consent 
5. Capable of giving signed informed consent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the ICF and 
in this protocol. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. History or presence of cardiovascular(CV), respiratory, hepatic, renal, 
gastrointestinal (GI), endocrine, haematological, or neurological disorders 
capable of significantly altering the absorption, metabolism, or elimination of 
drugs; constituting a risk when taking the study intervention; or interfering with 
the interpretation of data 
2. Abnormal blood pressure as determined by the investigator 
3. Alanine aminotransferase (ALT) >1.5x upper limit of normal (ULN) 
4. Bilirubin >1.5xULN (When direct bilirubin <35% is eligible.). 
5. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones). 
6. QTcF > 500 msec 
NOTES: 
• The QTcF is the QT interval corrected for heart rate according to Fridericia’s 
formula, machine-read or manually over-read. 


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• The specific formula that will be used to determine eligibility and 
discontinuation for an individual participant should be determined prior to 
initiation of the study. In other words, several different formulae cannot be 
used to calculate the QT correction (QTc) for an individual participant and 
then the lowest QTc value used to include or discontinue the participant from 
the trial. 
7. The values of haemoglobin (Hgb) at screening: ≥16.0 g/dL 
8. History of deep vein thrombosis, pulmonary embolism or other thrombosis 
related condition 
9. History of myocardial infarction (MI) or acute coronary syndrome, stroke or 
transient ischemic attack 
10. Participants that have undergone cholecystectomy 
11. History of malignancy within the prior 2 years or currently receiving treatment 
for cancer 
NOTES: 
• Only exception is localized squamous cell or basal cell carcinoma of the skin 
definitively treated 12 weeks prior to enrolment. 
12. Any evidence of heart failure, as defined by the New York Heart Association 
(NYHA) functional classification system 
Prior/Concomitant Therapy 
13. Past or intended use of over-the-counter or prescription medication including 
vitamins, diet foods and herbal medications within 14 days prior to first dosing 
Prior/Concurrent Clinical Study Experience 
14. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day 
15. Current enrolment or past participation (i.e. administration of last dose of 
investigational study intervention) within the last 30 days (or 5 half-lives, 
whichever is longer) before signing of consent in this clinical study involving an 
investigational study intervention or any other type of medical research 
Diagnostic assessments 
16. The participant with positive serological test for syphilis (RPR and TPHA), 
Human immunodeficiency virus (HIV) Antigen/Antibody, Hepatitis B surface 
antigen (HBsAg), Hepatitis C virus (HCV) antibody, or Human T-cell 
lymphotropic virus type 1 (HTLV-1) antibody at screening 
17. Positive pre-study drug screen 
Other Exclusions 
18. Regular alcohol consumption within 6 months prior to the study defined as: 
• For an average weekly intake of >14 units for males. One unit is equivalent to 
350 mL of beer, 150 mL of wine or 45 mL of 80 proof distilled spirits. 
19. Smoking or history of regular use of tobacco- or nicotine-containing products 
(e.g. nicotine patch, electronic cigarette) within 6 months prior to screening 


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20. Sensitivity to any of the study interventions, or components thereof, or drug or 
other allergy that, in the opinion of the investigator or medical monitor, 
contraindicates participation in the study 
21. History of donation of blood or blood products ≥ 400 mL within 3 months or ≥ 
200 mL within 1 month prior to the first dosing day 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
• 
Subjects must fast from all food and drink (except water) at least 10 hours prior 
to any laboratory safety evaluations. 
• 
Refrain from consumption of red wine, apples, star fruit, or citrus fruits/juices 
including blood oranges (with the exception of oranges, mandarins and lemons) 
from 7 days prior to the first dose of study medication until collection of the final 
PK sample, unless in the opinion of the Investigator and GSK Medical Monitor 
this will not interfere with the study procedures and compromise subject safety. 
• 
Subjects must refrain from any food and drink except those provided during 
hospitalisation. Furthermore, subjects should avoid being crapulous and keep 
routine eating habits in mind when discharged. 
• 
Lunch and dinner will be provided at approximately 4 and 10 hours post dose, 
respectively. 
Part 1 
• 
Subjects will refrain from any food and drink (except water) at least 10 hours 
before dosing and 4 hours after dosing on Day 1 of Period 1 and Period 2. 
• 
No water is allowed within 2 hours before and after dosing, but it is allowed ad 
libitum at all other times. 
Part 2 
• 
Subjects should fast 10 hours before administration of a standard diet of CKD or 
dosing on Day 1 of Period 1 and Period 2. 
• 
The standard CKD meal will consist of the following contents based on the 
dietary recommendations for CKD patients issued by the Japanese Society of 
Nephrology [Jpn J Nephrol, 2014]. 
Contents 
Calorie (kcal) 
Protein (g) 
Salt (g) 
Potassium (mg) 
Criteria 
500 - 700 
12 - 16 
1≤, <2 
≤500 
 
• 
Study subjects who are in fed state should consume a standard CKD meal in 20 
minutes or less as breakfast and the drug product should be administered 30 
minutes after the end of the meal. 
• 
No water is allowed until 2 hours after dosing, but it is allowed ad libitum at all 
other times. 
• 
The meal contents of Periods 1 and 2 on administration day are the same. 


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5.3.2. 
Caffeine, Alcohol, and Tobacco 
• 
During each dosing session, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g. coffee, all type of tea, cola drinks, and 
chocolate) for 24 hours before the start of dosing until after collection of the final 
PK sample. 
• 
During each dosing session, subjects will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK sample.  
• 
Use of tobacco products will not be allowed from screening until the follow-up 
visit. 
5.3.3. 
Activity 
• 
Subjects will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Subjects may participate in light 
recreational activities during studies (e.g. watching television, reading, radio 
calisthenics). 
5.4. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently randomised. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure subjects to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened. 
 
6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed 
product(s), placebo, or medical device(s) intended to be administered to a study 
subject according to the study protocol. 


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6.1. 
Study Intervention(s) Administered 
Study intervention 
name: 
Daprodustat 2 mg tablet 
Daprodustat 4 mg tablet 
Dosage formulation: 
White film coated tablet 
White film coated tablet 
Unit dose strength(s)/ 
Dosage level(s): 
2 mg tablet strength / 4 mg 
dosage level 
4 mg tablet strength / 4 mg 
dosage level 
Route of administration  Oral 
Dosing instructions: 
Administered in the fasted state 
in the morning with 150 mL of 
room temperature water 
Administered in the fasted (and 
fed in part 2) state in the 
morning with 150 mL of room 
temperature water 
Packaging and labelling 
Study intervention will be provided in bottles. Each bottle will be 
labelled as required per country requirement.  
Manufacturer 
GlaxoSmithKline 
 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm that appropriate temperature 
conditions have been maintained during transit for all study intervention received 
and any discrepancies are reported and resolved before use of the study 
intervention. 
2. Only subjects enrolled in the study may receive study intervention and only 
authorised site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labelled storage 
conditions with access limited to the investigator and authorised site staff. 
3. The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, 
and record maintenance (i.e. receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual.  
5. Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. 
6. A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK. 
 


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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open label study. Subjects will be divided into the study of Parts 1 and 2, 
and assigned to one of two groups (Part 1: A or B, Part 2: C or D) in accordance with 
the randomisation schedule generated by the Biomedical Data Sciences Department at 
GSK. 
A description of each group is provided in the table below: 
Part 1 (Bioequivalence part) 
• Daprodustat 2 mg tablet x 2, single dose, in the fasted state 
• Daprodustat 4 mg tablet x 1, single dose, in the fasted state 
Group 
n 
Period 1 
Period 2 
A 
26 
2 mg tablet x 2 
4 mg tablet x 1 
B 
26 
4 mg tablet x 1 
2 mg tablet x 2 
 
Part 2 (Food effect part) 
• Daprodustat 4 mg tablet, single dose, in the fed state 
• Daprodustat 4 mg tablet, single dose, in the fasted state 
Group 
n 
Period 1 
Period 2 
C 
6 
4 mg tablet x 1 (fed) 
4 mg tablet x 1 (fasted) 
D 
6 
4 mg tablet x 1 (fasted) 
4 mg tablet x 1 (fed) 
 
6.4. 
Study Intervention Compliance 
Subjects will receive study intervention directly from the investigator or designee, 
under medical supervision in the clinic. The date and time of each dose administered 
in the clinic will be recorded in the source documents. The dose of study intervention 
and study subject identification will be confirmed at the time of dosing by a member 
of the study site staff other than the person administering the study intervention. Study 
site personnel will examine each subject’s mouth to ensure that the study intervention 
was ingested. 
6.5. 
Concomitant Therapy 
Subjects must abstain from taking other prescription or non-prescription drugs 
(including vitamins and dietary or herbal supplements) within 14 days or 5 half-lives 
(whichever is longer) before the start of study intervention until completion of the 
follow-up visit, unless, in the opinion of the investigator and sponsor, the medication 
will not interfere with the study. 
6.6. 
Dose Modification 
This protocol allows no dose modification. 


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6.7. 
Intervention after the End of the Study 
Subjects will not receive any additional intervention from GSK, after completion of 
the study because only healthy subjects are eligible for study participation. 
 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
A subject may permanently discontinue study treatment at any time at his own request, 
or at the discretion of the investigator for safety or compliance reasons. A subject 
must permanently discontinue study intervention for the pre-specified reasons below. 
• 
Hgb value greater than the ULN. 
• 
Diagnosis of cancer (new or recurrent), with the exception of localized squamous 
cell or basal cell carcinoma of the skin. 
• 
Liver chemistry abnormalities exceeding the threshold criteria (Section 7.1.1). 
• 
QTc abnormalities exceeding the threshold criteria (Section 7.1.2). 
In all cases, the reason for study intervention discontinuation and the date of the last 
dose will be recorded in the subject’s case report form (CRF) and the subject will be 
withdrawn from the study as described in Section 7.2. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Study intervention will be discontinued for a subject if liver chemistry stopping 
criteria are met: 
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm 
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
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 Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 4. 
7.1.2. 
QTc Stopping Criteria 
The same QTc formula must be used for each individual subject to determine 
eligibility for and discontinuation from the study. This formula may not be changed or 
substituted once the subject has been enrolled. 
• 
For example, if a subject is eligible for the protocol based on QTcF, then 
QTcF must be used for discontinuation of this individual subject as well. 
• 
Once the QTc formula has been chosen for a subject’s eligibility, the same 
formula must continue to be used for that subject for all QTc data being 
collected for data analysis. Safety electrocardiograms (ECGs) and other non-
protocol specified ECGs are an exception.   
If the single QTc value meets either bulleted criterion, the additional double QTc 
values should be obtained over a brief (e.g. 5 - 10 minute) recording period. 
A subject that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study intervention. 
• 
QTcF > 500 msec 
• 
Change from baseline:  QTc >60 msec 
See the SoA for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons.  
• 
The participant will be permanently discontinued both from the study 
intervention and from the study at that time. 
• 
If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
• 
If a participant withdraws from the study, he/she may request destruction of 
any samples taken and not tested, and the investigator must document this in 
the site study records. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 


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• 
The site must attempt to contact the participant and reschedule the missed 
visit as soon as possible and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he will be considered to 
have withdrawn from the study.  
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timings are summarized in the SoA.  
• 
Protocol waivers or exemptions are not allowed.  
• 
Immediate safety concerns should be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject should 
continue or discontinue study intervention. 
• 
Adherence to the study design requirements, including those specified in the 
SoA, is essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will 
maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical 
management (e.g. blood count) and obtained before signing of ICF may be 
utilized for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and was performed within the time frame defined 
in the SoA. 
• 
The maximum amount of blood collected from each subject over the 
duration of the study, including any extra assessments that may be required, 
will not exceed 400 mL. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples. 
8.1. 
Efficacy Assessments 
Efficacy assessments are not evaluated in this study. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 


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8.2.1. 
Physical Examinations 
• 
A physical examination will include, at a minimum, assessments of the Skin, 
CV, Respiratory, GI and Neurological systems.  
• 
Height and weight will be measured and recorded at screening. 
• 
Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
8.2.2. 
Vital Signs 
• 
Axillary temperature, pulse, and blood pressure will be assessed. 
• 
Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated 
device is not available. 
• 
Vital signs will be measured in a supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse. 
8.2.3. 
Electrocardiograms 
• 
Single 12-lead ECG will be obtained as outlined in the SoA using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTcF intervals. Refer to Section 7.1.2 for QTcF withdrawal criteria 
and additional QTcF readings that may be necessary. 
8.2.4. 
Clinical Safety Laboratory Assessments 
• 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed 
and to the SoA for the timing and frequency.  
• 
The investigator must review the laboratory report, document this review, 
and record any clinically relevant changes occurring during the study in the 
adverse event (AE) section of the CRF. The laboratory reports must be filed 
with the source documents. Clinically significant abnormal laboratory 
findings are those which are not associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the 
subject's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to 
normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor.  
• 
If such values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the aetiology should be identified and 
the sponsor notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 2 must 
be conducted in accordance with the laboratory manual and the SoA. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 


