Conditions: Anaemia
Keywords: darbepoetin alpha challenge agents daprodustat FBF-CKD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6
Healthy volunteers: no

Brief summary:
Daprodustat has demonstrated an ability to effectively raise hemoglobin concentrations with lower erythropoietin (EPO) levels than those observed after administration of recombinant human erythropoietin (rhEPOs). Therefore, daprodustat has the potential to treat anemia of chronic kidney disease (CKD) with a lower cardiovascular (CV) risk than is observed with the rhEPOs. While the effect of rhEPOs on endothelial function has been assessed, to date the effect of daprodustat or other prolyl hydroxylase inhibitor (PHI) compounds on endothelial function has not. Therefore, the purpose of this study is to compare the effect of daprodustat to darbepoetin alfa on endothelial function by assessing FBF in participants with anemia of CKD by using venous occlusion plethysmography as a means to estimate the potential for daprodustat to have a lower risk of CV events as compared to rhEPO.

This study will use a randomized, repeat dose, open label, parallel group design, in adult, not on-dialysis, male and female participants with anemia of CKD that are currently not treated with rhEPOs.

The study will comprise of three study periods: a screening period starting up to 30 days prior to Day 1, a 42 day (6 week) treatment period, and a follow-up visit up to 14 days later. The total duration of participants involvement is up to 14 weeks (including screening and follow up visit). Approximately 50 participants will be randomized to either daprodustat or darbepoetin alfa.

Detailed description:

Arms:
arm 1: Participants will receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days. arm 2: Participants will receive Darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).

Interventions: intervention 1: Daprodustat intervention 2: Darbepoetin alfa intervention 3: Acetylcholine intervention 4: Sodium nitroprusside intervention 5: L-N-monomethyl arginine acetate (L-NMMA)
Intervention descriptions: intervention 1: Daprodustat will be available as 1 mg, 2 mg and 4 mg oral tablets. Daprodustat will be administered once daily by oral route without regard for food. intervention 2: Darbepoetin alfa will be given as solution for injection for subcutaneous administration every 2 weeks. intervention 3: Acetylcholine will be used as a challenge agent and will be infused at 7.5, 15 and 30 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm. intervention 4: Sodium nitroprusside will be used as a challenge agent and will be infused at 3 and 10 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm. intervention 5: L-N-monomethyl arginine acetate will be used as a challenge agent and will be infused at a doses of 2 and 8 micromoles/minute for 6 minutes into the brachial artery of the test arm.

Protocol document:
Prot_000.pdf: 
2016N291495_02
CONFIDENTIAL
GlaxoSmithKline group of companies
205767
1
TITLE PAGE
Protocol Title: A randomized, repeat dose, open label, parallel group, multi-center study 
to evaluate the effect of daprodustat compared to darbepoetin alfa on 
forearm blood flow in participants with anemia of chronic kidney disease 
that are not dialysis dependent
Protocol Number: 205767/Amendment 02
Short Title: Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat –
Forearm Blood Flow (ASCEND-FBF) 
Compound Number:  GSK1278863
Sponsor Name and Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual (SRM)
Regulatory Agency Identifying Number(s):
IND Number 101,291
EudraCT number: 2017-002268-42
Approval Date: 07-AUG-2019
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


2016N291495_02
CONFIDENTIAL
205767
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
07-Aug-2019
Amendment 1
29-Jan-2018
Original Protocol
17-Nov-2017
Amendment 2  07-AUG-2019
Overall Rationale for the Amendment: Due to a challenge agent suddenly becoming 
commercially unavailable with no immediate ability to reobtain this, the study has been 
modified to allow flexibility for the forearm blood flow testing to be performed with this 
agent if it becomes available again, and to be performed without it if not.
Section # and 
Name
Description of Change
Brief Rationale
Short Title
The short title of the study was changed.
All global studies for this asset have a 
similar nomenclature; this change is to 
align globally.
1 Synopsis
The short title was changed.
See above
1 Synopsis
“Citrate” was changed to “acetate” for L-
NG-monomethyl arginine acetate (L-
NMMA) throughout the document.
For correction.
1 Synopsis
A note was added at the end.
For clarity of how the challenge agents 
are to be used in the study.
1 and 4 
Objectives and 
Endpoints
The word “ratio” was removed from several 
endpoints.
For clarity of reading only; there is no 
change in how the endpoints are 
characterized nor calculated.
1 and 4 
Objectives and 
Endpoints
A Safety section was added.  The existing 
safety endpoints were then moved to this 
section.  No additions or deletions in the 
endpoint text.
To better characterize the nature of the 
endpoint.
1 and 4 
Objectives and 
Endpoints
The last exploratory endpoint was 
removed.
No further models have been deemed
necessary to explore as the existing
exploratory endpoint is sufficient.  
2 Schedule of 
Activities
A central lab hematology check was added
to on study visits.  
For safety, to compare with HemoCue.  
This is also consistent with the other 
daprodustat protocols. 


2016N291495_02
CONFIDENTIAL
205767
4
Section # and 
Name
Description of Change
Brief Rationale
2 Schedule of 
Activities
The potential repeat FBF visits were added 
to the schedule of activities table.
For clarity on the procedures to be 
performed at the repeat FBF visits. 
3.1 Study 
Rationale
The term “if available” was added.
To allow for alteration in assessments 
depending on the availability of the 
challenge agent.
5.5 Dose 
Justification
“Clinical judgement” was added to the 
decision making regarding darbepoetin 
dosing.
For safety of the participants; this allows 
the PI to exercise clinical judgement and 
management when dosing rhEPO to 
study participants.
6.1 Inclusion 
Criteria and 6.2 
Exclusion Criteria
Minor additions to the lab reporting 
parameters were added to reflect both 
conventional and SI units.
For ease of identifying study criteria 
using both units.
6.2 Exclusion 
Criteria
Ferritin exclusion criteria was lowered.
To facilitate enrolment.
6.2 Exclusion 
Criteria
Updated the language in the exclusion 
criterion #17 regarding blood pressure.
Changed language to align with updates 
in benefit/risk profile and DCSI.
6.2 Exclusion 
Criteria
Minor update to the platelet count 
reporting.
For correction of reporting units..
7.1.1.2 
Darbepoetin Alfa 
Dosing 
Information
“Clinical judgement” was added to the 
decision making regarding darbepoetin 
dosing.  Additionally, the option to hold or 
delay a dose was included.
For safety of the participants; this allows 
the PI to exercise clinical judgement and 
management when dosing rhEPO to 
study participants.
7.1.2 Challenge 
Agents
A note was added at the beginning of the 
section.
For clarity of how the challenge agents 
are to be used in the study as well as 
described in the protocol.
7.2 Dose 
Modification
Added rows to Table 1 to allow subjects 
with a rapid rise in Hgb to have their 
treatment dose decreased.
To be consistent with management in 
other daprodustat studies as well as 
prevent unnecessary subject withdrawal.
7.7.2 Prohibited
Medications
High dose clopidogrel (300mg) was added.
An additional example of a strong 
CYP2C8 inhibitor was added.
8.1 
Discontinuation 
Criteria
A statement was added at the end for the 
PI to be able to withdraw the participant at 
his/her discretion.
For safety of the participants; this allows 
the PI to exercise clinical judgement and 
management.
8.1.2 Hgb 
Stopping Criteria
The structure of Table 2 was modified.
For clear distinction between assessment 
of the Hgb and resultant action(s).
8.1.2 Hgb 
Stopping Criteria
The allowable increase of Hgb over a 2 
week period was changed.
To be consistent with management in 
other similar studies as well as prevent 
unnecessary subject withdrawal.
8.1.2 Hgb 
Stopping Criteria
A stopping criterion was added of Hgb 
increase over a 4 week period
For patient safety.
8.1.2 Hgb 
Stopping Criteria
Removed criterion for mandatory 
withdrawal of subjects who show rapid rise 
in Hgb.  Subjects exhibiting a rapid rise in 
To be consistent with management in 
other daprodustat studies as well as 
prevent unnecessary subject withdrawal.


2016N291495_02
CONFIDENTIAL
205767
5
Section # and 
Name
Description of Change
Brief Rationale
Hgb over a 2- or 4-week period may now 
have their treatment dose decreased at 
Day 28 instead (see change made to 
Section 7.2, above).
9.2.5 Adverse 
Events of Special 
Interest
An AESI was added to this section.
A new AESI of ‘worsening of 
hypertension’ has been identified (see 
risk table in Appendix 7).
9.2.8 Pregnancy
Text was updated to reflect guidance given 
in Appendix 5.
For correction. 
9.6.1 Venous 
Occlusion…..
Description of the procedure to be followed 
if one or both of the secondary challenge 
agents are unavailable. 
For clarity.
9.6.1.2 
Participants 
Unable to….
Provision was made in the protocol for a 
potential repeat of the FBF procedures on 
Day 1 if the participant agrees.
For retention of participants in the study.
9.6.1.3 FBF 
Quality Control 
Criteria
An update was made as to where the QC 
criteria can be found.
For correction.
9.6.1.4 Delayed 
or Repeat FBF 
Procedures
This was revised to describe the study 
procedures to be followed in the event of 
delays or repeats to FBF procedures.
For clarity of guidance to the 
investigators.
10.1 Sample Size 
Determination
Additional language was provided to further 
describe the procedures for sample size; 
no changes made to the intent of this 
analysis.
For clarification of maximum number of 
subjects if sample size re-estimation 
suggests a different sample size is 
needed.
10.1.2 Sample 
Size Re-
estimation
See above (10.1).
See above (10.1).
10.2.1.2 
Secondary 
Comparisons and 
10.3.3 Other 
Analyses
This analysis was updated to reflect the 
potential for decreased data due to 
unavailability of challenge agents.
For clarification of procedures in this 
instance. 
10.3.4 Interim 
Analysis
Text was added to this section.
To better explain the purpose of the 
potential interim analysis, as well as add 
more details around the operating 
characteristics and decision thresholds.
12.2 Clinical 
Laboratory Tests
Provision was made for the new 
hematology lab test to be performed locally 
if the central lab is unavailable.
For better flow of study and promote
recruitment and retention.
12.7 Appendix 7: 
Risk Assessment
Several updates were made to the risk 
assessment table.
To reflect current information regarding 
risk and to align with changes made to 
the risk table across the global asset 
program.
12.8.2 (Sub 
Study) Objectives 
The word “ratio” was removed from the 
endpoints.
For consistency with the main endpoints; 
see above.


2016N291495_02
CONFIDENTIAL
205767
6
Section # and 
Name
Description of Change
Brief Rationale
and Endpoints
12.8.3 (Sub 
Study) Study 
Design
Update was made to the selection of 
participants from each treatment group. 
To facilitate recruitment and ease of site 
management.
12.8.5 (Sub 
Study) Study 
Assessments
Minor updates made to the description of 
the devices used.
For clarification and correction.


2016N291495_02
CONFIDENTIAL
205767
7
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................10
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................14
3.
INTRODUCTION....................................................................................................17
3.1.
Study Rationale ..........................................................................................17
3.2.
Background ................................................................................................18
3.3.
Benefit: Risk Assessment ...........................................................................19
3.3.1.
Risk Assessment .........................................................................19
3.3.2.
Benefit Assessment.....................................................................19
3.3.3.
Overall Benefit: Risk Conclusion..................................................19
4.
OBJECTIVES AND ENDPOINTS...........................................................................20
5.
STUDY DESIGN ....................................................................................................21
5.1.
Overall Design ............................................................................................21
5.2.
Number of Participants ...............................................................................22
5.3.
Participant and Study Completion...............................................................22
5.4.
Scientific Rationale for Study Design ..........................................................22
5.5.
Dose Justification........................................................................................22
6.
STUDY POPULATION...........................................................................................23
6.1.
Inclusion Criteria.........................................................................................23
6.2.
Exclusion Criteria........................................................................................24
6.3.
Lifestyle Restrictions...................................................................................26
6.3.1.
Meals and Dietary Restrictions ....................................................26
6.3.2.
Caffeine, Alcohol and Tobacco ....................................................26
6.3.3.
Activity .........................................................................................26
6.4.
Screen Failures...........................................................................................27
7.
TREATMENTS.......................................................................................................27
7.1.
Treatments Administered............................................................................27
7.1.1.
Study Treatments ........................................................................28
7.1.1.1.
Daprodustat Dosing Information .................................28
7.1.1.2.
Darbepoetin Alfa Dosing Information ..........................29
7.1.2.
Challenge Agents ........................................................................29
7.1.2.1.
Acetylcholine Dosing Information................................30
7.1.2.2.
Sodium Nitroprusside Dosing Information...................30
7.1.2.3.
L-NG-monomethyl Arginine Acetate (L-NMMA) 
Dosing Information .....................................................30
7.2.
Dose Modification .......................................................................................30
7.3.
Method of Study Treatment Assignment .....................................................31
7.4.
Blinding.......................................................................................................31
7.5.
Preparation/Handling/Storage/Accountability..............................................31
7.6.
Treatment Compliance................................................................................32
7.7.
Concomitant Therapy..................................................................................32


2016N291495_02
CONFIDENTIAL
205767
8
7.7.1.
Permitted Medications and Non-Drug Therapies..........................32
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................33
7.7.3.
Standard of Care .........................................................................33
7.7.4.
Iron Management Criteria ............................................................33
7.8.
Treatment after the End of the Study ..........................................................33
8.
DISCONTINUATION CRITERIA.............................................................................34
8.1.
Discontinuation of Study Treatment ............................................................34
8.1.1.
Liver Chemistry Stopping Criteria ................................................34
8.1.2.
Hgb Stopping Criteria...................................................................35
8.2.
Withdrawal from the Study..........................................................................36
8.3.
Lost to Follow Up........................................................................................37
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................37
9.1.
Efficacy Assessments.................................................................................38
9.2.
Adverse Events...........................................................................................38
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................38
9.2.2.
Method of Detecting AEs and SAEs.............................................38
9.2.3.
Follow-up of AEs and SAEs.........................................................39
9.2.4.
Regulatory Reporting Requirements for SAEs .............................39
9.2.5.
Adverse Events of Special Interest ..............................................39
9.2.6.
Cardiovascular and Death Events................................................40
9.2.7.
Possible Suicidality Related Adverse Events ...............................40
9.2.8.
Pregnancy ...................................................................................40
9.3.
Treatment of Overdose...............................................................................41
9.4.
Safety Assessments ...................................................................................41
9.4.1.
Physical Examinations.................................................................41
9.4.2.
Vital Signs....................................................................................41
9.4.3.
Electrocardiograms......................................................................42
9.4.4.
Clinical Safety Laboratory Assessments ......................................42
9.5.
Pharmacokinetics .......................................................................................42
9.6.
Pharmacodynamics ....................................................................................43
9.6.1.
Venous Occlusion Plethysmography to Measure Forearm 
Blood Flow (FBF).........................................................................43
9.6.1.1.
Participants on Anti-coagulant Therapy ......................44
9.6.1.2.
Participants Unable to Complete FBF 
Procedure...................................................................44
9.6.1.3.
FBF Quality Control Criteria........................................44
9.6.1.4.
Delayed or Repeat FBF Procedures...........................44
9.6.2.
Pulse Wave Analysis and Pulse Wave Velocity to 
measure vascular compliance......................................................45
9.7.
Genetics .....................................................................................................45
9.8.
Biomarkers .................................................................................................45
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................45
10. STATISTICAL CONSIDERATIONS........................................................................46
10.1.
Sample Size Determination ........................................................................46
10.1.1.
Sample Size Sensitivity................................................................46
10.1.2.
Sample Size Re-estimation..........................................................46
10.2.
Populations for Analyses ............................................................................46


2016N291495_02
CONFIDENTIAL
205767
9
10.2.1.
Treatment Comparisons ..............................................................47
10.2.1.1.
Primary Comparisons.................................................47
10.2.1.2.
Secondary Comparisons ............................................47
10.3.
Statistical Analyses.....................................................................................48
10.3.1.
Efficacy Analyses.........................................................................48
10.3.2.
Safety Analyses...........................................................................48
10.3.3.
Other Analyses (Pharmacodynamic)............................................48
10.3.4.
Interim Analyses ..........................................................................50
11. REFERENCES.......................................................................................................51
12. APPENDICES........................................................................................................53
12.1.
Appendix 1: Abbreviations and Trademarks................................................53
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................56
12.3.
Appendix 3: Study Governance Considerations..........................................58
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................62
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................68
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................71
12.7.
Appendix 7: Risk Assessment.....................................................................74
12.8.
Appendix 8: Non-Contact, Optical Forearm Plethysmography (NC-
OFP) Sub-Study .........................................................................................88
12.8.1.
Introduction and Rationale ...........................................................88
12.8.2.
Objectives and Endpoints ............................................................88
12.8.3.
Study Design ...............................................................................88
12.8.4.
Additional Inclusion Criteria .........................................................88
12.8.5.
Study Assessments .....................................................................88
12.8.6.
Withdrawal from Non-Contact, Optical Plethysmography 
Sub-Study....................................................................................89
12.8.7.
Sample Size ................................................................................89
12.8.8.
Analyses Plan..............................................................................89
12.9.
Appendix 9: Protocol Amendment History...................................................90


2016N291495_02
CONFIDENTIAL
205767
10
1.
SYNOPSIS
Protocol Title: A randomized, repeat dose, open label, parallel group, multi-center study 
to evaluate the effect of daprodustat compared to darbepoetin alfa on forearm blood flow 
in participants with anemia of chronic kidney disease that are not dialysis dependent
Short Title: Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat –
Forearm Blood Flow (ASCEND-FBF)
Rationale: Several recent studies have demonstrated that the treatment of patients with 
anemia of CKD that returns them to normal - as compared to lower - hemoglobin (Hgb)
levels by using recombinant human erythropoietins (rhEPOs) is associated with a higher 
mortality rate, an increased risk for a composite endpoint of death, myocardial infarction
(MI), hospitalization for congestive heart failure and stroke, and an increased risk of 
death and major cardiovascular events (CV) (i.e. myocardial infarction, stroke, heart 
failure, myocardial ischemia).  The reason for the increased risk for mortality and CV 
events is not known, but has been hypothesized to be due to the dose of epoetin alfa 
administered rather than the level of Hgb achieved, with higher doses associated with 
increased risk.
It is known that endothelial dysfunction may be predictive of CV events.  In this regard, it 
has been shown that endothelial dysfunction, as assessed by flow-mediated dilation of the 
brachial artery, is an independent predictor of major cardiovascular events in peritoneal 
dialysis patients; however, in this study it was not clear whether these patients received 
rhEPO.  It has increasingly become apparent that the vascular endothelium plays a critical 
role in normal vascular homeostasis through several mechanisms, in particular release of 
endothelium-derived relaxing factor/nitric oxide (NO), effects on vascular smooth muscle 
to maintain vasodilator tone, and vasoconstriction through release of endothelin and 
conversion of angiotensin-I to angiotensin-II.  Thus, it has been shown that rhEPO, 
administered as epoetin alfa, administered to both patients with anemia of CKD as well 
as participants with normal renal function, impaired methacholine-stimulated increases in 
forearm blood flow, while no effect was seen for sodium nitroprusside-stimulated 
vasodilation.  In addition, patients with renal failure who were dialysis-dependent and 
treated for their anemia with three-times weekly subcutaneous doses of rhEPO for 12 
weeks, had an increase in forearm vascular resistance in response to norepinephrine as 
compared to pre-treatment values.  These results suggest that epoetin alfa, and potentially 
other rhEPOs, can negatively affect endothelial function, an effect which may, at least in 
part, play a role in the increased CV risk seen with administration of these agents.
Daprodustat has demonstrated an ability to effectively raise Hgb concentrations with 
lower EPO levels than those observed after administration of rhEPOs.  Therefore, 
daprodustat has the potential to treat anemia of CKD with a lower CV risk than is 
observed with the rhEPOs.  While the effect of rhEPOs on endothelial function has been 
assessed, to date the effect of daprodustat or other prolyl hydroxylase inhibitor (PHI)
compounds on endothelial function has not.  Therefore, the purpose of this study is to 
compare the effect of daprodustat to darbepoetin alfa on endothelial function by assessing 
FBF in patients with anemia of CKD by using venous occlusion plethysmography as a 
means to estimate the potential for daprodustat to have a lower risk of CV events as 


2016N291495_02
CONFIDENTIAL
205767
11
compared to rhEPO.  Venous occlusion plethysmography is recognized as a robust 
methodology in the study of human vascular physiology when used in combination with 
intra-arterial administration of challenge agents to assess the effect of agents on FBF.  In 
the present study, which involves two forearm blood flow procedures six weeks apart, it 
is planned to use acetylcholine (ACh) to assess the effect of daprodustat and darbepoetin 
alfa on endothelial-dependent vasodilation, sodium nitroprusside (SNP) for assessing 
endothelial-independent vasodilation, and L-NG-monomethyl arginine acetate (L-
NMMA), an inhibitor of NO synthase, as a measure of basal NO synthesis.
N.B. Throughout the document the use of these challenge agents is described on the 
assumption that they are available for both FBF visits for an individual participant.  If 
either of the secondary endpoint challenge agents (SNP and L-NMMA) are unavailable,
then that agent will be excluded from the FBF procedure for that individual participant.
Therefore, if L-NMMA is not available then the FBF procedure will be finished after the 
last SNP infusion. Similarly, if SNP is not available for any reason, then the L-NMMA (if 
available) will be given following the ACh challenge.  If both challenge agents become 
unavailable for any reason, then only ACh will be given.
In the event that a challenge agent becomes available again while a patient is mid-study 
(i.e. between Day 1 and Day 42 FBF procedures), then the challenge agent will still not 
be used at Day 42 due to the lack of baseline comparator data.  
Objectives and Endpoints:
Objectives
Endpoints
Primary
To compare the effect of daprodustat to 
darbepoetin alfa on endothelial function

Change in FBF ratio from Day 1 to Day 42 in 
response to acetylcholine
Principle Secondary
To further compare the effect of daprodustat to 
darbepoetin alfa on endothelial function

Change in the absolute FBF from Day 1 to 
Day 42 in response to acetylcholine
Secondary
To compare the effect of daprodustat to 
darbepoetin alfa on endothelium-independent 
vasodilation

Change in FBF ratio from Day 1 to Day 42 in 
response to sodium nitroprusside

Change in the absolute FBF from Day 1 to 
Day 42 in response to sodium nitroprusside
To compare the effect of daprodustat to 
darbepoetin alfa on basal endothelial NO 
synthesis

Change in FBF ratio from Day 1 to Day 42 in 
response to L-NMMA

Change in the absolute FBF on Day 1 to 
Day 42 in response to L-NMMA
To compare the effect of daprodustat on the FBF
response to acetylcholine, sodium nitroprusside 
and L-NMMA between Day 42 and Day 1

Change in FBF ratio in response to each 
individual challenge agent at Day 42 vs Day 
1 in participants treated with daprodustat

Change in the absolute FBF in response to 
each individual challenge agent at Day 42 vs 


2016N291495_02
CONFIDENTIAL
205767
12
Objectives
Endpoints
Day 1 in participants treated with 
daprodustat
To compare the effect of darbepoetin alfa on the 
FBF response to acetylcholine, sodium 
nitroprusside and L-NMMA between Day 42 and 
Day 1

Change in FBF ratio in response to each 
individual challenge agent at Day 42 vs Day 
1 in participants treated with darbepoetin 
alfa

Change in the absolute FBF in response to 
each individual challenge agent at Day 42 vs 
Day 1 in participants treated with 
darbepoetin alfa
To compare the effect of daprodustat to 
darbepoetin alfa on vascular compliance

Change in Augmentation Index (an indicator 
of arterial stiffness) as estimated by radial 
arterial pulse contours from Day 1 to Day 42

Change in pulse wave velocity (PWV) from 
Day 1 to Day 42
Safety
Assess safety and tolerability

Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs) 
including AEs of special interest

Reasons for discontinuation of randomized 
study treatment

Absolute values and changes from baseline 
in clinical laboratory parameters, 
electrocardiogram (ECG) parameters, blood 
pressure (BP) and heart rate (HR)
Exploratory
To explore the relationship between diabetes 
status and endothelial function

FBF response to each individual challenge 
agent in relation to diabetes status
Overall Design: This study will use a randomized, repeat dose, open label, parallel group 
design, in adult, male and female participants with anemia of CKD not on dialysis (ND)
that are currently not treated with rhEPOs (i.e. no rhEPO use within the 12 weeks prior to 
the screening visit and through Day 1).

The study will comprise three study periods: a screening period starting up to 30 
days prior to Day 1, a 42 day (6 week) treatment period with 4 visits starting at 
Day 1, and a follow-up visit up to 14 days later.

Participants will be randomized to either daprodustat or darbepoetin alfa.  A 
central randomization approach will be used with stratification by center.

All participants will be treated with the goal of achieving a Hgb level within the 
range of 10.0 to 12.0 g/dL, consistent with national guidelines.

FBF and PWV will be conducted at the beginning (Day 1) and end (Day 42) of 
the treatment period.


2016N291495_02
CONFIDENTIAL
205767
13

This study will include an optional, Non-Contact, Optical Forearm 
Plethysmography (NC-OFP) Sub-Study.
Number of Participants: A sufficient number of participants will be enrolled such that 
at least 50 participants comprise the Pharmacodynamic Per-Protocol (PDPP) Population 
(i.e. all randomized participants who provide pharmacodynamic (PD) data at Day 1 and 
Day 42 and complete the protocol without important deviations).
Treatment Groups and Duration: Eligible participants will be randomized to receive 
either daprodustat (Day 1 through Day 41) or darbepoetin alfa (administered Day 1, 14 & 
28).


2016N291495_02
CONFIDENTIAL
205767
14
2.
SCHEDULE OF ACTIVITIES (SOA)
Procedure
Screening1
Treatment Period2
Follow-up3
Up to 30 
Days
Day 1
Repeat 
Day 117
Day 14
Day 28
Day 42
Repeat 
Day 4217
Informed consent
X
Eligibility Criteria
X
X4
Physical examinations, Medical History, 
Demographics
X
X5
HemoCue Hgb
X
X6
X
X
X
X
X
eGFR
X
Vital signs
X
X6
X
X
X
X
X
X
Clinical chemistry7
X
X
X
Hematology7
X
X
X
X
X
X
Serum pregnancy test (FRP only)
X
Urine pregnancy test (FRP only)8
X
X
X
X
X
X
X
Folate & Vitamin B12
X
12 Lead ECG
X
X6
X
X
Ferritin & TSAT
X
hs-CRP
X
X
X
Females only: FSH9
X
Brachial artery palpation
X
Randomization
X
Daprodustat administration10
<==========================================>
Darbepoetin alfa administration10
X10
X
X
See footnote 
18
Study treatment adjustment11
X
Liver chemistry monitoring
X
X
International Normalized Ratio (INR)12
X
X
X
X
X


2016N291495_02
CONFIDENTIAL
205767
15
Procedure
Screening1
Treatment Period2
Follow-up3
Up to 30 
Days
Day 1
Repeat 
Day 117
Day 14
Day 28
Day 42
Repeat 
Day 4217
Hepatitis B and C screening13
X
HbA1c, lipids7
X
Forearm Blood Flow (FBF)14
X
X
X
X
Pulse Wave Velocity (PWV)14
X
X
X
X
AE and SAE Assessment
X15
X
X
X
X
X
X
X
Blood draw for storage biomarkers16
X
X
Review concomitant medications
X
X
X
X
X
X
X
X
1All participants will undergo screening assessments within 30 days of enrolment.
2Allowable time window 2 days except for the forearm blood flow (FBF) & pulse wave velocity (PWV) as noted.
3Allowable time window 3 days. Follow up will occur 7-14 days ± 3 following completion of the last FBF procedure.  See Section 8.2 for guidance regarding EW participants.
4 Eligibility criteria to be assessed prior to performance of the FBF procedure include HemoCue hemoglobin (Hgb), vital signs & 12-lead electrocardiogram (ECG).
5Only a brief physical exam on Day 1.
6 As detailed in Exclusion Criteria (Section 6.2).
7Clinical chemistry, hematology and other laboratory tests as listed in Appendix 2.
8Local urine pregnancy testing will be standard for protocol unless serum testing is required by local regulations or Institutional Review Board (IRB)/ Independent Ethics Committee (IEC).
9As detailed in Inclusion Criteria (Section 6.1).
10The initial dose of study treatment will be given after the completed Day 1/Repeat Day 1 FBF & PWV procedures. Participants will receive EITHER daprodustat OR darbepoetin alfa.  The 
final dose of daprodustat will be Day 41 (i.e., the day prior to the FBF & PWV procedures), while the final dose of darbepoetin alfa will be Day 28. If repeat procedures are needed the dosing 
will be extended (See Section 9.6.1.4).
11See Section 7.2 for details on study treatment adjustment
12Applies only to participants on anti-coagulant therapy; further details concerning measurement of the international normalised ratio (INR) and subsequent actions can be found in the study 
reference manual (SRM).
13If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required
14 The FBF & PWV assessments are to be performed following confirmation of INR < 3.0 for participants on anticoagulant therapy.  The Day 42 FBF & PWV assessments can be delayed up 
to 1 week (i.e., Day 49)., while randomization (Day 1) should be delayed until the participant’s INR < 3.0 (Section 9.6.1.1).
15 Only serious adverse events (SAEs) assessed as related to study participation are collected at this visit.  See Appendix 4 for additional details.
16 As described in Section 9.8
17 Indicates the procedures to be performed on the repeat visits only if the visit is deemed necessary.  See Section 9.6.1.4
18  Darbepoetin is only to be given on Day 42 if a Repeat Day 42 is needed.


2016N291495_02
CONFIDENTIAL
205767
16

The timing and number of planned study assessments, including: safety, 
pharmacodynamic or other 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 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 IRB/IEC will be informed of any safety 
issues that require alteration of the safety monitoring scheme or amendment of 
the ICF.