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The investigator and any qualified designees are responsible for detecting, 
documenting, and reporting events that meet the definition of an AE or SAE and 
remain responsible for following up AEs that are serious, considered related to the 
study intervention or the study, or that caused the subject to discontinue the study 
intervention (see Section 7).  
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from the start of intervention until the follow-up visit 
at the time points specified in the SoA. However, any SAEs assessed as related to 
study participation (e.g., study intervention, protocol-mandated procedures, or 
invasive tests) will be recorded from the time a subject consents to participate in 
the study. 
• 
All AEs will be collected from the start of intervention until the follow-up visit at 
the time points specified in the SoA. 
• 
Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section. 
• 
All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in Appendix 
3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of 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 
considers the event to be reasonably related to the study intervention or study 
participation, the investigator must promptly notify the sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3. 
• 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the subject is the preferred method 
to inquire about AE occurrence. 
8.3.3. 
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 8.3.4) will be followed until the event is resolved, stabilized, 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is given in Appendix 3. 
8.3.4. 
Adverse Events of Special Interest (AESI) 
AESI have been identified based on non-clinical studies with daprodustat, clinical 
experience with recombinant human erythropoietins (rhEPOs), and current 


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information regarding HIF-regulated pathways in mediating hypoxia-associated 
pathophysiology. The currently identified AESI for daprodustat are as follows: 
• Thrombosis and tissue ischemia secondary to excessive erythropoiesis 
• Death, MI, stroke, venous thromboembolism, thrombosis of vascular access 
• Cardiomyopathy 
• Pulmonary artery hypertension (PAH) 
• Increased cancer-related mortality and tumor progression and recurrence 
• Esophageal and gastric erosions 
• Proliferative retinopathy, macular edema, choroidal neovascularization 
• Exacerbation of rheumatoid arthritis 
8.3.5. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study intervention under clinical investigation are 
met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study 
intervention under clinical investigation. The sponsor will comply with 
country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB, and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected 
serious adverse reactions (SUSAR) according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE 
or other specific safety information (e.g. summary or listing of SAE) from 
the sponsor will review and then file it along with the IB and will notify the 
IRB, if appropriate according to local requirements. 
8.4. 
Treatment of Overdose 
For this study, any dose of daprodustat greater than 4 mg within a 24-hour time period 
will be considered an overdose. 
There is no specific antidote for overdose with daprodustat.  The expected 
manifestations of daprodustat overdose include signs and symptoms associated with 
an excessive and/or rapid increase in Hgb concentration. 
In the event of a suspected overdose, it is recommended that the appropriate 
supportive clinical care be instituted, as dictated by the subject’s clinical status. 
Additionally, subjects should be monitored closely for CV events, increased heart rate 
and haematologic abnormalities. 
In the event of an overdose, the investigator should: 
1. Contact the Medical Monitor immediately. 


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2. Closely monitor the subject for AE/SAE and laboratory abnormalities until 
daprodustat can no longer be detected systemically (at least 14 days). 
3. Obtain a plasma sample for PK analysis within 14 days from the date of the last 
dose of study intervention if requested by the Medical Monitor (determined on a 
case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF. 
Decisions regarding dose interruptions or modifications will be made by the 
investigator in consultation with the Medical Monitor based on the clinical evaluation 
of the subject. 
8.5. 
Pharmacokinetics 
Blood samples of approximately 3 mL will be collected for measurement of plasma 
concentrations of daprodustat as specified in the SoA. Instructions for the collection 
and handling of biological samples will be provided by the sponsor. The actual date 
and time (24-hour clock time) of each sample will be recorded. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Health Economics OR Medical Resource Utilization and 
Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters 
are not evaluated in this study. 
 
9. 
STATISTICAL CONSIDERATIONS 
The primary objective of Part 1 is to assess the bioequivalence of different 
daprodustat tablets strength (2 mg vs 4 mg) in healthy Japanese male subjects. 
The primary objective of Part 2 is to investigate food effect on PK of daprodustat in 
the fed state and fasted state in healthy Japanese male subjects. 
9.1. 
Statistical Hypotheses 
Part 1 
The bioequivalence between daprodustat 2 mg tablet and 4 mg tablet will be 
demonstrated using a framework of statistical hypothesis testing. The ratio of the 


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geometric means (2mg/4mg) for AUC(0-t) and Cmax is the measure in the following 
statistical hypotheses: 
H0 (null hypothesis)  
: 2mg/4mg ≤ 0.80 or 2mg/4mg ≥ 1.25, 
H1 (alternative hypothesis) 
: 0.80 < 2mg/4mg < 1.25 
A judgment by 90% CI will be conducted in this study. The null hypothesis is rejected 
if the 90% confidence interval (CI) of 2mg/4mg falls within a range of 0.80 to 1.25, 
which results a conclusion of the bioequivalence. This is equivalent to carrying out 
two one-sided tests of hypothesis at the 5% level of significance.  
If the 90% CI of 2mg/4mg doesn’t fall within a range of 0.80 to 1.25 (i.e., null 
hypothesis is not rejected), the bioequivalence is established if the point estimate 
(2mg/4mg) falls within a range of 0.90 to 1.11. 
Part 2 
No formal statistical hypotheses will be tested. 
9.2. 
Sample Size Determination 
Part 1 
Refer to regulatory definition of bioequivalence criteria; 90% CI of the ratio for 
AUC(0-t) and Cmax between tablet strengths (2 mg x 2 vs. 4 mg x 1) should lie in the 
range of 0.80-1.25. Assuming the true ratio is 1.0 and the coefficient of variation 
within subject (%CVw) is 35%, in a 2-way crossover design 52 subjects in total (i.e. 
26 subjects for each group) will be randomised to achieve at least 90% power for 
meeting the bioequivalence criteria.  
The %CVw has been assumed conservatively from Japanese data in the previous 
Japanese study (PHI115385, Part 1) based on a power model using all dose groups. 
The power model used to estimate %CVw is as below. 
loge(PK parameter) =  + Si + β*log(Dj) + εij 
where  is the intercept, β is the slope, Si is the random effect for subject i, Dj is the 
dose, εij is the random error. The %CVw estimates based on the random error are 
24.3% and 26.8% for AUC(0-inf) and Cmax, respectively. For a little more 
conservative looking at higher variation in lower strength doses, an estimate 
of %CVw has been set to be 35% for sample size considerations.  
Part 2 
The number of subjects is determined based on the feasibility rather than statistical 
considerations. A total of 12 subjects (i.e. 6 subjects for each group) will be 
randomised in a 2-way crossover design. Assuming a %CVw of 35% for AUC(0-t) 
and Cmax as described, it is estimated that the lower and upper bounds of the 90% CI 
for the ratio of AUC(0-t) and Cmax in the fed and fasted state will be within +/- 30%. 
If the estimated ratio is 1.0, its 90% CI would be approximately (0.78, 1.29). 


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9.2.1. 
Sample Size Sensitivity 
Part 1 
The powers for achieving the bioequivalence criterion based on the sample size of 52 
are shown in the following table with various scenarios changing the %CVw. 
 
%CVw 
25% 
30% 
35% 
40% 
45% 
Power 
99.6% 
97.1% 
90.2% 
79.5% 
66.7% 
 
Part 2 
The lower and upper bounds of the 90% CI for the ratio of AUC(0-t) or Cmax in the 
fed and fasted state are shown in the following table with various scenarios 
changing %CVw based on the sample size of 12, assuming the estimated ratio is 1.0. 
 
%CVw 
25% 
30% 
35% 
40% 
45% 
90% CI 
(0.83, 1.20) 
(0.80, 1.24) 
(0.78, 1.29) 
(0.75, 1.33) 
(0.73, 1.37) 
  
9.2.2. 
Sample Size Re-estimation or Adjustment 
No sample size re-estimation or adjustment is planned. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled 
All subjects who signed the ICF 
Safety 
This population will be defined for each Part. 
• All randomised subjects who received at least one dose of 
study intervention. 
PK 
This population will be defined for each Part. 
• All subjects in the Safety population who had at least 1 non-
missing PK assessment (Non-quantifiable [NQ] values will be 
considered as non-missing values). 
 
9.4. 
Statistical Analyses 
9.4.1. 
Pharmacokinetic Analyses 
All PK analyses will be performed on the PK Population for each Part.  
For each tablet strength (Part 1) and the fed and fasted state (Part 2), the plasma 
concentrations of daprodustat will be summarized by nominal time and individual 


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plasma concentration-time profiles and median/mean profiles will be plotted. Each of 
the figures will contain one plot on the untransformed scale (i.e. a linear plot) and one 
plot on the log transformed scale (i.e. a log-linear plot). 
For both Part 1 and Part 2, from the plasma concentration-time data, the following PK 
parameters will be determined by non-compartmental methods with Phoenix 
WinNonlin (version 6.3 or higher), as data permit: AUC(0-t), AUC(0-inf), Cmax, 
Tmax, t1/2, %AUCex, CL/F, Vz/F, kel, MRT, and correlation coefficient between 
time and log concentration of daprodustat for the points used in estimation of kel. The 
bioequivalence between the tablets will be confirmed with comparisons of the values 
of the logarithmic parameters [AUC(0-t) and Cmax]. 
Calculations will be based on the actual sampling times recorded during the study. PK 
data, except for the correlation coefficient between time and log concentration for the 
points used in estimation of kel, will be presented in graphical and/or tabular form and 
will be summarized descriptively, using summary statistics (n, arithmetic mean with 
associated 95% CI, standard deviation (SD), minimum, median, and maximum). 
Except for Tmax, geometric mean with associated 95% CI, SD on loge scale and 
coefficient of variation between subjects (%CVb) will also be provided. Listings will 
be generated for each derived plasma PK parameters. 
The following statistical analysis methods will be used to assess the bioequivalence in 
Part 1 and the food effect in Part 2: 
Part 1 
Statistical Analysis Methods 
The exposure (Cmax and AUC(0-t)) of daprodustat will be assessed by using a mixed 
effect model as described below: 
loge (PK parameter) = 0 +i + j + k + l + εijkl 
where 0 is the intercept, i is the random subject effect for ith subject, j is the tablet 
strength effect (j = 2 mg or 4 mg), k is the period effect (k = period 1 or period 2), l is 
the group effect (l= group A or group B), and εijkl is the random error. The Kenward-
Roger degree of freedom approach will be used.  
Point estimates (loge) for the model-based means of PK parameters on loge scale will be 
provided for each tablet strength and a point estimate of the mean difference between 
tablet strengths (loge2mg - loge4mg) will be constructed along with the associated 90% 
CIs using the residual variances. The point estimates, the point estimate of the mean 
difference, and the associated 90% CIs on loge scale will be exponentially back-
transformed to obtain the model-based geometric means (), and the ratio for AUC(0-t) 
and Cmax (2mg/4mg) and the associated 90% CIs, respectively.  
The bioequivalence will be evaluated using the following criteria of Japan BE guideline. 
Evaluate using criterion 1 first, if criteria are not met, criterion 2 is used. 
• 
Criterion 1 
The 90% CIs of the ratios of the geometric means for AUC(0-t) and Cmax 
(2mg/4mg ) are within the range of 0.80 - 1.25. 


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• 
Criterion 2 
The ratio of the geometric means for AUC(0-t) and Cmax (2mg/4mg) is within the 
range of 0.90 - 1.11. 
 
Part 2 
Statistical Analysis Methods 
To estimate the food effect on PK parameters (Cmax and AUC(0-t)) of daprodustat, the 
PK parameters will be analysed using a mixed effect model as described as below: 
loge (PK parameter) = 0 +i + j + k + l + εijkl 
where 0 is the intercept, i is the random subject effect for ith subject, j is the food effect 
(j = fed or fasted), k is the period effect (k = period 1 or period 2), l is the group effect 
(l= group C or group D), and εijkl is the random error. The Kenward-Roger degree of 
freedom approach will be used. 
Point estimates (loge) for the model-based means of PK parameters on loge scale will be 
provided for the fed and fasted state and a point estimate of the mean difference between 
fed and fasted state (logefed - logefasted) will be constructed along with the associated 
90% CIs using the residual variances. The point estimates, the point estimate of the mean 
difference, and the associated 90% CIs on loge scale will be exponentially back-
transformed to obtain the model-based geometric means (), the ratio for AUC(0-t) and 
Cmax (fed/fasted) and the associated 90% CIs, respectively. 
 
9.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population for each Part.  
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards. 
AEs, changes from baseline in clinical laboratory tests, vital signs (blood pressure, 
pulse and body temperature), and 12-lead ECG parameters will be summarized for 
each tablet strength (Part 1) and the fed or fasted state (Part 2). No statistical 
comparison will be made for the safety summaries. 
9.5. 
Interim Analyses 
No interim analysis is planned in this study. 
 