2016N291495_02
CONFIDENTIAL
205767
17
3.
INTRODUCTION
Daprodustat (GSK1278863) is a small molecule, oral inhibiter of the hypoxia-inducible 
factor (HIF) prolyl-4-hydroxylase (PHD) enzymes.  This novel molecule may present 
several important advantages over recombinant, human erythropoietins (rhEPOs) and 
analogs for the treatment of anemia of chronic kidney disease (CKD).  It is an oral 
medication and does not require cold-chain storage as do some rhEPOs, thus increasing 
ease of use for patients.  Moreover, data indicate that - similar to other HIF-PHD 
inhibitors - daprodustat can effectively raise hemoglobin (Hgb) concentrations in CKD 
patients that are either hemodialysis-dependent (HD) or not on dialysis (ND) with lower 
erythropoietin (EPO) levels than those observed after administration of rhEPOs (Besarab, 
2015; Holdstock, 2016).  Because of the increased cardiovascular (CV) risk associated 
with raising Hgb concentrations through large increases in EPO levels (Pfeffer, 2009), 
daprodustat has the potential to treat patients with less CV risk than rhEPOs (vida infra).  
Additional potential benefits include improving iron availability for erythropoiesis and 
successfully treating rhEPO hypo-responders (Holdstock, 2016).
3.1.
Study Rationale
Several recent studies have demonstrated that the treatment of patients with anemia of 
CKD that returns them to normal - as compared to lower - Hgb levels by using rhEPOs is 
associated with a higher mortality rate (Besarab, 1998), an increased risk for a composite 
endpoint of death, myocardial infarction, hospitalization for congestive heart failure and 
stroke (Singh, 2006), and an increased risk of death and major cardiovascular events (i.e. 
myocardial infarction, stroke, heart failure, myocardial ischemia; Pfeffer, 2009).  The 
reason for the increased risk for mortality and CV events is not known, but has been 
hypothesized to be due to the dose of epoetin alfa administered rather than the level of 
Hgb achieved (Szczech, 2008), with higher doses associated with increased risk.
It is known that endothelial dysfunction may be predictive of CV events (Lerman, 2005; 
Ras, 2013).  In this regard, it has been shown that endothelial dysfunction, as assessed by 
flow-mediated dilation of the brachial artery, was an independent predictor of major 
cardiovascular events in peritoneal dialysis patients; however, in this study it was not 
clear whether these patients received a rhEPO (Lee, 2014).  It has increasingly become 
apparent that the vascular endothelium plays a critical role in normal vascular 
homeostasis through several mechanisms, in particular release of endothelium-derived 
relaxing factor/nitric oxide (NO), effects on vascular smooth muscle to maintain 
vasodilator tone, and vasoconstriction through release of endothelin and conversion of 
angiotensin-I to angiotensin-II (Deanfield, 2007).  Thus, it has been shown that EPO, 
administered as epoetin alfa, administered to both patients with anemia of CKD as well 
as participants with normal renal function, impaired methacholine-stimulated increases in 
forearm blood flow, while no effect was seen for sodium nitroprusside-stimulated 
vasodilation (Annuk, 2006).  In addition, patients with renal failure who were dialysis-
dependent and treated for their anemia with three-times weekly subcutaneous doses of 
rhEPO for 12 weeks, had an increase in forearm vascular resistance in response to 
norepinephrine as compared to pre-treatment values (Hand, 1995).  These results suggest 
that epoetin alfa, and potentially other rhEPOs, can negatively affect endothelial function, 


2016N291495_02
CONFIDENTIAL
205767
18
an effect which may, at least in part, play a role in the increased CV risk seen with 
administration of these agents.
Daprodustat has demonstrated an ability to effectively raise Hgb concentrations with 
lower EPO levels than those observed after administration of rhEPOs (vida supra).  
Therefore, daprodustat has the potential to treat anemia of CKD with a lower CV risk 
than is observed with the rhEPOs.  While the effect of rhEPOs on endothelial function 
has been assessed, to date the effect of daprodustat or other PHI compounds on 
endothelial function has not.  Therefore, the purpose of this study is to compare the effect 
of daprodustat to darbepoetin alfa on endothelial function by assessing forearm blood 
flow (FBF) in patients with anemia of CKD by using venous occlusion plethysmography
as a means to estimate the potential for daprodustat to have a lower risk of CV events as 
compared to rhEPO.  Venous occlusion plethysmography is recognized as a robust 
methodology in the study of human vascular physiology when used in combination with 
intra-arterial administration of challenge agents to assess the effect of agents on FBF 
(Wilkinson, 2001).  In the present study, it is planned to use acetylcholine (ACh) to 
assess the effect of daprodustat and darbepoetin alfa on endothelial-dependent 
vasodilation, sodium nitroprusside (SNP) (if available) for assessing endothelial-
independent vasodilation, and L-NG-monomethyl arginine acetate (L-NMMA) (if 
available), an inhibitor of NO synthase as a measure of basal NO synthesis (Wilkinson, 
2001).
In addition to the assessment of endothelial function as a biomarker of potential rhEPO-
induced cardiovascular risk, carotid to femoral pulse wave velocity (PWV) will be 
measured as an assessment of arterial stiffness.  PWV is considered the ‘gold standard’ 
methodology for assessing arterial stiffness, with a growing body of evidence showing 
the predictive value of PWV and CV disease and risk (Pereira, 2015).  In this regard, both 
normal values for PWV, from a population with no apparent risk factors, and values from 
a population with various CV risk factors have been proposed (Boutouyrie, 2010).  
Therefore, PWV will also be measured as an additional biomarker of potential rhEPO-
induced cardiovascular risk.
3.2.
Background
PHIs are an emerging class of agents under investigation for the treatment of anemia of 
CKD.  These molecules stimulate erythropoiesis through inhibition of HIF-PHD enzymes 
(PHD1, PHD2, PHD3).  This activity results in the accumulation of HIFα transcription 
factors which leads to increased transcription of HIF-responsive genes, stimulating 
components of the natural response to hypoxia.  During hypoxia, PHD enzymes are 
inhibited, resulting in the accumulation of unhydroxylated HIFα subunits, which dimerize 
with HIFβ subunits to affect the transcription of HIF-responsive genes, including EPO 
and others involved in increasing oxygen availability and utilization.  Other functions 
regulated by HIFs include iron metabolism and utilization, angiogenesis, extracellular 
matrix metabolism, apoptosis, energy and glucose metabolism, vascular tone, cell 
adhesion, and motility (Haase, 2013).


2016N291495_02
CONFIDENTIAL
205767
19
3.3.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
daprodustat can be found in the daprodustat Investigator’s Brochure (IB) and IB 
supplement(s), if applicable.
3.3.1.
Risk Assessment
The potential risks of clinical significance, including adverse events of special interest 
(See Section 9.2.5 for details), and the mitigation strategies for this protocol taking into 
account the results of completed clinical and nonclinical studies with daprodustat are 
outlined in Appendix 7.
3.3.2.
Benefit Assessment
In clinical trials of up to 24 weeks in duration, in participants with anemia of CKD, 
daprodustat has been shown to treat Hgb to target range.  Data from prior studies with 
daprodustat suggest that the increases in Hgb are achieved with EPO exposure lower than 
those observed with rhEPO (Holdstock, 2016).
3.3.3.
Overall Benefit: Risk Conclusion
Daprodustat demonstrates a positive benefit vs. risk based on the evidence as follows.  In 
clinical trials up to 24 weeks in duration, daprodustat maintained Hgb to target range in 
participants with anemia of CKD (both ND and HD) with a safety profile consistent with 
the patient population.
This protocol employs precautions to mitigate known and potential risks to enrolled 
participants (see Appendix 7 for details).  Given these precautions, as well as the 
potential benefit that daprodustat holds for the treatment of anemia of CKD compared to 
the current standard, the overall benefit risk balance is considered to be positive.


2016N291495_02
CONFIDENTIAL
205767
20
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To compare the effect of daprodustat to 
darbepoetin alfa on endothelial function

Change in FBF ratio from Day 1 to Day 42 in
response to acetylcholine
Principle Secondary
To further compare the effect of daprodustat to 
darbepoetin alfa on endothelial function

Change in the absolute FBF from Day 1 to 
Day 42 in response to acetylcholine
Secondary 
To compare the effect of daprodustat to 
darbepoetin alfa on endothelium-independent 
vasodilation

Change in FBF ratio from Day 1 to 42 in 
response to sodium nitroprusside

Change in the absolute FBF from Day 1 to 
Day 42 in response to sodium nitroprusside
To compare the effect of daprodustat to 
darbepoetin alfa on basal endothelial NO
synthesis

Change in FBF ratio from Day 1 to Day 42 in 
response to L-NMMA

Change in the absolute FBF from Day 1 to 
Day 42 in response to L-NMMA
To compare the effect of daprodustat on the FBF
response to acetylcholine, sodium nitroprusside 
and L-NMMA between Day 42 and Day 1

Change in FBF ratio in response to each 
individual challenge agent at Day 42 vs Day 
1 in participants treated with daprodustat

Change in the absolute FBF in response to 
each individual challenge agent at Day 42 vs 
Day 1 in participants treated with 
daprodustat
To compare the effect of darbepoetin alfa on the 
FBF response to acetylcholine, sodium 
nitroprusside and L-NMMA between Day 42 and 
Day 1

Change in FBF ratio in response to each 
individual challenge agent at Day 42 vs Day 
1 in participants treated with darbepoetin 
alfa

Change in the absolute FBF in response to 
each individual challenge agent at Day 42 vs 
Day 1 in participants treated with 
darbepoetin alfa
To compare the effect of daprodustat to 
darbepoetin alfa on vascular compliance

Change in Augmentation Index (an indicator 
of arterial stiffness) as estimated by radial 
arterial pulse contours from Day 1 to 42

Change in pulse wave velocity (PWV) from 
Day 1 to Day 42
Safety
Assess safety and tolerability

Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs) 
including AEs of special interest

Reasons for discontinuation of randomized 
study treatment

Absolute values and changes from baseline 
in clinical laboratory parameters, ECG 
parameters, blood pressure (BP) and heart 
rate (HR)


2016N291495_02
CONFIDENTIAL
205767
21
Objectives
Endpoints
Exploratory
To explore the relationship between diabetes 
status and endothelial function

FBF response to each individual challenge 
agent in relation to diabetes status
5.
STUDY DESIGN
5.1.
Overall Design
This study will use a randomized, repeat dose, open label, parallel group design, in adult, 
ND, male and female participants with anemia of CKD that are currently not treated with 
rhEPOs (i.e. no rhEPO use within the 12 weeks prior to the screening visit and through
Day 1).  The study design is outlined in Figure 1.

The study will comprise three study periods: a screening period starting up to 30 
days prior to Day 1, a 42 day (6 week) treatment period with 4 visits starting at 
Day 1, and a follow-up visit up to 14 days later (Figure 1).  The total duration of 
participant involvement is up to 14 weeks.

Participants will be randomized to either daprodustat or darbepoetin alfa. A 
central randomization approach will be used with stratification by center.

All participants will be treated with the goal of achieving a Hgb level within the
range of 10.0 to 12.0 g/dL, consistent with national guidelines (Medicines and 
Healthcare Products Regulatory Agency, 2007).

FBF and PWV will be conducted at the beginning (Day 1) and end (Day 42) of 
the treatment period as outlined in the SoA (See Section 2) and described in 
Section 9.6.

This study will include an optional, Non-Contact, Optical Forearm 
Plethysmography (NC-OFP) Sub-Study (See Appendix 8).
Figure 1
Study Outline


2016N291495_02
CONFIDENTIAL
205767
22
5.2.
Number of Participants
A sufficient number of participants will be enrolled such that at least 50 evaluable 
participants comprise the Pharmacodynamic Per-Protocol (PDPP) Population (See 
Section 10.3.1).
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit or the last scheduled procedure shown in the 
SoA (See Section 2).
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA (See Section 2) for the last 
participant in the trial.
5.4.
Scientific Rationale for Study Design
This study will use an open label, randomized, repeat dose, parallel group design, in 
adult, ND, male and female participants with anemia of CKD that are currently not 
treated with rhEPOs (i.e., no rhEPO use within the 12 weeks prior to the screening visit 
and through randomization (Day 1)).

This will be an open label study as FBF and PWV are both objective measures 
and not likely to be biased by the knowledge of the participant’s treatment.  In 
addition, as daprodustat is administered as an oral tablet, and darbepoetin alfa is 
administered subcutaneously, it would be logistically challenging to blind 
treatments.

Participants will be treated for 42 days (6 weeks) with study treatment.  The
treatment duration was chosen to coincide with the duration of treatment where 
previously increases in blood pressure were observed with administration of 
rhEPO (Santhanam, 2010).

The planned patient population is participants with anemia of CKD that are not on 
dialysis.  This population was chosen as it represents a relevant population for 
assessing endothelial functioning as a biomarker for the potential of CV events.  
In addition, this population is more likely to be untreated with rhEPO, as 
compared to the HD population.  Finally, it would not be feasible to administer 
therapeutic doses of daprodustat or darbepoetin alfa to participants that are not 
anemic due to the resulting increases in Hgb.

The challenge agents planned to be used in this study (ACh, SNP & L-NMMA) 
are well-established for assessment of endothelial function by venous occlusion 
plethysmography (Wilkinson, 2001).
5.5.
Dose Justification
The daprodustat starting dose and dose adjustment algorithm are based on dose-response 
longitudinal modeling of Hgb data collected across the daprodustat Phase 2 program


2016N291495_02
CONFIDENTIAL
205767
23
(GlaxoSmithKline Document Number 2015N248947_00, 2016; Holdstock, 2016).  In 
addition, the starting (2 mg) and maintenance (1, 2 & 4 mg) doses for all participants 
randomized to daprodustat have been studied previously in this population and have been 
shown to be effective, and generally well tolerated with an AE profile consistent with that 
of the patient population being studied (Holdstock, 2016).  Starting doses, dose steps, and 
elements of the dose adjustment scheme for daprodustat are provided in Section 7.1.
The darbepoetin alfa starting dose and dose adjustments are to be based on the local 
prescribing information as well as clinical judgement.  
Dosages of the challenge agents are based on a previous study (Cheriyan, 2011).  An 
advantage of brachial artery infusion using venous occlusion plethysmography is that 
most of the administered challenge agents are metabolized prior to realizing substantial 
systemic exposures.  This is certainly the case for ACh (used to induce NO endothelial 
production), which is often below a physiologically active concentration once it has 
traversed the entire arm length, L-NMMA (used to block NO synthesis) as well as 
sodium nitroprusside (infused to directly induce vasodilation at the level of the smooth 
muscle (i.e., non-endothelial based)).
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be at least 18 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are Stage 3, 4 or 5 CKD defined by eGFR using the CKD 
Epidemiology Collaboration (CKD-EPI) formula (Levey, 2009).
3.
Hgb as measured by HemoCue at screening visit and Day 1 is ≤ 11.0 g/dL (≤ 110 
g/L).
4.
Palpable brachial artery as assessed at screening.
5.
Participants, if necessary, may be on stable maintenance oral iron supplementation
(<50% change in overall dose and compliance of 80% of prescribed doses in the 4 
weeks prior to and including the screening period).  If participants have been on 
intravenous (IV) iron, then participants will not have received IV iron for 4 weeks 
prior to the Day 1 visit.


2016N291495_02
CONFIDENTIAL
205767
24
Sex
6.
Male or female
a. Female participants:
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
(ii)
A WOCBP who has been on an approved form of contraceptive as defined in 
Appendix 5 for the 4 weeks prior to Day 1 and agrees to follow the 
contraceptive guidance in Appendix 5 until the follow-up visit.
Informed Consent
7.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
On dialysis or clinical evidence of impending need to initiate dialysis within 12 
weeks of Day 1.
2.
Planned kidney transplant within 12 weeks of Day 1.
3.
Presence of an arteriovenous (AV) fistula
Prior/Concomitant Therapy
4.
rhEPO use within the 12 weeks prior to the screening visit and through Day 1.
5.
History of severe allergic or anaphylactic reactions or hypersensitivity to the study 
treatments or challenge agents, or excipients in the study treatments or challenge 
agents (see daprodustat IB for list of excipients, and the Study Reference Manual
(SRM) for product sheets for darbepoetin alfa and the challenge agents).
6.
Planned use of any prescription or non-prescription drugs or dietary supplements that 
are prohibited from screening until all assessments on Day 42 have been successfully 
completed (see Section 7.7.2).
Prior/Concurrent Clinical Study Experience
7.
The participant has participated in a clinical trial and has received an experimental 
investigational product within the prior 30 days or within 5 half-lives of the 
investigational product (whichever is longer) prior to screening and through Day 1.


2016N291495_02
CONFIDENTIAL
205767
25
Diagnostic assessments
8.
At or below the lower limit of the reference range at screening for Vitamin B12 (may 
rescreen in a minimum of 8 weeks).
9.
Ferritin ≤50 ng/mL (≤ 50 µg/L) at screening.
10. Transferrin saturation (TSAT) ≤15% (0.15) at screening.
11. Folate < 2.0 ng/mL (4.5 nmol/L; may rescreen in a minimum of 8 weeks) at 
screening.
12. High sensitivity C-reactive protein (hs-CRP) ≥ 50 µg/mL (≥50 mg/L) at screening.
Other Exclusions
13. Myocardial infarction or acute coronary syndrome ≤ 12 weeks prior to screening and 
through Day 1.
14. Hospitalization for greater than 24 hours ≤ 12 weeks prior to screening and through 
Day 1.
15. Stroke or transient ischemic attack ≤ 12 weeks prior to screening and through Day 1.
16. Class IV heart failure, as defined by the New York Heart Association (NYHA) 
functional classification system.
17. Resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 
110 mmHg at screening visit or current uncontrolled hypertension as determined by 
the investigator.
18. QT interval corrected for heart rate using Bazett’s formula (QTcB): QTcB 
>500 msec, or QTcB >530 msec in participants with bundle branch block.  There is 
no QTc exclusion for participants with a predominantly ventricular paced rhythm.
19. Active chronic inflammatory disease that could impact erythropoiesis.  A partial list 
can be found in the Study Reference Manual (SRM).
20. History of bone marrow aplasia or pure red cell aplasia.
21. Conditions, other than anemia of CKD, which can affect erythropoiesis.  A partial 
list can be found in the SRM.
22. Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease OR 
clinically significant GI bleeding from ≤ 8 weeks prior to screening and through Day 
1.
23. Liver disease (any of the following):

Alanine transaminase (ALT) > 2x upper limit of normal (ULN; screening only)

Bilirubin > 1.5x ULN (screening only)
NOTE: Isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated 
and direct bilirubin < 35%

Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones).


2016N291495_02
CONFIDENTIAL
205767
26
24. Major surgery within the 12 weeks prior to screening and through Day 1, or planned 
during the study.
25. Anticipated or planned vascular access surgery (i.e., AV fistula) within the 12 weeks 
prior to screening and through the Day 42 assessments.
26. Received a tissue heart valve replacement or repair within the 6 months prior to 
screening or has received a mechanical heart valve replacement.
27. Blood transfusion within 6 weeks prior to screening and through Day 1, or an 
anticipated need for blood transfusion during the study.
28. Clinical evidence of an acute infection, or history of infection requiring IV antibiotic 
therapy from 8 weeks prior to screening and through Day 1.
NOTE: Prophylactic oral antibiotics are allowed.
29. History of malignancy within the two years prior to screening and through Day 1 or 
currently receiving treatment for cancer, with the exception of localized squamous 
cell or basal cell carcinoma of the skin definitively treated 12 weeks prior to Day 1.
30. Platelet count < 50,000/µL.(<50 GI/L)
31. History of a bleeding disorder (e.g., hemophilia).
32. Any other condition, clinical or laboratory abnormality, or examination finding that 
the investigator considers would put the participant at unacceptable risk, which may 
affect study compliance or prevent understanding of the aims or investigational 
procedures or possible consequences of the study.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
Apart from a light breakfast (e.g., plain toast) and clear water which is allowed, 
participants are to refrain from any other food and drink for at least 8 h prior to the 
venous occlusion plethysmography performed on Days 1 and 42.
6.3.2.
Caffeine, Alcohol and Tobacco

Participants will be instructed to avoid caffeine/xanthine-containing products (i.e., 
coffee, tea, cola drinks, chocolate) for 6 hours prior to the venous occlusion 
plethysmography performed on Days 1 and 42.

Participants will be instructed to avoid alcohol for 24 h prior to the venous 
occlusion plethysmography performed on Days 1 and 42.

Participants will be instructed to avoid the use of nicotine and/or nicotine 
containing products for 24 h prior to the venous occlusion plethysmography 
performed on Days 1 and 42.
6.3.3.
Activity
Participants will refrain from strenuous exercise for 24 h prior to the venous occlusion 
plethysmography performed on Days 1 and 42.


2016N291495_02
CONFIDENTIAL
205767
27
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants 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 SAEs.
Participants that fail screening are eligible to be rescreened up to an additional 2 times as 
soon as the investigator assesses (or 8 weeks later if low vitamin B12) they may meet 
study entry criteria. If participants are rescreened, they must sign a new informed 
consent form.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.  Eligible participants will be randomized to receive either
daprodustat or darbepoetin alfa.
Participants randomized to daprodustat will receive this study treatment daily, starting 
Day 1 through Day 41 (i.e., day prior to FBF & PWV procedures).  Participants
randomized to darbepoetin alfa will receive this study treatment every 2 weeks, starting 
Day 1 through Day 28.
7.1.
Treatments Administered
Study Treatment 
Name:
Daprodustat
Darbepoetin alfa (Aranesp)
Dosage 
formulation:
Tablet
Solution for injection
Unit dose 
strength(s)/ 
Dosage level(s):
1 mg, 2 mg, 4 mg tablet strengths/1 mg, 2 
mg, 4 mg dosage levels
Darbepoetin alfa is commercially available 
in various single-dose vials and single-
dose prefilled syringes
Route of 
Administration
Oral
Subcutaneous injection
Dosing 
instructions:
1 tablet to be taken daily without regard 
for food
Administered subcutaneously every 2 
weeks as per product labelling
Packaging and 
Labeling
Study Treatment will be provided in a 
bottle. Each bottle will be labeled as per 
country requirement.
As per commercial packaging and product 
labelling
Manufacturer
GlaxoSmithKline (GSK)
Amgen


2016N291495_02
CONFIDENTIAL
205767
28
7.1.1.
Study Treatments
7.1.1.1.
Daprodustat Dosing Information
Daprodustat will be administered orally once daily starting after the completion of the 
FBF & PWV procedures on Day 1. The only exception to this is if a Repeat Day 1 is 
necessary (See Section 9.6.1.4). 


2016N291495_02
CONFIDENTIAL
205767
29
Daprodustat Starting Dose
All participants randomized to the daprodustat group will be dosed with 2 mg orally once 
daily starting on Day 1 (See Section 5.5)
Daprodustat Dose Adjustment Algorithm
Participants randomized to daprodustat will have doses adjusted, as required, to target 
Hgb within the range of 10.0 to 12.0 g/dL.  Dose adjustments will be assigned 
automatically via the IWRS (Interactive Web Response System) based on the 
participant’s Hgb value via onsite HemoCue assessment according to the algorithm in 
Table 1 on Day 28 as noted in the SoA (See Section 2).
The available dose steps for daprodustat are outlined in Figure 2 (highlighted box 
indicates starting dose).  Dose adjustments will result in the daprodustat dose being 
increased or decreased by one dose step (up or down) at a time.
Figure 2
Daprodustat Dose Steps
4 mg
1 mg
2 mg
7.1.1.2.
Darbepoetin Alfa Dosing Information
Darbepoetin alfa will be administered subcutaneously (SC) once every two weeks
starting after the completion of the FBF & PWV procedures on Day 1.
Darbepoetin Alfa Starting Dose and Dose Adjustments
Participants randomized to darbepoetin alfa will receive study treatment according to 
local labelling, clinical practice guidelines, and clinical judgement to maintain Hgb in the 
target range (10.0-12.0 g/dL).  For additional guidance on Hgb-based stopping criteria 
please refer to Section 8.1.2.  Darbepoetin alfa is to be administered as a single 
subcutaneous injection once every two weeks as outlined in the SoA (See Section 2), 
although doses can be temporarily held or delayed if necessary to maintain patient safety
(after consultation with the study medical monitor).  Doses can only be modified on Day 
28 as noted in the SoA (See Section 2).
7.1.2.
Challenge Agents
The use of these challenge agents is described on the assumption they are available for 
both visits for an individual participant.  If either of the secondary challenge agents (SNP 
and L-NMMA) are unavailable then that agent will be excluded from the procedure for 
that individual participant.  If, for any reason, both SNP and L-NMMA become 
unavailable, the participant will receive ACh only.  
All of the challenge agents will be infused in a fixed order (See Section 9.6.1, Figure 4) 
into the brachial artery, preferably the brachial artery of the nondominant (test) arm via a 
27-guage needle inserted under local anesthesia.  All challenge agents will be prepared 


2016N291495_02
CONFIDENTIAL
205767
30
aseptically and diluted in sterile saline (0.9%).  All infusions will be performed at a rate 
of 1 mL/min.
7.1.2.1.
Acetylcholine Dosing Information
Endothelial function will be assessed by determining the vasodilator response to 
acetylcholine.  Acetylcholine will be infused at 7.5, 15 & 30 g/min each for 6 min per 
infusion into the brachial artery of the test arm.
7.1.2.2.
Sodium Nitroprusside Dosing Information
Measurement of endothelium-independent vasodilation will be with sodium 
nitroprusside.  Sodium nitroprusside will be infused at 3 and 10 µg/min each for 6 min 
per infusion into the brachial artery of the test arm.
7.1.2.3.
L-NG-monomethyl Arginine Acetate (L-NMMA) Dosing Information
The effects of daprodustat or darbepoetin alfa on basal NO synthesis will be assessed 
using L-NMMA at a doses of 2 and 8 µmol/min for 6 min each per infusion into the 
brachial artery of the test arm.
7.2.
Dose Modification
Doses of daprodustat can be modified on Day 28 based on the participant’s Hgb level as 
measured using the HemoCue device.  The dose modifications, based on the Hgb value 
and change from previous measurement, are found in Table 1.
Doses of darbepoetin alfa can be modified on Day 28 based on the participant’s Hgb 
level as measured using the HemoCue device based on local product labelling, clinical 
practice guidelines, and clinical judgement.
Table 1
Daprodustat Dose Modification Algorithm
Hgb (g/dL)
Hgb change since
Day 1 visit
Dose Adjustment
< 7.5
Any change
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  If 
confirmed, permanently discontinue study treatment and 
withdraw subject from the study (See Section 8.1.2).
7.5 to < 10.0
Decreasing or No 
change (i.e., < 0.5 g/dL 
increase)
Increase to the next higher dose step
7.5 to < 10.0
Increasing by at least 
0.5 g/dL
Maintain dose
10.0 to ≤ 12.5
Any change
Maintain dose
> 12.5 to < 13.0
Increasing or No 
change
Decrease to the next lower dose step
Decreasing
Maintain dose


2016N291495_02
CONFIDENTIAL
205767
31
Hgb (g/dL)
Hgb change since
Day 1 visit
Dose Adjustment
13.0
Any change
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  If 
confirmed, permanently discontinue study treatment and 
withdraw subject from the study (See Section 8.1.2).
7.5 - <13.0
1.3 g/dL increase in 
Hgb over the previous 2 
weeks (as assessed on 
Day 28 only)1
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  If 
confirmed, decrease to next lower dose step (see Section 
7.1.1)
7.5 - <13.0
>2 g/dL increase in Hgb 
over the previous 4 
weeks.
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  If 
confirmed, decrease to next lower dose step (see Section 
7.1.1)
1 If increase in Hgb >1.3 g/dL is noted on Day 15, please refer to Hgb Stopping Criteria Table below (Section 8.1.2).
7.3.
Method of Study Treatment Assignment
Participants will be stratified as outlined in Section 5.1 and randomized 1:1 to receive 
daprodustat or darbepoetin alfa.
A randomization number will be assigned in accordance with the randomization schedule 
prepared in advance of the study by Clinical Statistics, GlaxoSmithKline, using validated 
internal software (Registration and Medication Ordering System Next Generation
(RAMOS-NG)).
7.4.
Blinding
This is an open-label study.  However, a central FBF reader, who will read and evaluate 
the FBF data, will be blinded to the treatment assignment.  Details of the blinding 
procedures can be found in the SRM.
7.5.
Preparation/Handling/Storage/Accountability

Daprodustat is to be stored at up to 30°C (86°F).  Maintenance of a temperature log 
(manual or automated) is required.

Darbepoetin alfa, acetylcholine, sodium nitroprusside and L-NMMA are to be 
handled and stored as per package labeling.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.

Only participants enrolled in the study are to be administered any study 
treatments.


2016N291495_02
CONFIDENTIAL
205767
32

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are to be reported and resolved before use of the study treatment.
7.6.
Treatment Compliance
Participants that are randomized to daprodustat will be instructed to return all unused 
study treatment at each clinic visit. A record of the number of daprodustat tablets 
dispensed to and returned by each participant will be maintained and reconciled with 
study treatment and compliance records.
Participants that are randomized to darbepoetin alfa will have supervised administration 
of study treatment in the clinic, with the details of each administered darbepoetin alfa 
dose maintained and reconciled with study treatment and compliance records.
Study treatment start and stop dates and dosing details, including dates for study
treatment dose increases or reductions, will be recorded in the electronic Case Report 
Form (eCRF).
7.7.
Concomitant Therapy
Concomitant medications, including over-the-counter medications and supplements, 
taken during the study will be recorded in the eCRF.  Start/stop dates and route of 
administration will be recorded for general concomitant medications. Additional details 
(e.g., changes in dose, reason for change, reason for addition or termination) will be 
recorded for certain medications at each visit (e.g., iron and anti-hypertensive 
medications).
NOTE: Participants should be maintained on the current dose and frequency of anti-
hypertensive therapy, whenever possible.
7.7.1.
Permitted Medications and Non-Drug Therapies
Unless specified as a prohibited medication in Section 7.7.2, all concomitant medications 
should be considered permitted provided they are not contraindicated for the individual 
participant concerned.
Participants are to be advised to maintain any anti-hypertensive medications at a 
consistent dosage and frequency; however, participants are to delay administration of 
any anti-hypertensive medications until after all study-related procedures are 
completed on Days 1 & 42.


2016N291495_02
CONFIDENTIAL
205767
33
Participants may take non-steroid anti-inflammatory drugs (NSAIDs) and aspirin during 
the treatment period; however, participants are to avoid NSAIDs and aspirin for 24 
hours prior to the FBF & PWV procedures until after all study-related procedures 
are completed on Days 1 & 42.
7.7.2.
Prohibited Medications and Non-Drug Therapies
No rhEPO use is permitted within the 12 weeks prior to the screening visit through Day 
1.
Use of any of the following prohibited drugs from 1 week prior to screening until all 
assessments on Day 42 have been successfully completed is prohibited and will constitute 
a protocol violation, with the exception of strong cytochrome P450 2C8 (CYP2C8) 
inhibitors or inducers, which can be used for up to 14 days.

Strong inhibitors of CYP2C8 (e.g., gemfibrozil, high dose clopidogrel [300 mg])

Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)

Intravenous administration of iron

Any rhEPO other than darbepoetin alfa administered as study treatment as per 
protocol
7.7.3.
Standard of Care
During the study, investigators are expected to monitor the participant’s overall clinical 
status to ensure standards of care are met to enable consistency of practice with Kidney 
Disease: Improving Global Outcomes (KDIGO) guidelines or local equivalent.
7.7.4.
Iron Management Criteria
Participants must be iron replete, as per local/regional guidelines prior to randomization 
and must remain iron replete throughout the study. Oral iron is allowed during the course 
of the study.
Participants that receive IV iron during the treatment period (i.e., from Day 1 through 
Day 42) are to discontinue study treatment (See Section 8.1) and be withdrawn (See 
Section 8.2).
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study. The investigator is responsible for ensuring that consideration has been given to 
post-study care of the participant’s medical condition.


2016N291495_02
CONFIDENTIAL
205767
34
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants that discontinue study treatment will be withdrawn from the study.  See 
Section 8.2 for a description of withdrawal procedures.
A participant must discontinue study treatment for the pre-specified reasons below.