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10. 
SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
(ICH) Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, IB, and other relevant documents 
(e.g. advertisements) must be submitted to an IRB by the investigator and 
reviewed and approved by the IRB before the study is initiated.  
• 
Any amendments to the protocol will require IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects.  
• 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB 
annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB. 
• Notifying the IRB of SAE or other significant safety findings as 
required by IRB procedures. 
• Providing oversight of the conduct of the study at the site and 
adherence to requirements of 21 Code of Federal Regulation (CFR), 
ICH guidelines, the IRB, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations. 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory 
authorities. Investigators are responsible for providing information on financial 
interests during the course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study 
to the participant or his legally authorized representative and answer all 
questions regarding the study.  


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• 
Participants must be informed that their participation is voluntary. 
Participants or their legally authorized representative will be required to sign 
a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB or 
study centre.  
• 
The medical record must include a statement that written informed consent 
was obtained before the participant was enrolled in the study and the date the 
written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
• 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any 
participant records or datasets that are transferred to the sponsor will contain 
the identifier only; participant names or any information which would make 
the participant identifiable will not be transferred.  
• 
The participant must be informed that his personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level 
of disclosure must also be explained to the participant. 
• 
The participant must be informed that his medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel 
appointed by the sponsor, by appropriate IRB members, and by inspectors 
from regulatory authorities. 
10.1.5. 
 Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an investigator 
signatory will be identified for the approval of the clinical study report 
(CSR). The investigator will be provided reasonable access to statistical 
tables, figures, and relevant reports and will have the opportunity to review 
the complete study results at a GSK site or other mutually-agreeable location. 
• 
GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study subjects, as appropriate. 
• 
GSK will provide the investigator with the randomisation codes for their site 
only after completion of the full statistical analysis. 
• 
The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study 
will be in accordance with GSK Policy. 
• 
GSK intends to make anonymized patient-level data from this trial available 
to external researchers for scientific analyses or to conduct further research 
that can help advance medical science or improve patient care. This helps 


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ensure the data provided by trial subjects are used to maximum effect in the 
creation of knowledge and understanding. 
• 
A manuscript will be progressed for publication in the scientific literature if 
the results provide important scientific or medical knowledge. 
10.1.6. 
Data Quality Assurance 
• 
All subject data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g. 
laboratory data). The investigator is responsible for verifying that data 
entries are accurate and correct by physically or electronically signing the 
CRF.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
The investigator must permit study-related monitoring, audits, IRB review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
Monitoring details describing strategy (e.g. risk-based initiatives in 
operations and quality such as Risk Management and Mitigation Strategies 
and Analytical Risk-Based Monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the 
Monitoring Plan. 
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• 
The sponsor assumes accountability for actions delegated to other 
individuals (e.g. Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of subjects 
are being protected; and that the study is being conducted in accordance with 
the currently approved protocol and any other study agreements, ICH GCP, 
and all applicable regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of 
this study must be retained by the investigator for 25 years from the issue of 
the final CSR/ equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written 
notification to the sponsor.  
10.1.7. 
Source Documents 
• 
Source documents provide evidence for the existence of the subject and 
substantiate the integrity of the data collected. Source documents are filed at 
the investigator’s site. 
• 
Data reported on the CRF or entered in the electronic case report form 
(eCRF) that are transcribed from source documents must be consistent with 


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the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
• 
Definition of what constitutes source data can be found in the list of the 
source documents. 
10.1.8. 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of GSK. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is 
reasonable cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may 
include but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of 
the IRB or local health authorities, the sponsor's procedures, or GCP 
guidelines 
• 
Inadequate recruitment of subjects by the investigator 
• 
Discontinuation of further study intervention development 
10.1.9. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. 
If this is foreseen, the investigator agrees to submit all manuscripts or 
abstracts to the sponsor before submission. This allows the sponsor to protect 
proprietary information and to provide comments.  
• 
The sponsor will comply with the requirements for publication of study 
results. In accordance with standard editorial and ethical practice, the 
sponsor will generally support publication of multicentre studies only in their 
entirety and not as individual site data. In this case, a coordinating 
investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 1 will be performed by the local laboratory.  
• 
Protocol-specific requirements for inclusion or exclusion of subjects are 
detailed in Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as 
determined necessary by the investigator or required by local regulations. 
 
Table 1 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
Mean corpuscular volume 
(MCV) 
Mean corpuscular 
haemoglobin (MCH) 
Mean corpuscular 
haemoglobin concentration 
(MCHC) 
Reticulocyte count (‰) 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell 
(RBC) count 
White blood cell 
(WBC) count 
Hgb 
Hct 
Clinical 
Chemistry1 
Blood urea 
nitrogen 
(BUN) 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
ALT/Serum Glutamic-
Pyruvic Transaminase  
(SGPT) 
Total Protein 
 
Glucose 
(fasting)  
Calcium 
Alkaline phosphatase 
Albumin 
Uric acid 
Triglyceride 
(TG) 
Total Cholesterol 
Low-density 
lipoprotein 
(LDL)-
cholesterol 
High-density 
lipoprotein 
(HDL)-
cholesterol 
Lactate 
dehydrogenase 
(LDH) 
γ-
glutamyltranspeptidase 
(GGT) 
Creatine 
phosphokinase 
(CPK) 
Amylase 
Chloride 
Phosphorus 
 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
• Urine drug screen* (at minimum): Phencyclidines (PCP), 
Benzodiazepines (BZO), Cocaine (COC), Amphetamines (AMP), 
Tetrahydrocannabinol (THC), Opiates (OPI), Barbiturates (BAR), Tricyclic 


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antidepressants (TCA) 
• Immunological*: Serological test for syphilis (RPR and TP), HIV 
antigen/antibody, HBs antigen, HCV antibody, HTLV-1 antibody 
*: Screening only 
NOTES: 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1 and Appendix 4. All events of ALT 3 ×ULN and bilirubin 2 × 
ULN (>35% direct bilirubin) or ALT 3 × ULN 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). 
 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study subject, temporally 
associated with the use of a study intervention, whether or not considered related 
to the study intervention. 
• 
NOTE: An AE can therefore be any unfavourable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (haematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g. ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
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 intervention administration 
even though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition  
• 
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 the AE. 
• 
Situations in which 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) 


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present or detected at the start of the study that do not worsen. 
 
10.3.2. 
Definition of SAE 
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). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
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 inpatient hospitalization or prolongation of existing hospitalization 
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 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils 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 persistent disability/incapacity 
• 
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, diarrhoea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere with 
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 SAE 
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 events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 


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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. 
 
10.3.3. 
Recording and Follow-Up of AE and SAE 
AE 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) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information 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 case, all subject identifiers, with the exception of the 
subject number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 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 causes sufficient discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe.  
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/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. 


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• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the IB and/or Product Information, for 
marketed products, in 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 in which 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 before the initial transmission of the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by GSK to elucidate the nature and/or causality of the AE or SAE as 
fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• 
If a subject dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
10.3.4. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
The investigator or medically-qualified sub-investigator must show evidence 
within the eCRF (e.g. check review box, signature, etc.) of review and 
verification of the relationship of each SAE to IP/study participation (causality) 


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within 72 hours of SAE entry into the eCRF. 
• 
After the study is completed at a given site, the electronic data collection tool 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, then the site can report this information on a paper SAE form 
or to the medical monitor by telephone. 
• 
Contacts for SAE reporting can be found in Appendix 5. 
 
 


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10.4. 
Appendix 4: Liver Safety Required Actions and Follow-up 
Assessments  
Phase I liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
 
ALT-absolute 
 
ALT ≥ 3xULN 
If ALT ≥ 3xULN AND bilirubin1,2  2xULN (> 35% direct bilirubin) or INR > 1.5, 
Report as an SAE. 
See additional Actions and Follow Up Assessments listed below 
Required Actions and Follow up Assessments  
Actions 
Follow Up Assessments 
• 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 chemistry event follow up 
assessments  
• Monitor the subject until liver chemistries 
resolve, stabilise, or return to within 
baseline (see MONITORING below) 
MONITORING: 
If ALT ≥ 3xULN AND bilirubin  2xULN or  
INR > 1.5: 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) 
and perform liver event follow up 
assessments within 24 hrs 
• Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
If ALT ≥ 3xULN AND bilirubin < 2xULN and  
INR ≤ 1.5: 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) 
and perform liver event follow up 
assessments within 24-72 hrs 
• Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
• Viral hepatitis serology3 
• Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Obtain blood sample for PK analysis within 
24 hrs after last dose. 
• CPK and 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 CRF 
• Record use of concomitant medications on 
the concomitant medications CRF page 
including acetaminophen, herbal remedies, 
other over the counter medications. 
• Record alcohol use on the liver event 
alcohol intake CRF page 
If ALT ≥ 3xULN AND bilirubin  2xULN or  
INR > 1.5: 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
• Liver imaging (ultrasound, magnetic 


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Liver Chemistry Stopping Criteria – Liver Stopping Event 
within baseline 
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 intervention for that subject if ALT  3xULN and bilirubin  2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT  3xULN and bilirubin  2xULN (> 35% direct bilirubin) or ALT  3xULN and INR > 1.5, 
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis); and the threshold value stated will not apply to subjects receiving 
anticoagulants 
3. Includes: Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and Hepatitis B core (HBc) antibody; 
Hepatitis C ribonucleic acid (RNA); Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain heterophile antibody or monospot testing) and Hepatitis E IgM antibody. 
 


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10.5. 
Appendix 5: Country-specific requirements 
SPONSOR INFORMATION  
Sponsor Legal Registered Address: 
GlaxoSmithKline K.K. (GSK) 
8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052 Japan 
Study Director: 
 Head, Medicines Development, Clinical 
Pharmacology Office 
Sponsor Contact Address: 
Lead Author: 
 
Manager, GlaxoSmithKline K.K., Medicines Development, Clinical Pharmacology 
Office 
Sponsor’s Emergency Contact Information (10:00 - 18:00, Monday to Friday, except 
national holidays and year-end and new-year holidays); 
Medicines Development (Clinical Pharmacology Office), GlaxoSmithKline K.K. 
TEL: 
 (direct dialling)  
FAX: 
 
Contact Information at Night and on Holidays (Monday to Friday: 18:00 - 10:00, 
Saturday, Sunday, national holidays, year-end and new-year holidays) 
 (mobile: 
  
 (mobile: 
 
GSK’s Medical Monitor: 
 
GlaxoSmithKline K.K. (GSK) 
8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052 Japan 
TEL: 
 (mobile)／
 (direct dialling)  
FAX: 
 
Medical Institution and Investigator: 
 
Medical Co. SOUSEIKAI Fukuoka Mirai Hospital 
5-1 Kashiiteriha 3-chome, Higashi-ku, Fukuoka 813-0017 Japan 
TEL: 
  
FAX: 
 
Laboratories: 
Clinical Laboratory  
Medical Co. SOUSEIKAI Fukuoka Mirai Hospital 
Person in charge: 
 
5-1 Kashiiteriha 3-chome, Higashi-ku, Fukuoka 813-0017 Japan 
TEL: 
 
FAX: 
  
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Serology tests (except HTLV-1) 
Person in charge: 
 
Medical Co. SOUSEIKAI Hakata Clinic 
6-18 Tenyamachi, Hakata-ku, Fukuoka 812-0025 Japan 
TEL: 
 
FAX: 
 
HTLV-1  
Person in charge: 
 
LSI Medience Inc. 
30-1 Shimura 3-chome, Itabashi-ku, Tokyo 174-8555, Japan  
TEL: 
  
FAX: 
 
Bioanalysis  
Person in charge: 
 
PPD 
3230 Deming Way, Middleton, Wisconsin 53562 USA 
TEL: 
 
FAX: 
 
Contract research organization: 
Role: Study Monitoring 
Person in charge (Monitor Leader): 
 
Mediscience Planning Inc. 
6-17 Tenyamachi, Hakata-ku, Fukuoka 812-0025 Japan 
TEL: 
 
FAX: 
 
Role: Medical Writing (Protocol & ICF) 
Person in charge: 
 
Mediscience Planning Inc. 
6-17 Tenyamachi, Hakata-ku, Fukuoka 812-0025 Japan 
TEL: 
 
FAX: 
 
Role: Medical Writing (Clinical Study Report) 
Person in charge: 
 
Mediscience Planning Inc. 
8-10 Toranomon 2-chome, Minato-ku, Tokyo 105-0001 Japan 
TEL: 
 
FAX: 
 
Role: Pharmacokineic Parameter Derivation 
Person in charge: 
 
Mediscience Planning Inc. 
HF Nihonbashi-hamacho Bldg.2-1, Nihonbashi-hamacho 1-chome, Chuo-ku, 
Tokyo 103-0007 Japan 
TEL: 
 
FAX: 
 