Meets Hgb stopping criteria (See Section 8.1.2)

Receives a blood transfusion

Receives an AV fistula or graft

Receives a kidney transplant

Participant initiating dialysis

Receives IV iron

Becomes pregnant or intends to become pregnant during the study

Diagnosis of cancer (new or recurrent), with the exception of localized 
squamous cell or basal cell carcinoma of the skin

Need for more than 14 days use of a strong CYP2C8 inhibitor or inducer (See 
Section 7.7.2)

Any other condition which in the opinion of the PI makes the participant 
unsuitable to continue in the study.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in Figure 3
OR

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the 
best interest of the participant.


2016N291495_02
CONFIDENTIAL
205767
35
Figure 3
Phase II Liver Chemistry Stopping and Increased Monitoring 
Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 6.
8.1.2.
Hgb Stopping Criteria
GSK will supply a point-of-care Hgb analyzer (HemoCue) to each site for rapid and 
convenient monitoring of Hgb levels and to ensure consistency of Hgb measurements 
across sites participating in the study.
Blood samples for measurement of Hgb concentrations via HemoCue will be collected 
and recorded in the eCRF.  Table 2 summarizes the Hgb values and corresponding action 
to be taken at each visit.


2016N291495_02
CONFIDENTIAL
205767
36
Table 2
Hgb Stopping Criteria
Hgb (g/dL) at visit
Action
<7.5
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  If 
confirmed, permanently discontinue study treatment and 
withdraw participant from the study.
7.5 - <13.0 
with:
2.0 g/dL decrease in Hgb 
over the previous 2 weeks 
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  If 
confirmed, permanently discontinue study treatment and 
withdraw participant from the study.
7.5 - <13.0
with:
1.3 g/dL increase in Hgb 
over the previous 2 weeks
(at Day 15 only)1
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  If 
confirmed, permanently discontinue study treatment and 
withdraw participant from the study.
13.0
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  If 
confirmed, permanently discontinue study treatment and 
withdraw participant from the study.
1 If increase in Hgb >1.3 g/dL is noted on Day 28, refer to Dose Modification (Section 7.2).
8.2.
Withdrawal from the Study
Participants that are randomized but not dosed with study treatment will be considered 
for study withdrawal if Day 1 FBF measurement with ACh does not meet quality control 
criteria or they are unable to complete the initial FBF assessment, including a Day 1 FBF 
procedure where necessary (See Section 9.6.1.2). These participants will not be 
considered in the safety analysis as they have not received study treatment.  Quality 
control procedures and criteria are described in the SRM.  In all cases, the reason for 
withdrawal and the date of the last dose will be recorded in the participant’s eCRF.

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons.

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.

The participant will be asked to attend the follow-up visit 7 to 14 days following 
the last dose of study treatment.  Refer to the SoA (See Section 2) for data to be 
collected at the time of follow-up and for any further evaluations that need to be 
completed.


2016N291495_02
CONFIDENTIAL
205767
37
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she 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:

The site must attempt to contact the participant, reschedule the missed visit as 
soon as possible, 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/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (See Section 2).

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 participant should continue or 
discontinue study treatment and be withdrawn.

Adherence to the study design requirements, including those specified in the SoA 
(See Section 2), 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., Hgb levels) and obtained before signing of the 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 (See Section 
2).

The maximum amount of blood collected from each participant over the duration 
of the study, including any extra assessments that may be required, will not 
exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.


2016N291495_02
CONFIDENTIAL
205767
38
9.1.
Efficacy Assessments
Efficacy is not evaluated in this study.
9.2.
Adverse Events
The definitions of an AE and SAE can be found in Appendix 4.
The investigator and any 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 treatment or the study, 
or that caused the participant to discontinue the study treatment (See Section 8.1).
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

Any SAEs assessed as related to study procedure (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded in the eCRF from the time a participant consents to 
participate in the study up to and including any follow-up contact.

AEs and SAEs will be collected from randomization (Day 1) until the follow-up 
visit at the time points specified in the SoA (See Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the eCRF and 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 h, as indicated in Appendix 4. 
The investigator will submit any updated SAE data to the sponsor within 24 h of 
it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

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 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.


2016N291495_02
CONFIDENTIAL
205767
39
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of Special 
Interest (AESI; as defined in Section 9.2.5), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt (i.e., within 24 h) notification by the investigator to the sponsor of a SAE 
is essential so that legal obligations and ethical responsibilities towards the safety 
of participants and the safety of a study treatment 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 treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), 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 SAEs) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
Adverse Events of Special Interest
AESIs have been identified based on non-clinical studies with daprodustat, clinical 
experience with rhEPOs, and current information regarding HIF-regulated pathways in 
mediating hypoxia-associated pathophysiology.  The currently identified AESIs for 
daprodustat are as follows:

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis

Death, MI, stroke, heart failure, thromboembolic events, thrombosis of vascular 
access

Cardiomyopathy

Pulmonary artery hypertension

Cancer-related mortality and tumor progression and recurrence

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization

Exacerbation of rheumatoid arthritis

Worsening of hypertension


2016N291495_02
CONFIDENTIAL
205767
40
9.2.6.
Cardiovascular and Death Events
For any cardiovascular events listed below and all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will be 
required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms.  The CV information should be 
recorded in the specific cardiovascular section of the eCRF within one week of receipt of 
a CV Event data query prompting its completion.
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported.  Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.7.
Possible Suicidality Related Adverse Events
If during the study there is an occurrence of an AE or SAE which in the investigator’s 
opinion is possibly related to suicidality, the Possible Suicidality Related Adverse Events 
(PSRAE) eCRF form should be completed (in addition to the AE and SAE pages, as 
appropriate).
This event may include, but is not limited to, one that involves suicidal ideation, a 
preparatory act toward imminent suicidal behavior, a suicide attempt, or a completed 
suicide.  The investigator will exercise his or her medical and scientific judgment in 
deciding whether an event is possibly related to suicidality.
9.2.8.
Pregnancy
Details of all pregnancies in female participants and the outcome for the neonate, if 
applicable, will be collected from the start of study treatment.
If a pregnancy is reported then the investigator should inform the Sponsor within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix 5.


2016N291495_02
CONFIDENTIAL
205767
41
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
9.3.
Treatment of Overdose
There is no specific antidote for overdose with daprodustat. The expected manifestations 
of daprodustat overdosage include signs and symptoms associated with an excessive 
and/or rapid increase in Hgb concentration.  Daprodustat is highly protein bound; thus, 
clearance of daprodustat by hemodialysis (HD) or peritoneal dialysis (PD) is very low 
and these are not effective methods to enhance the elimination of daprodustat. 
Daprodustat metabolites are, in part, cleared via hemodialysis.  In the event of a 
suspected overdose, it is recommended that the appropriate supportive clinical care be 
instituted, as dictated by the participant’s clinical status.  Additionally, participants 
should be monitored closely for CV events, increased heart rate and hematologic 
abnormalities.
Consult the approved product label for information on overdose for darbepoetin alfa.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (See Section 2).
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, gastrointestinal and neurological systems.  
Height and weight will also be measured and recorded at screening.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses, e.g., history of anemia or bleeding.
9.4.2.
Vital Signs

Temperature, pulse, respiratory rate, blood pressure, and weight will be 
assessed.

Blood pressure and pulse measurements will be assessed in a semi-supine 
position with a completely automated device.  Manual techniques will be used 
only if an automated device is not available.

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones).

Vital signs (to be taken before blood collection for laboratory tests) will consist 
of 1 pulse and 3 blood pressure measurements (3 consecutive blood pressure 
readings will be recorded at intervals of at least 1 minute).  The average of the 3 
blood pressure readings will be recorded on the eCRF.

Participants with resting systolic blood pressure > 170 mmHg or diastolic blood 
pressure > 100 mmHg can delay the Day 42 assessment up to 1 week (i.e., Day 


2016N291495_02
CONFIDENTIAL
205767
42
49) in order to allow the blood pressure to decrease.  For participants that will 
have delayed FBF procedures performed, details can be found in Section 9.6.1.4.
9.4.3.
Electrocardiograms

ECG measurements will be obtained as outlined in the SoA (See Section 2).  
Full 12-lead ECGs will be recorded with the participant in a semi-supine 
position.  Heart rate, PR interval, QRS duration, and QT (uncorrected) interval 
will be measured.  QTcB will be calculated (machine read or manually).

At each time point at which ECGs are required, two additional ECGs are 
required if the initial ECG measurement indicates prolonged QTc (See Section 
6.2) using the automated or manually calculated QTcB value.  The average 
QTcB value of all three ECGs will be used to determine eligibility.

Participants with an abnormal ECG can delay the Day 42 assessment up to 1 
week (i.e., Day 49) at the Principal Investigator’s discretion.  For participants 
that will have delayed FBF procedures performed, details can be found in 
Section 9.6.1.4.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA (See Section 2) 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 AE 
section of the eCRF. 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 participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 14 days after the last dose of study 
treatment 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 etiology 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 (See Section 
2).
9.5.
Pharmacokinetics
Pharmacokinetic (PK) parameters will not be evaluated in this study.


2016N291495_02
CONFIDENTIAL
205767
43
9.6.
Pharmacodynamics
Detailed guidelines for the FBF and PWV procedures are provided in the SRM to ensure 
that the same procedure is followed at every site to avoid any inconsistencies.  Brief 
descriptions of the procedures can be found in Section 9.6.1 and Section 9.6.2.
9.6.1.
Venous Occlusion Plethysmography to Measure Forearm Blood 
Flow (FBF)
Venous occlusion plethysmography has been used extensively to study human vascular 
physiology in vivo, and is at its most powerful when combined with intra-arterial drug 
administration, usually into the forearm vascular bed. The procedure for conducting the 
FBF measurements has been previously described (Cheriyan, 2011).  Briefly, in the 
morning, after a light breakfast and following an initial 30 minute rest period, participants 
will be placed in a supine position and a 27-gauge needle inserted into the brachial artery 
of the non-dominant arm. Mercury filled silastic strain gauges are attached to both arms, 
along with cuffs at the wrists and above the antecubital fossa (congesting cuff).  A rapid 
inflation of the congesting cuff to 40 mmHg, (thereby blocking the venous outflow of 
blood) along with the 200 mmHg wrist cuffs to isolate the forearm from the complicated 
hemodynamic features of the hand, produces a rapid increase in forearm volume while 
the challenge agents are infused (Figure 4).  This change is recorded via the strain gauges 
connected to the plethysmograph recorder.  Congesting cuff inflation is maintained for 
10-13 seconds, establishing a maximal volume, and repeated at approximately 15-20 
second intervals for at least 4-5 time sequences.  The maximal volume and the rate to 
reach plateau, is averaged and thereby recorded in both arms.
Figure 4
FBF Infusion Schedule
Saline will be infused prior to initating the challenge agent dosing and between the 
challenge agents for at least 20 minutes.
Endothelium-dependent function will be assessed by determining the vasodilator 
response to acetylcholine.  Acetylcholine will be infused intra-arterially at 7.5, 15 and 
30 g/min each for 6 minutes per infusion; measurement of endothelium-independent 
vasodilatation will be with sodium nitroprusside.  Sodium nitroprusside will be infused at 
3 and 10 µg/min each for 6 minutes. Effects on basal NO synthesis will be assessed 
using L-NMMA at a doses of 2 and 8 µmol/min each for 6 minutes.  If L-NMMA is not 


2016N291495_02
CONFIDENTIAL
205767
44
available then the FBF procedure will be finished after the last SNP infusion. Similarly, if 
the SNP is not available for any reason, then the L-NMMA (if available) will be given 
following the ACh challenge.
Measures as noted above are made in both arms concurrently, and thus the maximal 
strain gauge measure from the infused arm is divided by the same from the contralateral
(non-infused) arm, producing a ratio.
9.6.1.1.
Participants on Anti-coagulant Therapy
In order to minimize blood loss from the FBF procedure, participants on anti-coagulant 
therapy are to have INR assessed prior to initiation of the procedure.  Only participants 
with INR < 3.0 are to undergo the FBF & PWV assessments.  Participants with INR 3.0 
can delay the Day 42 assessment up to 1 week (i.e., Day 49) in order to allow INR to 
decrease below 3.0 (See SRM for further details).  For participants that will have delayed 
FBF procedures performed, details can be found in Section 9.6.1.4.
9.6.1.2.
Participants Unable to Complete FBF Procedure
If a participant is unable to complete the Day 1 FBF procedure with all three doses of the 
ACh infusion and there is reasonable expectation a second attempt will be successful, one 
additional attempt may be made in a subsequent visit up to 1 week later, if the participant 
agrees.  In this case, the participant should not be dosed with study drug until after the 
FBF procedures are completed at the repeat visit.
If participants are unable to complete the Day 42 FBF procedure with all three doses of 
the ACh infusion, one additional attempt may be made in a subsequent visit up to 1 week 
later, if the participant agrees.  For participants that will have repeat FBF procedures 
performed, details can be found in Section 9.6.1.4.
9.6.1.3.
FBF Quality Control Criteria
After both the Day 1 and Day 42 FBF procedures, the results will be checked for data 
quality as defined in the Study Reference Manual (SRM).  If the FBF fails the quality 
control (QC) criteria following the Day 42 procedure, one additional attempt may be 
made in a subsequent visit up to 1 week later, if the participant agrees.  For participants 
that will have repeat FBF procedures performed, details can be found in Section 9.6.1.4.
9.6.1.4.
Delayed or Repeat FBF Procedures
Delayed FBF Procedures:  In the instance that the FBF procedure needs to be delayed, 
participants should either continue receiving the daprodustat dispensed on Day 28, while 
the participants randomized to darbepoetin alfa should receive an appropriate dose on 
Day 42.  The assessments that are scheduled to be conducted on Day 42 are to be 
followed (See Section 2).
Repeat FBF Procedures:  If the FBF procedure is determined to be repeated for either 
Day 1 or Day 42, the assessments should be performed as per the SoA Table at the 
additional FBF visit. The PWV procedures should also be repeated.


2016N291495_02
CONFIDENTIAL
205767
45
In the instance that the Day 1 FBF procedure needs to be repeated, the participant should 
not be dosed with study drug until after the repeat/completed procedure.  The timing of 
all subsequent visits will begin from that completed procedure day.
In the instance that the Day 42 FBF procedure needs to be repeated, participants should 
either continue receiving the daprodustat dispensed on Day 28, while the participants 
randomized to darbepoetin alfa should receive an appropriate dose on Day 42.  The safety 
follow up visit will take place 7-14 days after the final procedure. 
9.6.2.
Pulse Wave Analysis and Pulse Wave Velocity to measure 
vascular compliance
Pulse wave analysis (PWA) is a reproducible, noninvasive method for assessing central 
blood pressure and augmentation index (AIx, a measure of the contribution that wave 
reflection makes to the arterial pressure waveform).  The amplitude and timing of the 
reflected wave ultimately depends on the stiffness of the small (pre-resistance) vessels 
and large arteries, and thus, AIx provides a measure of systemic arterial stiffness 
(Wilkinson, 2002).
Pulse wave analysis will be used to determine systemic arterial stiffness (SphygmoCor).  
A high-fidelity micromanometer will be used to obtain accurate readings of the peripheral 
pressure waveforms by flattening, but not occluding, the radial artery of the dominant 
arm using gentle pressure.  Data will be collected to produce a central pressure 
waveform, which has been correlated with the aortic waveform.  Augmentation 
represents the difference between the second and first systolic peaks of the central 
pressure waveform. AIx is defined as the augmentation (difference between systolic 
peaks) expressed as a percentage of the overall pulse pressure.
Pulse wave velocity will be assessed with similar equipment as described above, using 
the carotid and femoral arteries as the two points of measure.
9.7.
Genetics
Genetics will not be evaluated in this study.
9.8.
Biomarkers
Biomarkers will not be evaluated in this study.  However, blood (serum and plasma) 
samples may be collected by investigators as outlined in the SoA (See Section 2) for 
potential future analysis of biomarkers of cardiovascular physiology and vascular
function, with the consent of the participant.  These samples, if any, will be managed by 
the Investigator or designee, and are considered outside the scope of this protocol.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will 
not be evaluated in this study.


2016N291495_02
CONFIDENTIAL
205767
46
10.
STATISTICAL CONSIDERATIONS
Statistical analyses will be performed by, or under the direct auspices of Clinical 
Statistics and Programming, GSK.
The null hypothesis is that there is no difference between daprodustat and darbepoetin 
alfa on the acetylcholine-induced change in FBF ratio at Day 42 vs the alternative 
hypothesis that there is a difference.
10.1.
Sample Size Determination
A sufficient number of participants will be enrolled such that at least 50 participants 
comprise the Pharmacodynamic Per-Protocol (PDPP) Population (See Section 10.3.1).
The sample size may be adjusted following the sample size re-estimation (See Section 
10.1.2). 
Based on a coefficient of variation of 0.277 of change from baseline FBF ratio, a sample 
size of 25 participants per treatment arm, provides 80% power to show a statistically 
significant difference between groups, assuming a true difference of at least 25% 
(Cheriyan, 2011) at the alpha = 5% level of significance.
10.1.1.
Sample Size Sensitivity
A sensitivity analysis was performed to evaluate the impact of a range of sample sizes 
and estimates of variability on the power to detect differences in the primary endpoint.
Power of the Primary Analysis*
CV
Total Evaluable Sample Size
40
46
50
0.249
80%
85%
88%
0.277
72%
77%
81%
0.305
64%
70%
74%
*Under an assumed 25% increase for daprodustat compared to 
darbepoetin (on normal scale), and a 5% alpha level
10.1.2.
Sample Size Re-estimation
A blinded sample size re-estimation assessment may be conducted after approximately 20 
subjects have completed the Day 42 FBF procedure in order to adjust the final sample 
size if the variability of the study differs significantly from the variability estimate used 
for the original sample size calculation.  This blinded assessment will be performed 
before any unblinded interim analyses are conducted (see Section 10.3.4).
10.2.
Populations for Analyses
The primary population of interest is the pharmacodynamic per-protocol (PDPP) 
population as defined in Table 3.


2016N291495_02
CONFIDENTIAL
205767
47
Table 3
Description of Analysis Populations
Population
Description
Screened Population
All participants who signed an ICF to participate in the clinical trial.  This 
population will be used for summarizing screening failure rates and reasons for 
screening failure.
Safety Population
All randomized participants who receive at least one dose of study treatment will 
be included in the safety population.
This population will be used in the evaluation of safety and tolerability.
Pharmacodynamic 
Per-Protocol (PDPP) 
Population
All randomized participants who provide pharmacodynamic (PD) data at Day 1 
and Day 42 that meets the QC criteria (See Section 9.6.1.3) and completes the 
protocol without important deviations will be included in the PDPP population.
This population will be used in the evaluation of all endpoints with the exception 
of safety endpoints.
Because the current study is designed to assess the effects of study treatment on 
pharmacodynamic parameters, an intent-to-treat population will not be defined.
10.2.1.
Treatment Comparisons
10.2.1.1.
Primary Comparisons
The primary analysis of interest is the comparison of acetylcholine-induced response
between daprodustat and darbepoetin alfa based on the change in FBF ratio from Day 1 
to Day 42.
The pharmacodynamic per-protocol population will be used for analyzing the primary 
comparison.
10.2.1.2.
Secondary Comparisons
The primary comparison will be repeated for the two remaining challenge agents. If an 
insufficient number of subjects in the PDPP population have complete Day 1 and Day 42 
data for either of the two remaining challenge agents, then that challenge agent will not 
be statistically analysed. Instead, a summary table and subject level listing will be 
generated. Details regarding the exclusion from analysis will be included in the RAP.
(Section 4).
Comparisons within and between treatment for daprodustat and darbepoetin alfa will be 
made for other PD endpoints as well.
The pharmacodynamic per-protocol population will be used for analysing all secondary 
comparisons.


2016N291495_02
CONFIDENTIAL
205767
48
10.3.
Statistical Analyses
This section provides an overview of the analysis of data. The Reporting and Analysis 
Plan (RAP) which will be finalised before the interim analyses described in Section 
10.3.4 are performed, will contain the full details of the planned analysis.
10.3.1.
Efficacy Analyses
Not applicable.
10.3.2.
Safety Analyses
All safety data will be summarised using the Safety Population.
Safety endpoints will include all AEs, clinical laboratory test parameters, HemoCue Hgb 
measures, vital signs, ECG parameters and physical examination.
No formal statistical analyses will be performed for the safety endpoints.  These data will 
be listed by treatment using suitable displays for each endpoint.
10.3.3.
Other Analyses (Pharmacodynamic)
The primary analysis model will be based on the acetylcholine challenge agent data.
Following log-transformation the change in FBF ratio from Day 1 to Day 42 will be 
analyzed using analysis of covariance (ANCOVA) model including terms for the 
treatment group (daprodustat/darbepoetin alfa), challenge agent dose, 
treatment*challenge agent dose interaction term, FBF ratio on Day 1, gender, and site 
stratification variable. The primary comparison of interest is the difference between 
treatment groups in the primary endpoint associated with the acetylcholine challenge.  
The point estimate and corresponding 95% confidence interval will be derived, using the 
residual error from the model, for the comparison of the treatment groups. These 
estimates will be back-transformed to provide the point estimate and corresponding 95% 
confidence interval (CI) for the ratio of daprodustat/darbepoetin alfa for the primary 
analysis.
In addition, this model will provide the supporting analysis to the primary analysis 
deriving the estimates and 95% CIs for (1) Change in FBF ratio from Day 1 to Day 42 for 
each treatment group and (2) Difference in FBF ratio between the challenge agent and 
saline on both Day 1 and Day 42. These estimates will be back-transformed to provide 
the point estimates and corresponding 95% CIs for the ratios for “Day 42/Day 1” and 
“challenge agent/saline” (for each challenge agent dose level) where saline is considered 
as providing assay sensitivity for the challenge agent.
The first secondary endpoint will use the same model as the primary endpoint with 
absolute FBF instead of FBF ratio as the dependent variable. The other challenge agents, 
sodium nitroprusside and L-NMMA, will utilize a similar model. If an insufficient 
number of subjects in the PDPP population have complete Day 1 and Day 42 data for 
either of the two remaining challenge agents, then that particular challenge agent will not 


2016N291495_02
CONFIDENTIAL
205767
49
be statistically analysed. Instead, a summary table and subject level listing will be 
generated.
The secondary endpoints evaluating the within treatment comparison of daprodustat and 
darbepoetin alfa will utilize an ANCOVA model including terms for challenge agent 
dose, FBF measurement on Day 1, gender, and site. This model will be run for both 
treatment groups for each of the three challenge agents and for FBF ratio and absolute 
FBF.
The other secondary endpoint evaluating vascular compliance will make use of two 
models. The first model for augmentation index will utilize an ANCOVA model with 
terms for treatment group (daprodustat/darbepoetin alfa), challenge agent dose, 
treatment*challenge agent dose interaction term, augmentation index on Day 1, gender, 
and site. The second model for pulse wave velocity will utilize an ANCOVA model with 
terms for the treatment group (daprodustat/darbepoetin alfa), challenge agent dose, 
treatment*challenge agent dose interaction term, PWV on Day 1, gender, and site.
The exploratory endpoint looking at the relationship between diabetes status and 
endothelial function will use a similar ANCOVA model as our primary endpoint, adding 
in the indicator variable diabetes. This will be explored for all three challenge agents and 
modeled for FBF ratio and absolute FBF.
The last exploratory endpoint will analyze the FBF dose response relationships for each 
of the three challenge agents.
Sensitivity analyses will be performed for all endpoints analysing FBF ratio.  Instead of 
FBF ratio, percent change from saline infusion and absolute change from saline infusion 
will be modelled.
Distributional assumptions underlying the statistical analyses will be assessed by visual 
inspection of the residual plots.  Normality will be examined by normal probability plots, 
while homogeneity of variance will be assessed by plotting the residuals against the 
predicted values for the model.
Descriptive statistics (n, arithmetic mean and corresponding 95% confidence interval, 
standard deviation (SD), minimum, median, maximum) will be calculated by treatment 
group for all PD endpoints.  In addition, summary of data for all FBF ratio endpoints will 
be provided including geometric means (and corresponding 95% confidence interval) and 
between-subject coefficients of variation (CVb) will be calculated by treatment group, 
where:
CVb(%) = sqrt[exp(SD2)-1] X 100 where SD is the standard deviation of the loge-
transformed data.
Mean (standard error [SE]) plots of the change from baseline FBF ratio data will be 
produced by treatment group.  Separate plots will be produced for the FBF ratio for each 
challenge agent.
Further details will be included in the RAP.


2016N291495_02
CONFIDENTIAL
205767
50
10.3.4.
Interim Analyses
An interim analysis may be conducted after approximately 24 subjects have completed 
the Day 42 FBF procedure, unless the blinded sample size re-estimation suggests a 
different sample size. If the interim analysis for this study is expected to occur after the 
interim analysis of the larger Phase III ASCEND program, then this interim analysis may 
occur sooner.
If the observed percent change between daprodustat and darbepoetin alfa for FBF ratio 
from Day 1 to Day 42 in response to acetylcholine is less than 8%, then the study will be 
stopped. Assuming a true percent change of 25% and a standard deviation of 0.272, the 
decision guideline was determined to have favorable operating characteristics, such as an 
unconditional power of <30%, and an acceptable low probability of false stop (<10%). 
Since the study will not be stopped for positive results, type I error will not be inflated. If 
the sample size changes based on the blinded sample size re-estimation, then the 
operating characteristics may be revised to reflect a different standard deviation. Any 
such changes will be documented in the RAP.
While the above is a guideline for stopping the trial due to futility, the totality of the data 
will be considered when making the decision at the time of the interim analysis.
Further details of the interim analysis will be included in the RAP.


2016N291495_02
CONFIDENTIAL
205767
51
11.
REFERENCES
Annuk M, Linde T, Lind L, Fellstrom B. Erythropoietin impairs endothelial vasodilatory 
function in patients with renal anemia and in healthy subjects. Nephron Clin Pract. 2006; 
102:c30-c34.
Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al;. The 
effects of normal as compared with low hematocrit values in patients with cardiac disease 
who are receiving hemodialysis and epoetin. N Eng J Med. 1998; 339:584-590.
Besarab A, Provenzano R, Hertel J, Zabaneh R, Klaus SJ, Lee T, et al;. Randomized 
placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) 
to treat anemia in nondialysis-dependent chronic kidney disease. Nephrol Dial 
Transplant. 2015; 30:1665-1673.
Boutouyrie P for The reference Values for Arterial Stiffness Collaboration. Determinants 
of pulse wave velocity in healthy people and in the presence of cardiovascular risk 
factors: ‘Establishing normal and reference values’. Eur Heart J. 2010; 31:2338-2350.
Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SML, Maki-Petaja KM, et al;. 
Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated 
vasodilation and reduces inflammation in hypercholesterolemia. Circulation. 2011; 
123:515-523.
Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: Testing and 
clinical relevance. Circulation. 2007; 115:1285-1295.
GlaxoSmithKline Document Number 2015N248947_00. Phase 2 population 
pharmacodynamics analyses of GSK1278863 in anemic subjects with chronic kidney 
disease. 22-APR-2016.
Haase VH. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev. 2013; 
27:41-53.
Hand MF, Haynes WG, Johnstone HA, Anderton JL, Webb DJ. Erythropoietin enhances 
vascular responsiveness to norepinephrine in renal failure. Kidney Int. 1995; 48:806–13.
Holdstock L, Meadowcroft AM, Maier R, Johnson BM, Jones D, Rastogi A, et al;. Four-
week studies of oral hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 
for treatment of anemia. J Am Soc Nephrol. 2016; 27:1234-1244.
Lee MJ, Han SH, Lee JE, Choi HY, Yoon C-Y, Kim EJ, et al;. Endothelial dysfunction is 
associated with major adverse cardiovascular events in peritoneal dialysis patients. 
Medicine. 2014; 93:1-9.
Lerman A, Zeiher AM. Endothelial function: Cardiac Events. Circulation. 2005; 
111:363-368.


2016N291495_02
CONFIDENTIAL
205767
52
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI et al; CKD-
EPI (Chronic Kidney Disease Epidemiology Collaboration). A New Equation to Estimate 
Glomerular Filtration Rate. Ann Intern Med 2009; 150(9):604-12.
Medicines and Healthcare Products Regulatory Agency. Recombinant human 
erythropoietins: New advice for prescribing. Drug Safety Update. 2007; 1:2.
Pereira T, Correia C, Cardoso J. Novel methods for pulse wave velocity measurement. J 
Med Biol Eng. 2015; 35:555-565.
Pfeffer MA, Burdmann EA, Chen C-Y, Cooper ME, de Zeeuw D, Eckart K-U, et al;. A 
trial of darbepoetin alfa in Type 2 diabetes and chronic kidney disease. N Eng J Med.
2009; 361:2019-2032.
Ras RT, Streppel MT, Draijer R, Zock PL. Folw-mediated dilation and cardiovascular 
risk prediction: A systematic review with meta-analysis. Int J Cardiology. 2013; 
168:344-351.
Santhanam AVR, d’Uscio LV, Katusic ZS. Cardiovascular effect of erythropoietin: An 
update. Adv Pharmacol. 2010; 60:257-285.
Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al;. Correction of 
anemia with epoetin alfa in chronic kidney disease. N Eng J Med. 2006; 355:2085-2098.
Szczech, LA, Barnhart, HX, Inrig, JK, Reddan, DN, Sapp, S, Califf, RM, et al;. 
Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved Hgb outcomes. 
Kidney Int. 2008; 74:791-798.
Wilkinson IB, Webb DJ. Venous occlusion plethysmography in cardiovascular research: 
Methodology and clinical applications. Br J Clin Pharmacol. 2001; 52:631-646.
Wilkinson, IB, Prasad, K, Hall, IR, Thomas, AT, MacCallum, H, Webb, DJ, et al;.  
Increased central pulse pressure and augmentation index in subjects with 
hypercholesterolemia. J Am Coll Cardiol. 2002; 39:1005-1011.