Role: Data Loading 
Person in charge: 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Mediscience Planning Inc. 
HF Nihonbashi-hamacho Bldg.2-1, Nihonbashi-hamacho 1-chome, Chuo-ku,  
Tokyo 103-0007 Japan 
TEL: 
 
FAX: 
 
 
PPD
PPD


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10.6. 
Appendix 6: Abbreviations and Trademarks 
Abbreviations 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AMP 
Amphetamines 
AST 
Aspartate aminotransferase 
AUC 
Area under concentration-time curve 
AUC(0-t) 
Area under the concentration-time curve from time 0 to the last 
measurable concentration 
AUC(0-inf) 
Area under the concentration-time curve from time 0 to infinite 
%AUCex 
Percentage of AUC for time t to infinity by extrapolation to AUC(0-inf) 
BAR 
Barbiturates 
BCRP 
Breast cancer resistance protein 
BE 
Bioequivalence 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
BZO 
Benzodiazepines 
CFR 
Code of Federal Regulation 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
Chronic kidney disease 
CL/F 
Apparent clearance following oral dosing 
Cmax 
Maximum observed drug concentration 
COC 
Cocaine 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine phosphokinase 
CRF 
Case report form  
CSR 
Clinical study report 
CV 
Cardiovascular 
CVb 
Coefficient of variation between subjects 
CVw 
Coefficient of variation within subject  
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
ECHO 
Echocardiograph 
eCRF 
Electronic case report form 
EPO 
Erythropoietin 
GCP 
Good Clinical Practice 
GGT 
γ-glutamyltranspeptidase 
GI 
Gastrointestinal 
GSK 
GlaxoSmithKline 
HBc 
Hepatitis B core 
HBsAg 
Hepatitis B surface antigen 
Hct 
Haematocrit 
HCV 
Hepatitis C virus  
HDL 
High-density lipoprotein 
Hgb 
Haemoglobin  
HIF 
Hypoxia inducible factor 


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HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HTLV-1 
Human T-cell lymphotropic virus type 1  
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IDSL 
Integrated Data Standards Library 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
kel 
Elimination rate constant 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
log 
Logarithm 
LVEF 
Left ventricular ejection fraction 
MCH 
Mean corpuscular Hgb 
MCHC 
Mean corpuscular Hgb concentration 
MCV 
Mean corpuscular volume 
MI 
Myocardial infarction 
MRT 
Mean residence time 
MSDS 
Material Safety Data Sheet 
msec 
Millisecond 
NQ 
Non-quantifiable 
NYHA 
New York Heart Association 
OATP 
Organic anion transporter polypeptide  
OPI 
Opiates 
PAH 
Pulmonary artery hypertension  
PASP 
Pulmonary artery systolic pressure 
PCI 
Potential clinical importance  
PCM 
Progressive cardiomyopathy 
PCP 
Phencyclidines 
pH 
Hydrogen-ion exponent 
PHD 
prolyl-4-hydroxylase domain enzyme 
PK 
Pharmacokinetics 
PRVP 
Peak right ventricular pressure  
QTc 
QT correction 
QTcF 
QT duration corrected for heart rate by Friderician formula 
RBC 
Red blood cell 
rhEPO 
Recombinant human erythropoietin  
RNA 
Ribonucleic acid 
RPR 
Rapid Plasma Reagin 
SAE 
Serious adverse event 
SD 
Standard deviation 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SoA 
Schedule of Activities 
SUSAR 
Suspected unexpected serious adverse reactions 


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t1/2 
Terminal half-life 
TCA 
Tricyclic antidepressants 
TG 
Triglyceride 
THC 
Tetrahydrocannabinol 
Tmax 
Time to maximum observed drug concentration 
TP 
Treponema pallidum 
TPHA 
Treponema pallidum haemagglutination test  
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
Vz/F 
Apparent volume of distribution after oral administration  
WBC 
White blood cell 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
daprodustat 
 
WinNonlin 
 
 
 
 
 
 


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11. 
REFERENCES 
Daprodustat (GSK1278863) Investigator's Brochure, Ver.8, 2017 
Guideline for Bioequivalence Studies of Different Strengths of Oral Solid Dosage 
Forms [MHLW, 2012] 
Japanese Notification for Clinical Pharmacokinetic Studies of Pharmaceuticals 
[MHLW, 2001] 
Japanese Society of Nephrology. Dietary recommendations for chronic kidney disease, 
2014. Jpn J Nephrol. 2014;56(5):533-59. 
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.  
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. 
Campochiaro PA and the First ARVO/Pfizer Institute Working Group. Ocular versus 
Extraocular Neovascularization: Mirror Images or Vague Resemblances. Investigative 
Ophthalmol & Vis Sci. 2006;47(2):462-74. 
Westra J, Molema G, Kallenberg CG. Hypoxia-inducible factor-1 as regulator of 
angiogenesis in rheumatoid arthritis - therapeutic implications. Curr Med Chem. 
2010;17(3):254-63.  
Muz B, Khan MN, Kiriakidis S, et al. The role of hypoxia and HIF-dependent 
signalling events in rheumatoid arthritis. Arthritis Res Ther. 2009;11(1):201. 
Brodie MJ, Mintzer S, Pack AM, et al. Enzyme induction with antiepileptic drugs: 
cause for concern? Epilepsia. 2013;54(1):11-27. 
Ohnhaus EE, Breckenridge AM, Park BK. et al. Urinary excretion of 6 beta-
hydroxycortisol and the time course measurement of enzyme induction in man. Eur J 
Clin Pharmacol. 1989;36(1):39-46. 
 

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
207727
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a single centre, single dose, 
open-label, randomised, 2-way crossover study in healthy 
Japanese male subjects to evaluate bioequivalence of 
daprodustat tablets (2 mg tablet vs. 4 mg tablet) (Part 1) and 
the food effect on the pharmacokinetics of daprodustat (Part 
2)
Compound Number 
:
GSK1278863
Effective Date 
:
10-JUL-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 207727.

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
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
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RAP Team Approvals:
Approver
Date
Approval Method
09-JUL-2018
Pharma TMF
Lead Programmer; Statistical Programming & 
Reporting Group, Biomedical Data Sciences 
Japan
09-JUL-2018
Pharma TMF
Clinical Lead; Clinical Pharmacology Office
09-JUL-2018
Pharma TMF
Clinical Scientist; Clinical Pharmacology Office
09-JUL-2018
Pharma TMF
Operational Lead; Clinical Pharmacology Office
09-JUL-2018
Pharma TMF
Data Quality Lead; Data Practice Group, 
Biomedical Data Sciences Japan
09-JUL-2018
Pharma TMF
PK Analyst; Clinical Pharmacology Office
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
10-JUL-2018
Pharma TMF
Lead Authors Line Manager; Biostatistics Group 
2, Biomedical Data Sciences Japan
10-JUL-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......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses / Statistical Analyses .................................................9
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Interim Analyses .........................................................................................10
3.2.
Final Analyses ............................................................................................10
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................12
5.1.
Study Treatment & Sub-group Display Descriptors.....................................12
5.2.
Baseline Definitions ....................................................................................12
5.3.
Examination of Covariates, Other Strata and Subgroups............................13
5.3.1.
Covariates and Other Strata ........................................................13
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................14
6.1.
Overview of Planned Study Population Analyses........................................14
6.1.1.
Details of Planned Study Population Summaries .........................15
7.
SAFETY ANALYSES .............................................................................................16
7.1.
Adverse Events Analyses ...........................................................................16
7.1.1.
Details of Planned Adverse Events Summaries ...........................16
7.2.
Clinical Laboratory Analyses.......................................................................17
7.2.1.
Details of Planned Clinical Laboratory Displays ...........................18
7.3.
Other Safety Analyses ................................................................................18
7.3.1.
Details of Planned Other Safety Displays.....................................19
8.
PHARMACOKINETIC ANALYSES.........................................................................20
8.1.
Pharmacokinetic Analyses..........................................................................20
8.1.1.
Endpoint / Variables.....................................................................20
8.1.1.1.
Drug Concentration Measures....................................20
8.1.1.2.
Derived Pharmacokinetic Parameters.........................20
8.1.2.
Summary Measure ......................................................................21
8.1.3.
Population of Interest...................................................................21
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................21
8.1.5.
Statistical Analyses / Methods .....................................................21
8.1.5.1.
Statistical Methodology Specification..........................21
8.1.6.
Details of Planned Pharmacokinetic Displays ..............................24
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9.
REFERENCES.......................................................................................................25
10. APPENDICES........................................................................................................26
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................26
10.2.
Appendix 2: Schedule of Activities ..............................................................27
10.2.1.
Protocol Defined Schedule of Events...........................................27
10.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................28
10.3.1.
Study Phases ..............................................................................28
10.3.1.1.
Study Phases for Adverse Events ..............................28
10.3.1.2.
Study Phases for Concomitant Medication .................29
10.4.
Appendix 4: Data Display Standards & Handling Conventions....................30
10.4.1.
Reporting Process .......................................................................30
10.4.2.
Reporting Standards....................................................................30
10.4.3.
Reporting Standards for Pharmacokinetic....................................31
10.5.
Appendix 5: Derived and Transformed Data ...............................................32
10.5.1.
General........................................................................................32
10.5.2.
Study Population..........................................................................32
10.5.3.
Safety ..........................................................................................33
10.6.
Appendix 6: Reporting Standards for Missing Data.....................................34
10.6.1.
Premature Withdrawals................................................................34
10.6.2.
Handling of Missing Data.............................................................34
10.6.2.1.
Handling of Missing and Partial Dates and 
Times .........................................................................34
10.7.
Appendix 7: Values of Potential Clinical Importance ...................................36
10.7.1.
Laboratory Values........................................................................36
10.7.2.
ECG.............................................................................................37
10.7.3.
Vital Signs....................................................................................37
10.8.
Appendix 8: Abbreviations & Trade Marks ..................................................38
10.8.1.
Abbreviations...............................................................................38
10.8.2.
Trademarks .................................................................................39
10.9.
Appendix 9: List of Data Displays ...............................................................40
10.9.1.
Data Display Numbering..............................................................40
10.9.2.
Mock Example Shell Referencing ................................................40
10.9.3.
Deliverables.................................................................................40
10.9.4.
Study Population Tables..............................................................41
10.9.5.
Safety Tables...............................................................................42
10.9.6.
Pharmacokinetic Tables...............................................................45
10.9.7.
Pharmacokinetic Figures .............................................................46
10.9.8.
ICH Listings .................................................................................47
10.10. Appendix 10: Example Mock Shells for Data Displays ................................53
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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 GlaxoSmithKline Document Number
2017N354137_00.
REVISION HISTORY
Note that minor wording changes are not included in below.
Reporting and Analysis Plan_207727_Amendment_Final_V1.1 [10-JUL-2018]
Section # and 
Name
Description of Change
Brief Rationale
6.1 - Overview of 
Planned Study 
Population 
Analyses
Listing of reasons for treatment discontinuation was added.
eCRF screen was 
changed to capture 
treatment 
discontinuation.
6.1.1- Details of 
Planned Study 
Population 
Summaries
Removed the detail of summary display for race and racial 
combinations
Corrections
10.9 - Appendix 9: 
List of Data 
Displays
Table 1.5, Table 1.6
Programming notes corrected.
Listing 4, Listing 5
Listing for treatment 
discontinuation added
Listing 8, Listing 9
IDSL/Example shell corrected
Table 3.7, Table 3.8
Order of PK parameters in a title 
modified
Figure 3.9, Figure 3.10
Order of PK parameters in a title 
modified
Corrections
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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 (Dated: 
12/Mar/2018) are outlined below. The change was intended to create some displays 
required by EudraCT with the “Enrolled” population.
Protocol
Section 9.3
Population for Analyses
Population
Description
Enrolled
All subjects who signed the ICF
Safety
This population will be defined for each Part.
•All randomised subjects who received at least one dose of study intervention.
PK
This population will be defined for each Part.
•All subjects in the Safety population who had at least 1 non-missing PK 
assessment (Non-quantifiable [NQ] values will be considered as non-missing 
values).
Reporting & Analysis Plan
Section 4.
Analysis Populations
Population
Description
Screened
All subjects who signed the ICF
Enrolled
•All subjects who passed screening and entered the study.
•Note screening failures (who never passed screening even if rescreened) and 
subjects screened but never enrolled into the study (Reserve, Not Used) are 
excluded from the Enrolled population as they did not enter the study.
Safety
This population will be defined for each Part.
•All randomised subjects who received at least one dose of study intervention.
PK
This population will be defined for each Part.
•All subjects in the Safety population who had at least 1 non-missing PK 
assessment (Non-quantifiable [NQ] values will be considered as non-missing 
values).
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2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints
Part 1

To determine the bioequivalence of 
daprodustat 2 mg tablet vs. 4 mg 
tablet in healthy Japanese male 
subjects.
Part 2

To investigate the food effect on PK of 
daprodustat following a single dose of 
daprodustat in the fed and fasted 
state in healthy Japanese male 
subjects.
Part 1 and 2