2016N291495_02
CONFIDENTIAL
205767
53
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
ACh
Acetylcholine
AE
Adverse event
AESI
Adverse event of special interest
AI
Augmentation Index
ALT
Alanine transaminase
ANCOVA
Analysis of Covariance
AST
Aspartate transaminase
AUC
Area under curve
AV
Arteriovenous
BCRP
Breast cancer resistance protein
BP
Blood pressure
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CKD
Chronic kidney disease
CFR
Code of Federal Regulations
CL/F
Total body clearance
Cmax
Maximum plasma concentration
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase 
CSR
Clinical Study Report
CV
Cardiovascular
CVb
Between-subject coefficients of variation
CYP
Cytochrome P450
dL
Decilitre
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EPI
Epidemiology
EPO
Erythropoietin
FBF
Forearm Blood Flow
FRP
Females of reproductive potential
FSH
Follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
GI
Gastrointestinal
GSK
GlaxoSmithKline
HbA1c
Glycated hemoglobin
hCG
Human chorionic gonadotrophin
HD
Hemodialysis dependent
HDL-c
High density lipoprotein-C
Hgb
Hemoglobin


2016N291495_02
CONFIDENTIAL
205767
54
HIF
Hypoxia-inducible factor
HIPAA
Health Insurance Portability and Accountability Act
HPLC
High-performance liquid chromatography
HR
Heart rate
HRT
Hormone replacement therapy
hs-CRP
High sensitivity C-reactive protein
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
INR
International Normalized Ratio
IRB
Institutional Review Board
IP
Investigational Product
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IWRS
Interactive Web Response System
KDIGO
Kidney Disease: Improving Global Outcomes
Kg
Kilogram
L
Liter
LDH
Lactate dehydrogenase 
LDL-C
Low density lipoprotein-C
L-NMMA
NG-monomethyl arginine acetate
LVEF
Left Ventricular Ejection Fraction
µg
Microgram
µmol
Micromole
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
Mg
Milligram
mmHg
Millimeters of mercury
mL
Milliliter
MSDS
Material Safety Data Sheet
Msec
Millisecond
NC-OFP
Non-Contact, Optical Forearm Plethysmography
ND
Not ondialysis
ng
Nanogram
nmol
Nanomole
NO
Nitric oxide
NSAID
Non Steroidal Anti Inflammatory Drug
NYHA
New York Heart Association
PAH
Pulmonary artery hypertension


2016N291495_02
CONFIDENTIAL
205767
55
PASP
Pulmonary artery systolic pressure
PCI
Percutaneous Coronary Intervention
PCM
Progressive cardiomyopathy
PD-PP
Pharmacodynamic Per-Protocol Population
PED
Peritoneal dialysis 
PHD
Prolyl hydroxylase
PHI
Prolyl hydroxylase inhibitor
PK
Pharmacokinetic
PRVP
Peak Right Ventricular Pressure
PSRAE
Possible suicidality related adverse events 
PWV
Pulse Wave Velocity
QC
Quality Control
QTcB
QT duration corrected for heart rate by Bazett’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RDW
Red blood cell distribution width
RNA
Ribonucleic Acid
rhEPO
Recombinant human erythropoietin 
SAE
Serious adverse event
SC
Subcutaneous
SD
Standard deviation
SNP
Sodium nitroprusside
SoA
Schedule of Events
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TSAT
Transferrin saturation
U
Units
ULN
Upper limit of normal
VEGF
Vascular Endothelial Growth Factor
WBC
White blood cell
WOCBP
Woman of Child Bearing Potential
UK
United Kingdom
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Aranesp
HemoCue
MedDRA
RAMOS-NG
SphygmoCor


2016N291495_02
CONFIDENTIAL
205767
56
12.2.
Appendix 2: Clinical Laboratory Tests
All study-required laboratory assessments will be performed by a central laboratory with 
the exception of HemoCue Hgb, INR measurements and urine pregnancy tests which will 
be performed at the clinical site. The results of each HemoCue Hgb must be entered into 
the participant’s eCRF.
A local Hematology lab will be allowed in the event that central labs are unavailable.
Tests included in Table 4 must be conducted in accordance with the Laboratory Manual 
and Study Protocol SoA (See Section 2). Laboratory requisition forms must be 
completed and samples must be clearly labeled with the participant number, protocol 
number, site/centre number, and visit date. Details for the preparation and shipment of 
samples will be provided by the laboratory and are detailed in the SRM. Reference 
ranges for all safety parameters will be provided to the site by the laboratory responsible 
for the assessments.
Refer to the SRM for appropriate processing and handling of samples.


2016N291495_02
CONFIDENTIAL
205767
57
Table 4
Protocol Required Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC indices:
WBC count with 
Differential
RBC count
MCV
Neutrophils
Reticulocyte count
MCH
Lymphocytes
Hgb
MCHC
Monocytes
Hematocrit
RDW
Eosinophils
WBC count (Absolute)
Basophils
Clinical Chemistry1
Sodium (serum)
AST1
Carbon Dioxide (total)
Potassium (serum)
ALT1
Albumin
Creatinine (serum)
Chloride (serum)
Urea (serum)
Glucose
Bilirubin (total and 
direct/indirect)
Alkaline Phosphatase
Other laboratory tests
Serum ferritin
TSAT
hs-CRP
Total cholesterol
LDL-C (direct)
HDL-C
Triglycerides
Serum/Urine hCG 
pregnancy test2
FSH3
HbA1c
Folate
Vitamin B12
Serology (hepatitis B 
surface antigen 
[HBsAg], and hepatitis 
C virus antibody)
Abbreviations: RBC: red blood cells, WBC, white blood cells; MCV, mean corpuscular volume; MCH, mean 
corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; RDW, red blood cell distribution 
width, AST, aspartate transaminase; LDL-C, low density lipoprotein-C; HDL-C, high density lipoprotein-C, hCG= 
human chorionic gonadotropin.
1Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver stopping 
or monitoring event are given in Section 8.1.1 and Section 12.6.
2For females of reproductive potential only.
3Screening only. As needed in postmenopausal women were their menopausal status is in doubt (see Inclusion 
Criteria Section 6.1).
All laboratory tests with values that are considered clinically-significantly abnormal 
during participation in the study or within 14 (3) days after the last dose of study
treatment should be repeated until the values return to normal or baseline.  If such values 
do not return to normal within a period judged reasonable by the investigator the sponsor 
should be notified.


2016N291495_02
CONFIDENTIAL
205767
58
12.3.
Appendix 3: Study Governance Considerations
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 ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
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.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all
questions regarding the study.

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 


2016N291495_02
CONFIDENTIAL
205767
59
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/IEC or study center.

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.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
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/her 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/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
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 multicenter studies only in their entirety and not 


2016N291495_02
CONFIDENTIAL
205767
60
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.
Dissemination of Clinical Study Data
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of participants begins.
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually 
agreeable location.
GSK will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study participants, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, 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/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

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 participants 
are being protected; and that the study is being conducted in accordance with the 


2016N291495_02
CONFIDENTIAL
205767
61
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 
Clinical Study Report(CSR) or equivalent summary unless local 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.
Source Documents

Source documents provide evidence for the existence of the participant 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 eCRF that are transcribed from 
source documents must be consistent with 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 SRM.
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/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


2016N291495_02
CONFIDENTIAL
205767
62
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study treatment, whether or not considered 
related to the study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology or clinical chemistry) 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 treatment 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 
treatment 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.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, 
"lack of efficacy" or "failure of expected pharmacological action" constitutes an 
AE or SAE.


2016N291495_02
CONFIDENTIAL
205767
63
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 participant’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
participant’s condition.

Medical or surgical procedure (eg, 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) 
present or detected at the start of the study that do not worsen.
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 
participant 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 participant 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 fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 


2016N291495_02
CONFIDENTIAL
205767
64
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere 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 participant 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 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.
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs or any event that may potentially be one of these categories:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
Recording 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) 


2016N291495_02
CONFIDENTIAL
205767
65
related to the event.

The investigator will then record all relevant AE/SAE information in the eCRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of 
the participant 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 participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficiently 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 treatment 
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.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (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.


2016N291495_02
CONFIDENTIAL
205767
66

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 participant 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 t GSK within 24 hours of 
receipt of the information.
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) 
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 participant or receives 


2016N291495_02
CONFIDENTIAL
205767
67
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 (see next section) or to the [medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting can be found in the SRM.


2016N291495_02
CONFIDENTIAL
205767
68
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in
Table 5.


2016N291495_02
CONFIDENTIAL
205767
69
Table 5
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent1
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation2

oral

intravaginal

transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation2

injectable
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation2

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
1Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies.
2Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the 
contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 1 day, corresponding to time needed to eliminate study treatment plus 30 days for 
study treatments with genotoxic potential  after the last dose of study treatment.
Pregnancy Testing
WOCBP should only be included after a confirmed menstrual period and a negative urine 
pregnancy test.


2016N291495_02
CONFIDENTIAL
205767
70
Additional pregnancy testing should be performed at monthly intervals during the 
treatment period and seven days after the last dose of study treatment and as required 
locally.
Urine pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.
Pregnancy testing will be performed using the test kit provided by the central laboratory
and in accordance with instructions provided in its package insert.
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK 
within 24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which 
will be forwarded to GSK. Generally, follow-up will not be required for longer 
than 6 to 8 weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to 
GSK as described in Appendix 4. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of 
an SAE through spontaneous reporting.
Any female participant who becomes pregnant while participating must 
permanently discontinue study treatment. Participants will be expected to attend 
study visits through the Follow-up visit, according to the study visit schedule, unless 
consent is actively withdrawn.


2016N291495_02
CONFIDENTIAL
205767
71
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
treatment and may continue subject in the study 
for any protocol specified follow up assessments

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 24 hrs after 
last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 


2016N291495_02
CONFIDENTIAL
205767
72
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-72 
hrs

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]).

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1 Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. Additionally, 
if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury. 
2 All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will not 
apply to subjects receiving anticoagulants
3 New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4 Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing);  Hepatitis E IgM antibody 
5 PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to blood 
sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the 
date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated 
above, do not obtain a PK sample. Instructions for sample handling and shipping are in the SRM.


2016N291495_02
CONFIDENTIAL
205767
73
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos. 2009; 37:1779-1784.


2016N291495_02
CONFIDENTIAL
205767
74
12.7.
Appendix 7: Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Daprodustat 
Excessive erythropoiesis leading to thrombosis 
and/or tissue ischemia
In animal studies, excessive erythropoiesis (Hgb/Hct > upper limit normal)
attributed to daprodustat was associated with vascular 
congestion/inflammation, microthrombi, and tissue ischemia in a number of 
organs.
In the phase 2 proof of concept study, a high incidence of discontinuation due 
to hemoglobin stopping criteria (Hgb > 13.5 g/dL or Hgb increased > 1 g/dL 
over any 2-week period) was observed.  In non-dialysis subjects administered 
10 mg, 25 mg, 50 mg or 100 mg of daprodustat daily, a total of 21 of 61 
subjects (34%) met these criteria.  In hemodialysis-dependent subjects 
administered either 10 mg or 25 mg of daprodustat daily, a total of 8 of 31 
subjects (26%) met these criteria.
Phase 2 dose-ranging studies, and associated statistical and exposure 
response modelling has informed Phase 3 dose rationale, starting doses, dose 
levels, and dose adjustment scheme to optimize Hgb management.
Integrated AE data [including 2 global phase 2b studies (24-week treatment 
duration) and 2 Japanese phase 3 studies (52-week treatment duration)]: Few 
subjects experienced a possible thrombosis related adverse event in the setting 
of excessive erythropoiesis [3/688 (0.5%) subjects on daprodustat vs. 0/404 on 
rhEPO].
Following review of clinical data received to date, this has not been identified as 
a safety concern for daprodustat when dose is managed appropriately 
according to target Hgb. However, experience with daprodustat is currently 
insufficient to fully characterize this risk.
Specific eligibility criteria related to requirements for 
entry Hgb are detailed in Section 6.1
Hgb will be closely monitored throughout the dosing 
period as outlined in the SoA (See Section 2)
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat based 
on achieved Hgb (including rate of change) is 
provided in Section 7.2 and Section 8.1
Instream monitoring of safety data by internal safety 
review team
Worsening hypertension
In a dog cardiovascular study, single oral doses of daprodustat (up to 90 
mg/kg) did not produce effects on blood pressure.

Specific eligibility criteria related to blood 
pressure, including exclusion of subjects with 
uncontrolled hypertension, are detailed in 


2016N291495_02
CONFIDENTIAL
205767
75
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Marketed rhEPO and its analogues have been associated with risks related to 
uncontrolled hypertension, including the need for initiation of or increases in 
antihypertensive therapy when used in patients with anemia of CKD (i.e. 25% 
Epogen, 27% Mircera, and 40% Aranesp treated patients with renal anemia 
required initiation or increase in their anti-hypertensive medications; 
hypertensive encephalopathy and seizures have been reported. The 
contribution of rhEPO-associated hypertension to the unfavourable effects on 
cardiovascular outcomes remains uncertain).
Integrated AE data from clinical trials with daprodustat [including 2 global phase 
2b studies (24-week treatment duration) and 2 Japanese phase 3 studies (52-
week treatment duration)]: 
o
The majority (>90%) of subjects had baseline history of hypertension.
o
No meaningful difference was seen between treatment groups in AEs 
(preferred term) of “hypertension” [29/688 (4%) daprodustat vs. 19/404 
(4%) rhEPO; 0.91 relative risk (RR) (95% confidence interval: 0.5, 1.67)] or 
“blood pressure increased” [16 (2%) daprodustat vs. 7 (2%) rhEPO; RR 
1.22 (0.48,3.11)]. Results were not substantively different between non-
dialysis and haemodialysis subjects.
o
Although no clinically meaningful changes in blood pressure were 
observed, subjects in both treatment groups required increases in anti-
HTN medications:
o
In the 24-week global phase 2b studies, 25/170 (15%) of ND 
subjects receiving daprodustat vs. 18/80 (14%) control and 
22/177 (12%) of HD subjects receiving daprodustat vs. 2/39 
(5%) control.
o
In the 52-week Japan phase 3 studies, 57/149 (38%) of ND 
subjects receiving daprodustat vs. 68/150 (45%)  rhEPO and 
51/136 (38%) of HD subjects receiving daprodustat vs. 66/135 
Section 6.2

Blood pressure will be closely monitored 
throughout the dosing period as outlined in the 
SoA Table Section 2.

Monitoring of emerging safety data by an 
internal GSK Safety Review Team.