Plasma PK parameters for daprodustat: AUC(0-t), Cmax, 
and the other parameters [AUC(0-inf), Tmax, t1/2, 
%AUCex, CL/F, Vz/F, kel and MRT]
Secondary Objectives
Secondary Endpoints
Part 1 and 2

To assess the safety and tolerability of 
single dose of daprodustat following 
administration of daprodustat in 
healthy Japanese male subjects.
Part 1 and 2

Safety: Adverse events (AEs), clinical laboratory tests, 
vital signs (blood pressure, pulse and body temperature), 
and 12-lead electrocardiogram (ECG) parameters.
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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

This study consists of two parts; Part 1 is a single centre, single dose, open-label, 
randomised, 2-way crossover study in healthy Japanese male subjects. Part 2 is a 
single centre, single dose in the fed and fasted state, open-label, randomised, 2-way 
crossover study in healthy Japanese male subjects.
In both part (Part 1 and Part 2), healthy subjects will have a screening visit within 30 
days prior to the first dose of study treatment, two treatment periods, and re-visit 7 
(±1) days after the second dose for follow-up. All subjects will be administered 
daprodustat as a single oral dose, with assessments conducted for up to 24 hours 
post-dose. Subjects will be housed in the Clinical Research Unit from Day -1 through
Day 2 of each period. At least 5-day wash-out period will occur between each 
treatment period.
Dosing

Subjects will be divided into the study of Part 1 and 2, and will be randomized to one 
of two groups (Part 1: A or B, Part 2: C or D) in the following table;
Part 1 (Bioequivalence part)

Daprodustat 2 mg tablet x 2, single dose, in the fasted state

Daprodustat 4 mg tablet x 1, single dose, in the fasted state
Group
n
Period 1
Period 2
A
26
2 mg tablet x 2
4 mg tablet x 1
B
26
4 mg tablet x 1
2 mg tablet x 2
Part 2 (Food effect part)

Daprodustat 4 mg tablet, single dose, in the fed state

Daprodustat 4 mg tablet, single dose, in the fasted state
Group
n
Period 1
Period 2
C
6
4 mg tablet x 1 (fed)
4 mg tablet x 1 (fasted)
D
6
4 mg tablet x 1 (fasted)
4 mg tablet x 1 (fed)
Blood sampling for PK analysis will be performed prior to dosing and until 24 hours post-
dose following each dose. The duration of each subject’s participation will be 
approximately 6 weeks from screening to the follow-up.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

Subjects will be assigned to one of two groups in accordance with the randomisation 
schedule generated by the Biomedical Data Sciences Department at GSK, prior to the 
start of the study, using validated internal software.
Interim 
Analysis

No interim analysis is planned.
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2.4.
Statistical Hypotheses / Statistical Analyses
Part 1:
The bioequivalence between daprodustat 2 mg tablet and 4 mg tablet will be 
demonstrated using a framework of statistical hypothesis testing. The ratio of the 
geometric means (2mg/4mg) for AUC(0-t) and Cmax is the measure in the following 
statistical hypotheses:
H0 (null hypothesis)
: 2mg/4mg ≤ 0.80 or 2mg/4mg ≥ 1.25
H1 (alternative hypothesis)
: 0.80 < 2mg/4mg < 1.25
A judgment by 90% CI will be conducted in this study. The null hypothesis is rejected if 
the 90% confidence interval (CI) of 2mg/4mg falls within a range of 0.80 to 1.25, which 
results a conclusion of the bioequivalence. This is equivalent to carrying out two one-
sided tests of hypothesis at the 5% level of significance. 
If the 90% CI of 2mg/4mg doesn’t fall within a range of 0.80 to 1.25 (i.e., null hypothesis 
is not rejected), the bioequivalence is established if the point estimate (2mg/4mg) falls 
within a range of 0.90 to 1.11.
Part 2:
No formal statistical hypothesis will be tested.
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3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis is planned.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
Randomization codes have been distributed according to RandAll NG procedures.
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened
All participants who signed the ICF.
Study Population
Enrolled

All participants who passed screening and entered the 
study.

Note screening failures (who never passed screening 
even if rescreened) and participants screened but never 
enrolled into the study (Reserve, Not Used) are 
excluded from the Enrolled population as they did not 
enter the study.
Study Population
Safety
This population will be defined for each Part.

All randomised participants who received at least one 
dose of study treatment.
Study Population, 
Safety
Pharmacokinetic
(PK)
This population will be defined for each Part.

All participants in the Safety population who had at least 
1 non-missing PK assessment (Non-quantifiable [NQ] 
values will be considered as non-missing values).
PK
Refer to Section 10.9: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarized and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
Part 1 (Schedule 1)
D1
2 mg x 2
2 mg x 2
1
D2
4 mg x 1
4 mg x 1
2
Part 2 (Schedule 2)
D3
4 mg fed
4 mg fed
1
D4
4 mg fasted
4 mg fasted
2
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
2mg x 2 / 4mg x 1
2.
fed / fasted
5.2.
Baseline Definitions
Baseline definitions defined in the table are applicable to each period.
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline.
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety
Haematology
X
X
Day -1
Chemistry
X
X
Day -1
12-lead ECG & Vital 
Signs
X
X
Day 1 (Pre-dose)
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
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5.3.
Examination of Covariates, Other Strata and Subgroups
5.3.1.
Covariates and Other Strata
The list of covariates may be used in descriptive summaries and statistical analyses.
Additional covariates of clinical interest may also be considered.
Category
Details
Covariates
See Section 8.1.5.1, describing pharmacokinetic analyses using statistical model
5.4.
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
10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol Population
10.2
Appendix 2: Schedule of Activities
10.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
10.4
Appendix 4: Data Display Standards & Handling Conventions
10.5
Appendix 5: Derived and Transformed Data
10.6
Appendix 6: Reporting Standards for Missing Data
10.7
Appendix 7: 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 Safety population, unless otherwise 
specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.
Details of the planned displays are presented in Appendix 9: List of Data Displays.
Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Disposition for the Subject Conclusion Record
Y
Y
Treatment Status and Reasons for Discontinuation of Study 
Treatment
Y
Screening Status and Reasons for Screen Failure
Y
Y
Number of Subjects Enrolled by Country and Site ID
Y
Planned and Actual Treatments
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Inclusion/Exclusion Criteria Deviations
Y
Population Analysed
Subjects Excluded from PK Population
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Y
Race and Racial Combinations
Y
Age Ranges
Y
Medical Conditions and Concomitant Medications
Medical Conditions
Y
Concomitant Medications
Y
Exposure
Exposure to Study Treatment
Y
Meal
Meal start and end days/times on fed treatment
Y
NOTES:

Y = Yes display generated.
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6.1.1.
Details of Planned Study Population Summaries
Summaries will be provided by Part (2 mg x 2 and 4 mg x 1 in Part 1, fed and fasted in 
Part 2), unless otherwise specified.
Subject Disposition
Subject Disposition for the Subject Conclusion Record
The number and percentage of subjects who completed the study as well as subjects who 
withdrew from the study will be summarized. Reason for withdrawal will also be 
summarized for subjects who withdrew from the study. Only the total column will appear.
Screening Status and Reasons for Screen Failure
This will be based on Screened population. The number and percentage of subjects who 
passed screening and who failed screening and therefore were not entered into the study 
will be summarized along with the reasons for failure will be summarized for those 
subjects who failed screening. Only the total column will appear.
Number of Subjects Enrolled by Country and Site ID
This will be based on Enrolled population. The number of subjects summarized by 
Country, Site ID and Investigator name will be presented. Only the total column will 
appear. 
Protocol Deviations
Important Protocol Deviations
The number and percentage of subjects who had important protocol deviations defined as
part of the protocol deviation management plan for the study, will be summarized. Only 
the total column will appear.
Demographic and Baseline Characteristics
Demographic Characteristics
The number and percentage of subjects or summary statistics will be provided for each 
demographic characteristic and only the total column will appear: Sex, Age (years), Age 
Group (years), Ethnicity, Race detail, Height, Weight, and Body Mass Index. Age Group 
(years) will be categorized into three ('18', '19-64', '65'). Each demographic characteristic 
will be summarized using the minimum set of summary statistics.
Age Ranges
This will be based on Enrolled population. The number and percentage of subjects within 
each age range category will be provided. Only the total column will appear. Only age ranges 
that are applicable to the study will be included (i.e., only ‘18-64 years’). This is based on 
the standard of EMA clinical trial results disclosure requirements.
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7.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
7.1.
Adverse Events Analyses
Display Type
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
All AEs by SOC and PT
Y
Y
All AEs by Maximum Intensity
Y
Drug-Related AEs by SOC and PT
Y
Drug-Related AEs by Maximum Intensity
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT and Verbatim Text
Y
Serious and Other Significant AEs
Serious AEs
Y
AEs Leading to Withdrawal from Study 
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.
7.1.1.
Details of Planned Adverse Events Summaries
Summaries will be provided by Part (2 mg x 2 and 4 mg x 1 in Part 1, fed and fasted in 
Part 2), unless otherwise specified.
Adverse Events (AEs)
All AEs by SOC and PT
The number and percentage of subjects with all relevant adverse events will be 
summarized by MedDRA System Organ Class and Preferred Term by treatment group
and total. The counting of events and the percentages will be based on the number of 
subjects on each treatment, so subjects may appear in more than one treatment category.
All AEs by Maximum Intensity by SOC and PT
The number and percentage of subjects with adverse events by intensity (e.g., mild, 
moderate, severe) will be summarized by MedDRA System Organ Class and Preferred 
Term by treatment group and total. The counting of events and the percentages will be 
based on the number of subjects on each treatment, so subjects may appear in more than 
one treatment category.
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Drug-related AEs by SOC and PT
The number and percentage of subjects with all drug-related adverse events will be 
summarized by MedDRA System Organ Class and Preferred Term by treatment group 
and total. The counting of events and the percentages will be based on the number of 
subjects on each treatment, so subjects may appear in more than one treatment category.
Drug-related AEs by Maximum Intensity by SOC and PT
The number and percentage of subjects with drug-related adverse events by intensity 
(e.g., mild, moderate, severe) will be summarized by MedDRA System Organ Class and 
Preferred Term by treatment group and total. The counting of events and the percentages 
will be based on the number of subjects on each treatment, so subjects may appear in 
more than one treatment category.
7.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. The details of the planned displays are in Appendix 9: List of Data 
Displays.
Display Type
Absolute
Summary
Individual
T
F
L
Chemistry
Chemistry Changes from Baseline
Y
Chemistry Values
Y
Y
Chemistry Data Shifts from Baseline Relative to Normal Range
Y
All Chemistry Data for Subjects with any Value of PCI
Y
Chemistry Values of PCI
Y
Haematology
Haematology Changes from Baseline
Y
Haematology Values
Y
Y
Haematology Data Shifts from Baseline Relative to Normal 
Range
Y
All Haematology Data for Subjects with any Value of PCI
Y
Haematology Values of PCI
Y
Urinalysis
Urinalysis Concentration Changes from Baseline (Gravity and 
pH)
Y
Urinalysis Data (Gravity and pH)
Y
Y
Urinalysis Data (Glucose, Protein, Blood, Ketones, Bilirubin, and 
Urobilinogen)
Y
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Medical Conditions for Subjects with Liver Stopping Events
Y
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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.
7.2.1.
Details of Planned Clinical Laboratory Displays
Summaries will be provided by Part (2 mg x 2 and 4 mg x 1 in Part 1, fed and fasted in 
Part 2), unless otherwise specified.
Chemistry/Haematology Laboratory Tests
Laboratory Changes from Baseline and Values
Each quantitative laboratory test and the changes in value from baseline will be 
summarized at every assessed time point using n, mean, standard deviation, median, 
minimum, and maximum by treatment group.
Laboratory Data Shifts from Baseline Relative to Normal Range
The number and percentage of subjects with laboratory results within each normal range 
(Low, Normal, High) during each period will be summarized relative to their baseline 
category by laboratory test. The percentages are based on the number of subjects in the 
treatment group with data for the laboratory test at the specified planned time (n).
Subjects are only counted once in the total column.
Urinalysis Laboratory Tests
Urinalysis Concentration Changes from Baseline (Gravity and pH)
Gravity and pH test and the changes in value from baseline will be summarized at every 
assessed time point using n, mean, standard deviation, median, minimum, and maximum
by treatment group.
Urinalysis Data (Glucose, Protein, Blood, Ketones, Bilirubin, and Urobilinogen)
The number and percentage of subjects with the above urinalysis results (character 
results) will be summarized by treatment group.
7.3.
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 9: List of Data Displays.
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Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
ECG
ECG Findings
Y
Y
ECG Values
Y
Y
Y
All ECG Values for Subjects with any Value of PCI
Y
Vital Signs
Vitals Values
Y
Y
Y
All Vital Signs for Subjects with any Value 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.
7.3.1.
Details of Planned Other Safety Displays
Summaries will be provided by Part (2mg tablet x 2 and 4mg tablet x 1 in Part 1, fed state 
and fasted state in Part 2), unless otherwise specified.
ECG
ECG Findings
The number and percentage of subjects with ECG findings (ECG interpretation) will be 
summarized by treatment group.
ECG Values
Each ECG parameter value and the change from baseline will be summarized by 
treatment group at every assessed time point using n, mean, standard deviation, median, 
minimum, and maximum.
Vital Signs
Vital Signs
Each vital sign parameter and the changes in value from baseline will be summarized by 
treatment group at every assessed time point using n, mean, standard deviation, median, 
minimum, and maximum.
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8.
PHARMACOKINETIC ANALYSES
8.1.
Pharmacokinetic Analyses
8.1.1.
Endpoint / Variables
8.1.1.1.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 10.4.3
Reporting Standards for Pharmacokinetic)
8.1.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters of daprodustat will be calculated by standard non-
compartmental analysis according to current working practices and using the currently 
supported version of WinNonlin 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 concentration-time data, as data permits.
Parameter
Parameter Description
AUC(0-t) 
(h*ng/mL)
The area under the concentration-time curve from zero time (pre-dose) to the time of last
quantifiable concentration (AUC(0-t)) will be calculated by a combination of linear and
logarithmic trapezoidal methods. The linear trapezoidal method will be employed for all
incremental trapezoids arising from increasing concentrations and the logarithmic
trapezoidal method will be used for those arising from decreasing concentrations (i.e.,
Linear Up/Log Down calculation method in Phoenix WinNonlin Professional).
AUC(0-inf) 
(h*ng/mL)
The area under the concentration-time curve from zero time (pre-dose) extrapolated to
infinite time (AUC(0-inf)) will be calculated as follows:
AUC(0-inf) = AUC(0-t) + Ct / kel
Cmax 
(ng/mL)
Maximum observed plasma concentration following each dose will be obtained directly from 
the concentration-time data.
Tmax (h)
The time to maximum observed plasma drug concentration following each dose will be 
obtained directly from the concentration-time data.
t1/2 (h)
Terminal half-life will be calculated as follows:
t1/2 = ln2 / kel
%AUCex (%)
The percentage of AUC(0-inf) obtained by extrapolation (%AUCex) will be calculated as 
follows:
%AUCex = (AUC(0-inf) – AUC(0-t)) / AUC(0-inf) x 100
CL/F
(mL/h)
Apparent clearance following oral dosing will be calculated as follows:
CL/F = Dose / AUC(0-inf)
Vz/F
(mL)
Apparent volume of distribution after oral administration will be calculated as follows:
Vz/F = Dose / (kel x AUC(0-inf))
MRT
(h)
Mean residence time will be calculated as follows:
MRT = AUMC(0-inf) / AUC(0-inf)
Tlast (h)
The time of the last measurable (positive) concentration.
kel
The first order rate constant associated with the terminal (log-linear) portion of the curve.
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Parameter
Parameter Description
(lambda_z) 
(/h)
lambda_z_lo
wer
The lower limit on time for values to be included in the calculation of kel.
lambda_z_u
pper
The upper limit on time for values to be included in the calculation of kel.
#pts
The number of time points used in computing kel.
R-square
The goodness of fit statistic for the terminal elimination phase.
NOTES:

Additional parameters may be included as required.

Kel is the terminal phase rate constant.

Ct is the last observed quantifiable concentration.
8.1.2.
Summary Measure
In Part 1, the ratio of geometric mean for AUC(0-t) and Cmax between daprodustat 2 mg 
tablet x 2 and 4 mg tablet x 1 will be used for the comparison between daprodustat 2mg 
tablet x 2 vs. daprodustat 4mg tablet x 1.
In Part 2, the ratio of geometric mean for AUC(0-t) and Cmax between fed and fasted 
state will be used for the comparison between the fed state vs. the fasted state.
8.1.3.
Population of Interest 
The pharmacokinetic analyses will be based on the PK population, unless otherwise 
specified.
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Intercurrent events which may affect the evaluation of bioequivalence and food effect
will not be anticipated.
8.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Section 8.1.6: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.1.5.1.
Statistical Methodology Specification
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if participants have well defined plasma profiles).
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Endpoint / Variables

Derived plasma PK parameters (AUC(0-t), Cmax) of daprodustat
Model Specification (Part 1)
Part 1

The exposure (AUC(0-t) and Cmax) of daprodustat will be assessed by using a mixed effect 
model as described below:
loge (PK parameter) = 0 +i + j + k + l + εijkl
0: intercept
i: random subject effect for ith subject, following N(0, b2)
j: tablet strength effect (j = 2 mg or 4 mg)
k: period effect (k = period 1 or period 2)
l: group effect (l= group A or group B)
εijkl: random error for subject i, tablet strength j, period k, group l, following N(0, w2)

The model parameters will be estimated using Restricted Maximum Likelihood with the 
Newton-Raphson algorithm. 

The Kenward-Roger degree of freedom approach will be used. 

Given the random effect for subject i, the random error is assumed to be independently 
distributed within the subject.

The least square means for each tablet strength will be estimated based on the fitted model.
The mean difference between tablet strengths (2mg - 4mg) and its 90% CIs will be also 
estimated using the within-subject variance.

The estimates of least square means for each tablet strength, the treatment difference 
between tablet strength and the 90% CIs will be exponentially back-transformed to obtain the 
estimates of geometric means of AUC(0-t) and Cmax for each tablet strength, the ratio of 
geometric means (2mg/4mg) and its 90% CIs, respectively.

Within-subject variability (%CVw) for the PK parameters will be estimated using within-subject 
variance from the analysis model as follows:
%CVw (%) = [exp(w2) – 1]1/2 x 100

AUC(0-inf) will be analyzed in the same manner.
Part 2

To estimate the food effect on PK parameters (AUC(0-t) and Cmax) of daprodustat, the PK 
parameters will be analysed using a mixed effect model as described as below (almost the 
same as Part 1):
loge (PK parameter) = 0 +i + j + k + l + εijkl
0: intercept
i: random subject effect for ith subject
j: food effect (j = fed or fasted)
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k: period effect (k = period 1 or period 2)
l: group effect (l= group C or group D)
εijkl: random error for subject i, food effect j, period k, group l.

The model restrictions will be the same as Part 1. 

The way of construction for the estimates of summary statistics will be the same as Part 1 
o
Note that the ratio of geometric means (fed/fasted) and its 90% CIs for AUC(0-t) and Cmax
will be estimated.
o
AUC(0-inf) will be analyzed in the same manner.
Model Checking & Diagnostics

In case there is a problem with model convergence, the arithmetic means for loge-transformed 
AUC(0-t) and Cmax and the treatment differences (2mg - 4mg in Part 1, fed - fasted in Part 2) 
within each subject will be calculated using only data from the subjects who have completed 
both 2mg and 4mg in Part 1, or both fed and fasted in Part 2. The mean treatment difference 
and paired-t test based 90% CIs for treatment difference in loge scale will be estimated. The 
results will be provided in an exponentially back-transformed scale.
Model Results Presentation
Part 1 and Part 2

Results of Part 1 and Part 2 will be presented in the same manner, separately. 

The estimates of geometric means of PK parameters (AUC(0-t) and Cmax) will be presented 
for each tablet strength (Part 1) or for each food state (Part 2), respectively. The estimates of 
the geometric means ratio between tablet strengths (Part 1) or between fed and fasted state 
(Part 2) will be presented along with the associated 90% CIs and %CVw.

For Part 1, the bioequivalence between daprodustat 2 mg tablet and 4 mg tablet will be 
evaluated as follows:

The bioequivalence is established when the 90% CI of the ratio for AUC(0-t) and Cmax 
between tablet strength (2 mg x 2 vs. 4 mg x 1) are within the range of 0.80 to 1.25.

Even if the 90% CI doesn’t meet the above criteria, the bioequivalence is established when 
the point estimate of the ratio for AUC(0-t) and Cmax between tablet strength (2 mg x 2 vs. 
4 mg x 1) are within the range of 0.90 to 1.11.

AUC(0-inf) will also be provided in the model results presentation, but the evaluation of the 
bioequivalence will not be done based on AUC(0-inf).
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8.1.6.
Details of Planned Pharmacokinetic Displays
Summaries will be provided by Part (2mg tablet x 2 and 4mg tablet x 1 in Part 1, fed state 
and fasted state in Part 2), unless otherwise specified.
Daprodustat Plasma Concentration-Time Data
Daprodustat plasma concentrations at every scheduled time point will be summarized 
using n, mean, standard deviation, median, minimum, and maximum.
Derived Daprodustat Plasma Pharmacokinetic Parameters (non-transformed)
Daprodustat plasma pharmacokinetic parameters (AUC(0-t), AUC(0-inf), Cmax, Tmax,  
t1/2, %AUCex, CL/F, Vz/F, kel, and MRT) will be summarized using n, mean, 95% CI, 
standard deviation, median, minimum, and maximum.
Derived Daprodustat Plasma Pharmacokinetic Parameters (log-transformed)
For each pharmacokinetic parameters with a log-normal distribution (AUC(0-t), AUC(0-
inf), Cmax, t1/2, %AUCex, CL/F, Vz/F, kel, and MRT), the log-transformed parameters 
will be summarized using n, geometric mean, 95% CI of geometric mean, standard 
deviation of log-transformed data and between subject coefficient of variation (%CVb).
Analysis of Tablet Strength/Food Effect for AUC(0-t) and Cmax
The analysis results will be presented as described in Section 8.1.5.1 - Model Results 
Presentation. AUC(0-inf) will also be analysed and provided in a display.
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9.
REFERENCES
GlaxoSmithKline Document Number 2017N354137_00 Study ID 207727. A single 
centre, single dose, open-label, randomised, 2-way crossover study in healthy Japanese 
male subjects to evaluate the bioequivalence of daprodustat tablets (2 mg tablet vs. 4 mg 
tablet) (Part 1) and the food effect on the pharmacokinetics of daprodustat (Part 2). 
Report Date 12-Mar-2018. 
Japanese Society of Nephrology. Dietary recommendations for chronic kidney disease, 
2014. Jpn J Nephrol. 2014;56(5):533-59.
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10.
APPENDICES
10.1.
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 PDMP and the data handling will be determined prior to DBR.
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10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
Procedure
Scree
ning1
Intervention period (Period 1-2)
Follow-
up 7
Day
-1
Day 1
Day 2
Pre-dose
0 h
0.5 h
1 h
1.5 h
2 h
2.5 h
3 h
4 h
6 h
8 h
12 h
24 h
Informed consent
X
Demography/Medical history
X
Height, Weight, Body mass index (BMI)
X
Urine drug screen
X
Serology test2
X
Physical examination
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
Vital signs3
X
X
X
X
X
Clinical laboratory test4
X
X
X
X
Study intervention dosing5
X
PK blood sampling
X
X
X
X
X
X
X
X
X
X
X
X
AE6/Serious adverse events (SAE)6
<======================================================================================================>
Concomitant medication review
<======================================================================================================>
Admission to unit
X
Discharge
X
Outpatient visit
X
X
1: Within 30 days prior to Day 1 of Period 1.
2: Serology tests for syphilis [Rapid plasma reagin (RPR) & Treponema pallidum (TP)], Human immunodeficiency virus (HIV) antigen/antibody, Hepatitis B surface antigen (HBsAg), 
Hepatitis C virus (HCV) antibody and Human T-cell lymphotropic virus type 1 (HTLV-1) antibody.
3: Body temperature (axillary), systolic and diastolic blood pressure and pulse (supine).
4: Haematology, clinical chemistry and urinalysis.
5: Subjects will remain in a sitting or semi-supine position for approximately 4 hours if possible after dosing on Day 1. In Part 2, study subjects who are in fed state should take a 
standard meal as recommended for chronic kidney disease (CKD) by the Japanese Society of Nephrology in Japan [Jpn J Nephrol, 2014] in 20 minutes or less and the drug product 
should be administered 30 minutes after the end of the meal.
6: AEs and SAEs will be collected from the start of intervention until the follow-up visit at the time points specified. However, any SAEs assessed as related to study participation (e.g., 
study treatment, protocol-mandated procedures, or invasive tests) will be recorded from the time a subject consents to participate in the study.
7: 7(±1) days post-dose of Period 2.
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10.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
10.3.1.
Study Phases
Assessments and events (e.g., study withdrawal) will be classified according to the time 
of occurrence relative to dosing start Date and Time by Period. The following definitions 
will be applicable to both Part 1 and Part 2.
Study Phase
Definition
Pre-Treatment
Reference Day < Previous Day of Dosing Start Date in Period 1
Period 1
Previous Day of Dosing Start Date in Period 1 Reference Day < Previous Day of 
Dosing Start Date in Period 2 
Period 2
Previous Day of Dosing Start Date in Period 2 Reference Day
10.3.1.1.
Study Phases for Adverse Events
The study phases for AEs will be categorized into pre-treatment, period 1, and period 2 
based on AE onset date and time. 
Study Phase
Definition
Pre-Treatment
AE Onset Date and Time < Study First Dosing Start Date and Time
Period 1
Study First Dosing Start Date and Time AE Onset Date and Time < Dosing Start 
Date and Time in Period 2
Period 2
Dosing Start Date and Time in Period 2 AE Onset Date and Time
Time since Study
First Dose (min)
If study phase of the event is pre-treatment,
AE Onset Date and Time - Study First Dosing Start Date and Time
otherwise
AE Onset Date and Time – Study First Dosing Start Date and Time + 1 min
Time since Period 
First Dose (min)
If study phase of the AE is pre-treatment, set to missing
If study phase of the AE is period 1,
AE Onset Date and Time – Dosing Start Date and Time in Period 1 + 1 min
If study phase of the AE is period 2,
AE Onset Date and Time – Dosing Start Date and Time in Period 2 + 1 min
Time since Last 
Dose (min)
If study phase of the AE is pre-treatment, set to missing
If AE Onset Date and Time Study Last Dosing Start Date and Time,
AE Onset Date and Time – Study Last Dosing Start Date and Time+ 1 min 
Duration (min)
AE Resolution Date and Time – AE Onset Date and Time + 1 min
Drug-related
If relationship is marked ‘YES’ on eCRF or value is missing.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be treatment emergent.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
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10.3.1.2.
Study Phases for Concomitant Medication
The study phases for concomitant medications represent the period of medication star. 
The study phases will be categorized into pre-treatment, period 1, and period 2 based on 
medication start date and time.
Study Phase
Definition
Pre-Treatment
Start Date and Time < Study First Dosing Start Date and Time
Period 1
Study First Dosing Start Date and Time Start Date and Time < Dosing Start Date 
and Time in Period 2
Period 2
Dosing Start Date and Time in Period 2 Start Date and Time
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10.4.
Appendix 4: Data Display Standards & Handling 
Conventions
10.4.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: N/A
HARP Compound
: N/A
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.0).
Generation of RTF Files

RTF files will be generated.
10.4.2.
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 
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.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visit

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
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Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
10.4.3.
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 Office 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
No PK parameters derived by programmer are planned. : 
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to Standards for Handling NQ Impacted PK Parameters in GUI_51487.
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards: Standards for the Transfer and Reporting of 
PK Data using HARP
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10.5.
Appendix 5: Derived and Transformed Data
10.5.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

Participants 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 Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dosing Date:

Ref Date = Missing        → Study Day = Missing 

Ref Date < First Dosing Date → Study Day = Ref Date – First Dosing Date

Ref Date ≥ First Dosing Date → Study Day = Ref Date – (First Dosing Date) + 1
Period Day

Calculated as the number of days from Dosing Date in Period 1 or Period 2. 

If Study Phase of Ref Assessment or Event = Pre-Treatment or Missing
→ Period Day = Missing 

If Study Phase of Ref Assessment or Event = Period 1
→ If Ref Date is on or after Dosing Date in Period 1, Period Day = Ref Date – Dosing Date in 
Period 1 + 1 day
→ If Ref Date is before Dosing Date in Period 1, Period Day = Ref Date – Dosing Date in Period 1

If Study Phase of Ref Assessment or Event = Period 2
→ If Ref Date is on or after Dosing Date in Period 2, Period Day = Ref Date – Dosing Date in 
Period 2 + 1 day
→ If Ref Date is before Dosing Date in Period 2, Period Day = Ref Date – Dosing Date in Period 1
10.5.2.
Study Population
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.

Date of Informed Consent will be used as reference date of calculation.
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10.5.3.
Safety
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 default convention for reporting of clinical laboratory units will be the international system of units 
(SI units).
PCI

For PCI listings 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. 
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10.6.
Appendix 6: Reporting Standards for Missing Data
10.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as completion of 
all phases of the study including the follow up visit. 

If subjects prematurely withdraw from the study, additional replacement participants 
may be recruited and assigned to the same treatment sequence.

All available data from subjects who were withdrawn from the study will be listed and all 
available planned data will be included in summary tables and figures, unless otherwise 
specified.
10.6.2.
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 participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.6.2.1.
Handling of Missing and Partial Dates and Times
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF does not allow for the possibility of partial dates (i.e., only month and year) 
to be recorded for AE start and end dates; that is, the day of the month will not be
missing.

The eCRF allows for the possibility of missing times to be recorded for AE start and end 
dates. Missing times will be imputed using the following convention:
o
If the missing time is a start time, a '00:00' will be used for the time.
o
If the missing time is a stop time, a '23:59' will be used for the time.

The recorded missing time will be displayed in listings without imputed values.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The eCRF allows for the possibility of missing times to be recorded for concomitant 
medications start and end dates. Missing times will be imputed using the following 
convention:
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Element
Reporting Detail
o
If the missing time is a start time, a '00:00' will be used for the time.
o
If the missing time is a stop time, a '23:59' will be used for the time.

The recorded partial date and missing time will be displayed in listings without imputed 
values.
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10.7.
Appendix 7: Values of Potential Clinical Importance
10.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Haematocrit 
Ratio of 
1
0.54
∆from BL
↓0.075
Haemoglobin 
g/L
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
White Blood Cell Count
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
G/L
30
Calcium
mmol/L
2
2.75
Creatinine
mol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
mol/L
High
1.5xULN
T. Bilirubin + ALT
mol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT
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10.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450
Absolute PR Interval
msec
< 110
> 220
Absolute QRS Interval
msec
< 75
> 110
Change from Baseline
Increase from Baseline QTc
msec
> 60
10.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
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10.8.
Appendix 8: Abbreviations & Trade Marks
10.8.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
ALT
Alanine aminotransferase
AST
Aspartate transaminase
AUC(0-inf)
Area under the concentration-time curve from time zero (pre-dose) extrapolated 
to infinite time
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to last time 
of quantifiable concentration within a subject across all treatments
BL
Baseline
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
Cmax
Maximum observed concentration
CPMS
Clinical Pharmacology Modelling & Simulation
CSR
Clinical Study Report
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DP
Decimal Places
eCRF
Electronic Case Record Form
ECG
Electrocardiogram
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
MRT
Mean Residence Time
NQ
Non-quantifiable
PCI
Potential Clinical Importance 
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PT
Preferred Term
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
RTF
Rich Text File
SAC
Statistical Analysis Complete
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SOC
System Organ Class
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Abbreviation
Description
SOP
Standard Operation Procedure
t1/2
Terminal half-life
Tmax
Time to maximum observed blood drug concentration
TFL
Tables, Figures & Listings 
ULN
Upper Limit of Normal
WNL
WinNonlin
10.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
WinNonlin
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10.9.
Appendix 9: List of Data Displays
10.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.9
Not Applicable
Safety
2.1 to 2.36
Not Applicable
Pharmacokinetic
3.1 to 3.8
3.1 to 3.10
Section
Listings
ICH Listings
1 to 75
10.9.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 10: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
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.’
10.9.3.
Deliverables
Delivery Priority
Description
SAC
Final Statistical Analysis Complete
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10.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1A
Summary of Subject Disposition (Part 1)
ICH E3, FDAAA, EudraCT
Only total column will appear
SAC
1.2.
Safety
ES1A
Summary of Subject Disposition (Part 2)
ICH E3, FDAAA, EudraCT
Only total column will appear
SAC
1.3.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
Only total column will appear. Not provided 
separately by Part
SAC
1.4.
Enrolled
NS1
Summary of Number of Subject by Country and Site ID
EudraCT/Clinical Operations
Only total column will appear. Not provided 
separately by Part
SAC
Protocol Deviation
1.5.
Safety
DV1
Summary of Important Protocol Deviations (Part 1)
ICH E3
Only total column will appear
SAC
1.6.
Safety
DV1
Summary of Important Protocol Deviations (Part 2)
ICH E3
Only total column will appear
SAC
Demographic and Baseline Characteristics
1.7.
Safety
DM3
Summary of Demographic Characteristics (Part 1)
ICH E3, FDAAA, EudraCT
Only total column will appear
SAC
1.8.
Safety
DM3
Summary of Demographic Characteristics (Part 2)
ICH E3, FDAAA, EudraCT
Only total column will appear
SAC
1.9.
Enrolled
DM11
Summary of Age Ranges
EudraCT/Clinical Operations
Only total column will appear. Not provided 
separately by Part
SAC
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10.9.5.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
2.1.
Safety
AE1CP
Summary of All AE by SOC and PT (Part 1)
ICH E3
Include total column
SAC
2.2.
Safety
AE1CP
Summary of All AE by SOC and PT (Part 2)
ICH E3
Include total column
SAC
2.3.
Safety
AE5A
Summary of All AEs by Maximum Intensity by SOC and PT (Part 
1)
ICH E3
Include total column
SAC
2.4.
Safety
AE5A
Summary of All AEs by Maximum Intensity by SOC and PT (Part 
2)
ICH E3
Include total column
SAC
2.5.
Safety
AE1CP
Summary All Drug-Related AE by SOC and PT (Part 1)
ICH E3
Include total column
SAC
2.6.
Safety
AE1CP
Summary All Drug-Related AE by SOC and PT (Part 2)
ICH E3
Include total column
SAC
2.7.
Safety
AE5A
Summary of All Drug-Related AEs by Maximum Intensity by 
SOC and PT (Part 1)
ICH E3
Include total column
SAC
2.8.
Safety
AE5A
Summary of All Drug-Related AEs by Maximum Intensity by 
SOC and PT (Part 2)
ICH E3
Include total column
SAC
Laboratory: Chemistry 
2.9.
Safety
LB1
Summary of Chemistry Data (Part 1)
SAC
2.10.
Safety
LB1
Summary of Chemistry Data (Part 2)
SAC
2.11.
Safety
LB1
Summary of Chemistry Change from Baseline (Part 1)
ICH E3
Include baseline value
SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.12.
Safety
LB1
Summary of Chemistry Change from Baseline (Part 2)
ICH E3
Include baseline value
SAC
2.13.
Safety
LB4
Summary of Chemistry Data Shifts from Baseline Relative to 
Normal Range (Part 1)
ICH E3
SAC
2.14.
Safety
LB4
Summary of Chemistry Data Shifts from Baseline Relative to 
Normal Range (Part 2)
ICH E3
SAC
Laboratory: Haematology
2.15.
Safety
LB1
Summary of Haematology Data (Part 1)
SAC
2.16.
Safety
LB1
Summary of Haematology Data (Part 2)
SAC
2.17.
Safety
LB1
Summary of Haematology Change from Baseline (Part 1)
ICH E3
Include baseline value
SAC
2.18.
Safety
LB1
Summary of Haematology Change from Baseline (Part 2)
ICH E3
Include baseline value
SAC
2.19.
Safety
LB4
Summary of Haematology Data Shifts from Baseline Relative to 
Normal Range (Part 1)
ICH E3
SAC
2.20.
Safety
LB4
Summary of Haematology Data Shifts from Baseline Relative to 
Normal Range (Part 2)
ICH E3
SAC
Laboratory: Urinalysis
2.21.
Safety
LB1
Summary of Urinalysis Data (Gravity and pH) (Part 1)
SAC
2.22.
Safety
LB1
Summary of Urinalysis Data (Gravity and pH) (Part 2)
SAC
2.23.
Safety
LB1
Summary of Urinalysis Change from Baseline (Gravity and pH) 
(Part 1)
ICH E3
Include baseline value
SAC
2.24.
Safety
LB1
Summary of Urinalysis Change from Baseline (Gravity and pH) 
(Part 2)
ICH E3
Include baseline value
SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.25.
Safety
UR3b
Summary of Urinalysis Data (Glucose, Protein, Blood, Ketones, 
Bilirubin, and Urobilinogen) (Part 1)
SAC
2.26.
Safety
UR3b
Summary of Urinalysis Data (Glucose, Protein, Blood, Ketones, 
Bilirubin, and Urobilinogen) (Part 2)
SAC
ECG
2.27.
Safety
EG1
Summary of ECG Findings (Part 1)
IDSL
SAC
2.28.
Safety
EG1
Summary of ECG Findings (Part 2)
IDSL
SAC
2.29.
Safety
EG2
Summary of ECG Values (Part 1)
IDSL
SAC
2.30.
Safety
EG2
Summary of ECG Values (Part 2)
IDSL
SAC
2.31.
Safety
EG2
Summary of Change from Baseline in ECG Values (Part 1)
IDSL
Include baseline value
SAC
2.32.
Safety
EG2
Summary of Change from Baseline in ECG Values (Part 2)
IDSL
Include baseline value
SAC
Vital Signs
2.33.
Safety
VS1
Summary of Vital Signs (Part 1)
IDSL
SAC
2.34.
Safety
VS1
Summary of Vital Signs (Part 2)
IDSL
SAC
2.35.
Safety
VS1
Summary of Change from Baseline in Vital Signs (Part 1)
ICH E3
Include baseline value
SAC
2.36.
Safety
VS1
Summary of Change from Baseline in Vital Signs (Part 2)
ICH E3
Include baseline value
SAC
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10.9.6.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
Priority
3.1.
PK
PK01
Summary of Daprodustat Plasma Concentration-Time Data 
(Part 1)
SAC
3.2.
PK
PK01
Summary of Daprodustat Plasma Concentration-Time Data 
(Part 2)
SAC
3.3.
PK
PK03
Summary of Derived Daprodustat Plasma Pharmacokinetic 
Parameters (non-transformed) (Part 1)
SAC
3.4.
PK
PK03
Summary of Derived Daprodustat Plasma Pharmacokinetic 
Parameters (non-transformed) (Part 2)
SAC
3.5.
PK
PK05
Summary of Derived Daprodustat Plasma Pharmacokinetic 
Parameters (log-transformed) (Part 1)
SAC
3.6.
PK
PK05
Summary of Derived Daprodustat Plasma Pharmacokinetic 
Parameters (log-transformed) (Part 2)
SAC
3.7.
PK
PK_T1
Analysis of Tablet Strength Effect for Cmax, AUC(0-t), and 
AUC(0-inf) (Part 1)
Example Shell in Appendix 10
SAC
3.8.
PK
PK_T1
Analysis of Food Effect for Cmax, AUC(0-t), and AUC(0-inf)
(Part 2)
Example Shell in Appendix 10
SAC
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10.9.7.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.1.
PK
PK16b
Individual Daprodustat Plasma Concentration-Time Plots by 
Subject (Part 1)
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
3.2.
PK
PK16b
Individual Daprodustat Plasma Concentration-Time Plots by 
Subject (Part 2)
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
3.3.
PK
PK16b
Individual Daprodustat Plasma Concentration-Time Plots by 
Tablet Strength (Part 1)
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
3.4.
PK
PK16b
Individual Daprodustat Plasma Concentration-Time Plots by 
Food State (Part 2)
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
3.5.
PK
PK17
Mean (+SD) Daprodustat Plasma Concentration-Time Plots 
(Part 1)
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
3.6.
PK
PK17
Mean (+SD) Daprodustat Plasma Concentration-Time Plots 
(Part 2)
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
3.7.
PK
PK18
Median Daprodustat Plasma Concentration-Time Plots (Part 1)
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
3.8.
PK
PK18
Median Daprodustat Plasma Concentration-Time Plots (Part 2)
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
3.9.
PK
PK_F1
Plot of Individual Daprodustat Plasma Cmax, AUC(0-t), and 
AUC(0-inf) by Tablet Strength (Part 1)
Example Shell in Appendix 10
SAC
3.10.
PK
PK_F1
Plot of Individual Daprodustat Plasma Cmax, AUC(0-t), and 
AUC(0-inf) by Food State (Part 2)
Example Shell in Appendix 10
SAC
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10.9.8.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
Not provided separately
SAC
2.
Safety
ES3
Listing of Reasons for Study Withdrawal (Part 1)
ICH E3
SAC
3.
Safety
ES3
Listing of Reasons for Study Withdrawal (Part 2)
ICH E3
SAC
4.
Safety
SD3
Listing of Reasons for Treatment Discontinuation (Part 1)
ICH E3
SAC
5.
Safety
SD3
Listing of Reasons for Treatment Discontinuation (Part 2)
ICH E3
SAC
6.
Safety
TA2
Listing of Planned and Actual Treatments (Part 1)
IDSL
SAC
7.
Safety
TA2
Listing of Planned and Actual Treatments (Part 2)
IDSL
SAC
Protocol Deviations
8.
Safety
DV2A
Listing of Important Protocol Deviations (Part 1)
ICH E3
SAC
9.
Safety
DV2A
Listing of Important Protocol Deviations (Part 2)
ICH E3
SAC
10.
Safety
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
(Part 1)
ICH E3
SAC
11.
Safety
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
(Part 2)
ICH E3
SAC
Populations Analysed
12.
Safety
SP3A
Listing of Subjects Excluded from PK Population (Part 1)
ICH E3
SAC
13.
Safety
SP3A
Listing of Subjects Excluded from PK Population (Part 2)
ICH E3
SAC
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
14.
Safety
DM4
Listing of Demographic Characteristics (Part 1)
ICH E3
SAC
15.
Safety
DM4
Listing of Demographic Characteristics (Part 2)
ICH E3
SAC
16.
Safety
DM10
Listing of Race (Part 1)
ICH E3
SAC
17.
Safety
DM10
Listing of Race (Part 2)
ICH E3
SAC
Prior and Concomitant Medications
18.
Safety
MH3
Listing of Medical Conditions (Part 1)
IDSL
SAC
19.
Safety
MH3
Listing of Medical Conditions (Part 2)
IDSL
SAC
20.
Safety
CM5
Listing of Concomitant Medications (Part 1)
IDSL
SAC
21.
Safety
CM5
Listing of Concomitant Medications (Part 2)
IDSL
SAC
Exposure
22.
Safety
EX4
Listing of Exposure Data (Part 1)
ICH E3
SAC
23.
Safety
EX4
Listing of Exposure Data (Part 2)
ICH E3
SAC
Meal
24.
Safety
CP_ML1x
Listing of Dosing Times, Meal Start and End Times on Fed 
Treatment Days (Part 2)
SAC
Safety
Adverse Events
25.
Safety
AE9CP
Listing of All Adverse Events (Part 1)
ICH E3
SAC
26.
Safety
AE9CP
Listing of All Adverse Events (Part 2)
ICH E3
SAC
27.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events (Part 
1)
ICH E3
SAC
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
28.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events (Part 
2)
ICH E3
SAC
29.
Safety
AE2
Listing of Relationship between System Organ Class and 
Verbatim Text
IDSL
Not provided separately
SAC
Serious and Other Significant Adverse Events
30.
Safety
AE9CPa
Listing of Serious Adverse Events (Part 1)
ICH E3
SAC
31.
Safety
AE9CPa
Listing of Serious Adverse Events (Part 2)
ICH E3
SAC
32.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event 
(Part 1)
ICH E3
SAC
33.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event 
(Part 2)
ICH E3
SAC
34.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study 
(Part 1)
ICH E3
SAC
35.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study 
(Part 2)
ICH E3
SAC
Hepatobiliary (Liver)
36.
Safety
MH3
Listing of Medical Conditions for Participants with Liver Stopping 
Events (Part 1)
IDSL
SAC
37.
Safety
MH3
Listing of Medical Conditions for Participants with Liver Stopping 
Events (Part 2)
IDSL
SAC
38.
Safety
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events (Part 1)
IDSL
SAC
39.
Safety
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events (Part 2)
IDSL
SAC
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
All Laboratory
40.
Safety
LB6
Listing of All Chemistry Data (Part 1)
SAC
41.
Safety
LB6
Listing of All Chemistry Data (Part 2)
SAC
42.
Safety
LB6
Listing of All Chemistry Data for Subjects with Any Value of 
Potential Clinical Importance (Part 1)
ICH E3
SAC
43.
Safety
LB6
Listing of All Chemistry Data for Subjects with Any Value of 
Potential Clinical Importance (Part 2)
ICH E3
SAC
44.
Safety
LB6
Listing of All Haematology Data (Part 1)
SAC
45.
Safety
LB6
Listing of All Haematology Data (Part 2)
SAC
46.
Safety
LB6
Listing of All Haematology Data for Subjects with Any Value of 
Potential Clinical Importance (Part 1)
ICH E3
SAC
47.
Safety
LB6
Listing of All Haematology Data for Subjects with Any Value of 
Potential Clinical Importance (Part 2)
ICH E3
SAC
48.
Safety
LB6
Listing of Chemistry Values of Potential Clinical Importance 
(Part 1)
SAC
49.
Safety
LB6
Listing of Chemistry Values of Potential Clinical Importance 
(Part 2)
SAC
50.
Safety
LB6
Listing of Haematology Values of Potential Clinical Importance 
(Part 1)
SAC
51.
Safety
LB6
Listing of Haematology Values of Potential Clinical Importance 
(Part 2)
SAC
52.
Safety
LB6
Listing of Urinalysis Data (gravity and pH) (Part 1)
SAC
53.
Safety
LB6
Listing of Urinalysis Data (gravity and pH) (Part 2)
SAC
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
54.
Safety
LB14
Listing of Urinalysis Data (Glucose, Protein, Blood, Ketones, 
Bilirubin, and Urobilinogen) (Part 1)
ICH E3
SAC
55.
Safety
LB14
Listing of Urinalysis Data (Glucose, Protein, Blood, Ketones, 
Bilirubin, and Urobilinogen) (Part 2)
ICH E3
SAC
ECG
56.
Safety
EG4
Listing of All ECG Values (Part 1)
SAC
57.
Safety
EG4
Listing of All ECG Values (Part 2)
SAC
58.
Safety
EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance (Part 1)
IDSL
SAC
59.
Safety
EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance (Part 2)
IDSL
SAC
60.
Safety
EG4
Listing of ECG Values of Potential Clinical Importance (Part 1)
IDSL
SAC
61.
Safety
EG4
Listing of ECG Values of Potential Clinical Importance (Part 2)
IDSL
SAC
62.
Safety
EG6
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding (Part 1)
IDSL
SAC
63.
Safety
EG6
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding (Part 2)
IDSL
SAC
64.
Safety
EG6
Listing of Abnormal ECG Findings (Part 1)
IDSL
SAC
65.
Safety
EG6
Listing of Abnormal ECG Findings (Part 2)
IDSL
SAC
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
66.
Safety
VS5
Listing of All Vital Signs Data (Part 1)
IDSL
SAC
67.
Safety
VS5
Listing of All Vital Signs Data (Part 2)
IDSL
SAC
68.
Safety
VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance (Part 1)
IDSL
SAC
69.
Safety
VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance (Part 2)
IDSL
SAC
70.
Safety
VS5
Listing of Vital Signs of Potential Clinical Importance (Part 1)
IDSL
SAC
71.
Safety
VS5
Listing of Vital Signs of Potential Clinical Importance (Part 2)
IDSL
SAC
PK
72.
PK
PK08
Listing of Daprodustat Plasma Pharmacokinetic Concentration-
Time Data (Part 1)
IDSL
SAC
73.
PK
PK08
Listing of Daprodustat Plasma Pharmacokinetic Concentration-
Time Data (Part 2)
IDSL
SAC
74.
PK
PK14
Listing of Derived Daprodustat Plasma Pharmacokinetic 
Parameters (Part 1)
IDSL
All PK parameters in Section 8.1.1.2 will be 
provided in a listing
SAC
75.
PK
PK14
Listing of Derived Daprodustat Plasma Pharmacokinetic 
Parameters (Part 2)
IDSL
All PK parameters in Section 8.1.1.2 will be 
provided in a listing
SAC
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10.10.
Appendix 10: Example Mock Shells for Data Displays
Example: PK_T1
Page 1 of n
Protocol: 207727
Population: PK
Table X
Analysis of [Tablet Strength Effect/Food Effect] for Cmax, AUC(0-t), and AUC(0-inf) (Part [1 or 2])
Parameter
Treatment
N
n
Adjusted 
Geom Mean
Ratio 
(trt2/trt1)
90% CI
%CVw[1]
Cmax (unit)
trt1
xx
xx
xx.xxx
x.xxx
(x.xxx, x.xxx)
x.xxx
trt2
xx
xx
xx.xxx
AUC(0-t)(unit)
trt1
xx
xx
xx.xxx
x.xxx
(x.xxx, x.xxx)
x.xxx
trt2
xx
xx
xx.xxx
AUC(0-inf) (unit)
trt1
xx
xx
xx.xxx
x.xxx
(x.xxx, x.xxx)
x.xxx
trt2
xx
xx
xx.xxx
[1] Within-subject variability of each PK parameter
Programming notes: For Part1, trt1 = “4mg x 1” and trt2 = “2mg x 2”. For Part2, trt1 = “fasted” and trt2 = 
“fed”.
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Example: PK_F1
Page 1 of n
Protocol: 207727
Population: PK
Table X
Plot of Individual Daprodustat Plasma Cmax, AUC(0-t), AUC(0-inf) by [Tablet Strength Effect/Food Effect] (Part 
[1 or 2])
Note: Geometric mean and 95% CI 
Programming notes: For Part1, trt1 = “4mg x 1” and trt2 = “2mg x 2”. For Part2, trt1 = “fasted” and trt2 = 
“fed”.
Programming notes: AUC(0-inf) will also be presented.
Programming notes: Figures will be presented in left (Cmax), center (AUC(0-t), and right (AUC(0-inf).
2018N372208_00