2016N291495_02
CONFIDENTIAL
205767
76
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
(49%) for rhEPO.
The data received to date from completed clinical trials with daprodustat are 
insufficient to refute this risk.
Death, MI, stroke, heart failure, 
thromboembolic events, thrombosis of vascular 
access at Hgb levels which are within the 
normal range (i.e., not polycythemic conditions)
Marketed rhEPO and its analogs have been associated with an increased risk 
for death and serious cardiovascular events when used in patients with anemia
of CKD.  Clinical studies with marketed rhEPO/analogs have suggested 
“higher” target hemoglobin, rate of hemoglobin rise of greater than 1 g/dL in any 
2-week period, and/or higher doses may contribute to these risks.
Integrated AE data from clinical trials with daprodustat [including 2 global phase 
2b studies (24-week treatment duration) and 2 Japanese phase 3 studies (52-
week treatment duration)]: No meaningful difference was seen between 
treatment groups in the overall incidence of this AESI: [39/688 (5.5%) 
daprodustat vs. 25/404 (6%) rhEPO; 0.92 relative risk (95% confidence interval: 
0.55, 1.53)]. Within this composite AESI, the most frequent event types were 
heart failure (at least 12 events daprodustat vs. at least 13 events rhEPO) and 
thrombosis (at least 14 events daprodustat vs. at least 8 event rhEPO); and a 
numerical imbalance was noted in events of myocardial ischemia (at least 7 
events daprodustat vs. at least 1 event rhEPO). The small number of events 
makes it difficult to draw any firm conclusions.
The clinical data received to date from completed clinical trials with daprodustat 
are insufficient to substantiate or refute this risk.
Specific eligibility criteria related to CV risk are 
outlined in Section 6.2
Hgb will be closely monitored throughout the dosing 
period as outlined in the SoA (See Section 2)
Instream monitoring of safety data by internal safety 
review team


2016N291495_02
CONFIDENTIAL
205767
77
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Esophageal and gastric erosions
In animal studies, undesirable GI effects including emesis, abnormal feces 
and/or decreased food consumption/body weight loss and stomach 
erosions/ulcers with hemorrhage were observed with daprodustat.
In rodents, stomach erosions were observed with intravenous and oral 
administration of daprodustat.
Gender-averaged systemic exposure (AUC) at the no observed adverse effect 
levels (NOAEL) are 3.3 -fold (monkeys) and 737 -fold (rats) above human 
exposure (25 mg daprodustat).
In clinical trials to date with daprodustat, mild-moderate GI signs and symptoms 
represent the most frequently-reported adverse event, however causal 
association has not been established.
Integrated AE data from clinical trials with daprodustat [including 2 global phase 
2b studies (24-week treatment duration) and 2 Japanese phase 3 studies (52-
week treatment duration)]: No meaningful difference was seen between 
treatment groups in reports of this AESI [17 (2.7%) daprodustat vs. 10 (2.3%) 
rhEPO; 1.16 relative risk (95% confidence interval: 0.52, 2.58)].
Following review of clinical data received to date, GI erosions have not been 
identified as a safety concern for daprodustat.
Suspected GI bleeding or significant symptoms 
consistent with erosion or ulcers should be 
investigated diagnostically (i.e., endoscopic 
examination) as clinically warranted
Instream monitoring of safety data by internal safety 
review team
Cancer-related mortality and tumor progression 
and recurrence
Marketed rhEPO and its analogs have been associated with increased risk of 
cancer related morbidity and mortality when used in patients with cancer.
Administration of 60mg/kg daprodustat to mice caused minimal increases in 
circulating vascular endothelial growth factor (VEGF) while significant EPO 
increases were observed.
In clinical studies with daprodustat up to 4 weeks duration, a dose-ordered 
increase in VEGF plasma concentrations, an angiogenic factor that has been 
implicated in tumor growth, was observed at doses ranging from 10 to 150 mg.  
In clinical studies up to 24 weeks duration at doses up to 25 mg, changes in 
VEGF plasma concentrations were variable but similar relative to control.
Integrated AE data [including 2 global phase 2b studies (24-week treatment 
duration) and 2 Japanese phase 3 studies (52-week treatment duration)]: No 
Specific eligibility criteria related to personal history 
of malignancy is outlined in Section 6.2
Stopping criteria for participants with treatment 
emergent malignancy are outlined in Section 8.1
Instream monitoring of safety data by internal safety 
review team


2016N291495_02
CONFIDENTIAL
205767
78
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
meaningful difference was seen between treatment groups in the occurrence of 
this AESI: [8/688 (1.1%) daprodustat vs. 4/404 (0.9%) rhEPO; 1.14 relative risk 
(95% confidence interval: 0.31, 4.28)].
Clinical experience to date is not yet sufficient to substantiate or refute this as a 
safety concern for daprodustat.


2016N291495_02
CONFIDENTIAL
205767
79
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Pulmonary artery hypertension (PAH)
A role for HIF-regulated pathways in the pathophysiology of PAH has been 
suggested based on well established effects of acute and chronic hypoxia in 
man on the pulmonary vasculature (vasoconstriction), and by findings in 
patients with naturally occurring mutations that result in decreased HIF 
degradation [Smith, 2006; Formenti, 2011].
There have been no histopathologic findings suggestive of PAH in pre-clinical 
safety studies with daprodustat (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 healthy 
volunteers demonstrated that short-term (5 days) therapy with daprodustat 
5mg or 100mg had no clinically significant effect on transthoracic 
echocardiographically (ECHO) estimates of pulmonary artery systolic 
pressure (PASP) under either normoxic or hypoxic conditions.  ECHO 
assessments performed in Phase 2b studies (24 weeks treatment duration) 
did not identify any clinically meaningful changes in PASP in participants
not on dialysis for daprodustat.  In hemodialysis participants, mean 
absolute change from baseline in PASP was similar for both treatment 
groups; however, there was a numeric imbalance (daprodustat Total: 8 
[7%]; Control 0) in participants reaching the PASP 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 participants 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 
participants meeting the PASP percutaneous coronary intervention (PCI)
criterion. Overall, there is insufficient evidence to conclude a relationship to 
treatment with daprodustat. A post-hoc analysis was performed using a 
definition of PAH cited in the literature [Navaneethan, 2016]. Subjects with 
Instream monitoring of safety data by internal safety 
review team


2016N291495_02
CONFIDENTIAL
205767
80
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
sPAP >35 mmHg and/or tricuspid regurgitation maximum jet velocity (TRV) 
>2.5 m/s were considered as having PAH.  Regardless of baseline status of 
PAH, there was no clinically meaningful difference in the proportion of 
subjects with on-treatment PAH between the two treatment groups: 
o
Subjects with PAH at baseline: 35/113 (31%) vs. 21/54 (39%) 
(ND) and 37/115 (32%) vs. 7/21 (33%) (HD), daprodustat vs. 
control, respectively.
o
Subjects without PAH at baseline: 25/113 (22%) vs. 12/54 (22%) 
(ND) and 22/115 (19%) vs. 6/21 (29%) (HD), daprodustat vs. 
control, respectively.
Integrated AE data [including 2 global phase 2b studies (24-week treatment 
duration) and 2 Japanese phase 3 studies (52-week treatment duration)]: Four 
(0.5%) non-serious AEs in the daprodustat group vs 0 in rhEPO. 

Review of subject level information did not suggest adverse treatment 
effect: 2 subjects from phase2b that met protocol specified stopping 
criteria on scheduled ECHO had non-serious AEs of ‘pulmonary arterial 
pressure increased’ and 2 subjects from Japan Phase 3 had non-serious 
AE ‘pulmonary hypertension’ in setting of concurrent serious AEs of acute 
pulmonary embolus and mitral regurgitation identified during 
hospitalization for coronary angiography
Following review of clinical data received to date, this has not been 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.
Small increases in cardiac troponin in 6 month rat study with daprodustat were 
consistent with the background finding of spontaneous rodent cardiomyopathy.  
There were no elevations observed in cardiac troponin in 9 month monkey 
study with daprodustat.
Instream monitoring of safety data by internal safety 
review team


2016N291495_02
CONFIDENTIAL
205767
81
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cardiomyopathy has not been associated with naturally occurring mutation in 
man which results in increased HIF stabilization.
ECHO assessments performed in Phase 2b studies (24 weeks treatment 
duration) did not identify any clinically-meaningful changes in left ventricular 
ejection fraction (LVEF) with daprodustat.
Integrated AE data from clinical trials with daprodustat [including 2 global phase 
2b studies (24-week treatment duration) and 2 Japanese phase 3 studies (52-
week treatment duration)]: No meaningful difference was seen between 
treatment groups in reports of this AESI [1 (0.1%) daprodustat vs. 1 (0.2%) 
rhEPO; 0.64 relative risk (95% confidence interval: 0.02, 18.07)].
Following review of clinical data received to date, this has not been identified as 
a safety concern for daprodustat.
Proliferative retinopathy, macular edema, 
choroidal neovascularization
Increases in local (ocular) VEGF production with retinal neovascularization and 
macular edema observed in diabetic retinopathy and to choroidal leakage, 
edema and neovascularization seen in age-related macular degeneration 
[Campochiaro, 2006].
Administration of 60mg/kg daprodustat to mice caused minimal increases in 
circulating VEGF while significant EPO increases were observed.
No ocular abnormalities with daprodustat were seen in non-clinical studies of 
up to 13 weeks duration in mice and dogs, 26 weeks in rats, and 39 weeks in 
monkeys.
In clinical studies with daprodustat up to 4 weeks duration, a dose-ordered 
increase in VEGF plasma concentrations was observed at doses ranging from 
10mg to 150mg administered once daily and from 10mg to 30mg administered 
three times weekly. In studies up to 24 weeks duration at doses up to 25mg, 
changes in VEGF plasma concentrations were variable but similar relative to 
control.
Ophthalmologic assessments performed in Phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes in 
proliferative retinopathy, macular edema, or choroidal neovascularization from 
Instream monitoring of safety data by internal safety 
review team


2016N291495_02
CONFIDENTIAL
205767
82
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
daprodustat.
Integrated AE data [including 2 global phase 2b studies (24-week treatment 
duration) and 2 Japanese phase 3 studies (52-week treatment duration)]: No 
meaningful difference was seen between treatment groups in reports of this 
AESI [9 (2.9%) daprodustat vs. 6 (2.5%) rhEPO; 1.19 relative risk; (95% 
confidence interval: 0.42, 3.43)].
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 pro-inflammatory cytokines has been postulated to 
contribute to the neo-angiogenesis, proliferation and infiltration of rheumatoid 
synovial fibroblasts [Westra, 2010; Muz, 2009].
No abnormalities were seen in non-clinical studies conducted to date for 
daprodustat.
Integrated AE data [including 2 global phase 2b studies (24-week treatment 
duration) and 2 Japanese phase 3 studies (52-week treatment duration)]: No 
meaningful difference was seen between treatment groups in reports of this 
AESI [2 (0.3%) daprodustat vs. 1 (0.2%) rhEPO; 1.20 relative risk; (95% 
confidence interval: 0.07, 20.87) and the incidence of musculoskeletal AEs was 
generally lower in the daprodustat treatment group].
Following review of clinical data received to date, this has not been identified as 
a safety concern for daprodustat.
Instream monitoring of safety data by internal safety 
review team
Drug-drug interactions
Daprodustat is a substrate of CYP2C8:  Co-administration of daprodustat with a 
strong CYP2C8 inhibitor (i.e., gemfibrozil) increased the maximum plasma 
concentration (Cmax) and area under curve (AUC) of daprodustat, 4- and 19-
fold, respectively, while co-administration of a weak 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 2 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 
Co-administration of daprodustat with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and inducers 
(e.g., rifampin/rifampicin) is not permitted as 
outlined in Section 7.7.2
Co-administration of daprodustat with moderate 
CYP2C8 inhibitors (i.e., clopidogrel, teriflunomide, 
deferasirox) should be performed with caution. If 
one of these medications is started, stopped or the 


2016N291495_02
CONFIDENTIAL
205767
83
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
increase in the measured Hb 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 hemoglobin 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 
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 25mg and 100mg 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 2 studies suggested that while BCRP 
inhibitors were a covariate for daprodustat apparent total body clearance (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 polypedtides
(OATP)1B1/1B3: A clinical drug interaction study between 25mg and 100mg 
daprodustat with an OATP1B1/1B3 substrate (i.e., rosuvastatin) showed no PK 
interaction at these doses of daprodustat.
dose is changed, Hgb should be monitored every 4 
weeks Specific guidance on the management of 
potential drug-drug interactions and concomitant 
medications is provided in Section 7.2
Hgb will be closely monitored throughout the 
dosing period as outlined in the SoA (See Section 
2)
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb is provided in Section 7.2.
Instream monitoring of safety data by internal 
safety review team


2016N291495_02
CONFIDENTIAL
205767
84
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cyst progression in patients with autosomal 
dominant polycystic kidney disease (ADPKD)
Published data provide in vivo evidence for a potential role of HIF-1a in the 
growth of polycystic kidneys; Hif-1a deletion was sufficient to significantly 
mitigate a progressive polycystic phenotype in an ADPKD mouse model, while 
conversely pharmacologic HIF-1a stabilization was sufficient to convert a mild 
polycystic disease into a severely aggravated phenotype with marked loss of 
renal function (Kraus, 2018; Hofherr, 2018).
A review of the non-clinical data from toxicity studies conducted with 
daprodustat does not indicate an exacerbation in incidence or severity of kidney 
cysts in daprodustat-treated animals in comparison to controls.  However, the 
wild type animals used in these toxicity studies have a very low background 
incidence of renal cysts and are not comparable to the mice used in the Kraus 
article (Kraus, 2018) which are an inducible kidney epithelium-specific Pkd1-
deletion model.
There is limited experience with daprodustat in subjects with ADPKD in 
completed clinical trials. In the Japan phase 3 study in non-dialysis subjects, 
there were 5 subjects with ADPKD (all CKD stage 5) in each treatment group.  
Mean baseline eGFR was 10 mL/min/1.73m2 in the daprodustat subjects vs. 16 
mL/min/1.73m2 in the rhEPO subjects.  The mean (SD) percent change from 
baseline at Week 52 in eGFR was: -18% (8) vs. -21% (14) in daprodustat vs. 
rhEPO, respectively.
Following review of clinical data received to date, this has not been identified as 
a safety concern for daprodustat.

Kidney function  will be monitored throughout 
the dosing period as outlined in the SoA 
(Section 2).

Monitoring of emerging safety data by an 
internal GSK Safety Review Team.
Other
Darbepoetin alfa (Control)
See risks outlined in table for daprodustat for excessive erythropoiesis 
(polycythemia) leading to thrombosis and/or tissue ischemia; Death, MI, stroke, 
heart failure, thromboembolic events, thrombosis of vascular access; and for 
increased cancer-related mortality and tumor progression.
Uncontrolled hypertension.
Pure red cell aplasia.
See mitigation strategies outlined in table for 
daprodustat for Excessive erythropoiesis 
(polycythemia) leading to thrombosis and/or tissue 
ischemia; Risk of death, MI, stroke, heart failure,
throboembolic events, thrombosis of vascular 
access; and for Increased cancer-related mortality 
and tumor progression.
Specific eligibility criteria related to current 
uncontrolled hypertension are outlined in Section 


2016N291495_02
CONFIDENTIAL
205767
85
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
6.2
Specific eligibility criteria related to personal history 
of pure red cell aplasia are outlined in Section 6.2
Challenge Agents
Acetylcholine
Acetylcholine stimulates the production by the vascular endothelium of nitric 
oxide, a potent vasodilatory agent.  Distribution of acetylcholine to the 
peripheral vasculature has the potential to lead to a decrease in blood 
pressure; however acetylcholine is rapidly metabolized by acetylcholinesterase, 
minimizing the potential for pharmacological concentrations distant from the 
infusion site.
Study undertaken only at specialist centers by 
experienced study personell trained to conduct 
forearm blood flow assessment
Patients monitored continously throughout 
technique
Minimum dose given for required physiological 
response
Patients with recent cardiovascular events excluded 
from the study
N-monomethyl-L-arginine (NMMA)
L-NMMA inhibits nitric oxide synthase, leading to decreased production of nitric 
oxide, which can lead to increases in blood pressure.
Study undertaken only at specialist centers by 
experienced study personnel trained to conduct 
forearm blood flow assessment
Patients monitored continously throughout 
technique
Minimum dose given for required physiological 
response
Patients with recent cardiovascular events excluded 
from the study
Sodium nitroprusside
Sodium nitroprusside directly causes vasodilation leading to decreases in blood 
pressure.  Reported side effects of sodium nitroprusside administration are 
excessive hypotension and excessive accumulation of cyanide at high rates of 
infusion.
Study undertaken only at specialist centers by 
experienced study personnel trained to conduct 
forearm blood flow assessment
Patients monitored continously throughout 
technique
Minimum dose given for required physiological 


2016N291495_02
CONFIDENTIAL
205767
86
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
response
Patients with recent cardiovascular events excluded 
from the study
Study Procedures
Venous occlusion plethysmography
Primary risk associated with venous venous occlusion plethysmography is 
related to the cannulation of the brachial artery.  This has the potential for 
causing damage to the brachial artery, thrombosis, digital ischemia, and 
hemorrhage, as well as discomfort at the infusion site.
Study undertaken only at specialist centers by 
experienced study personnel trained to conduct 
forearm blood flow assessment
Cannulation of the brachial artery for infusion of the 
challenge agents will be done with a fine (27 
guage) needle to minimize any injury to the artery
Cannulation will be done under a local anesthetic to 
minimize participant discomfort


2016N291495_02
CONFIDENTIAL
205767
87
References
Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D.  Enzyme induction 
with antiepileptic drugs: Cause for concern? Epilepsia. 2013; 54:11-27.
Campochiaro PA.  Ocular versus extraocular neovascularization: mirror images or vague 
resemblances. Invest Ophthalmol Vis Sci. 2006; 47:462-74.
Formenti F, Beer PA, Croft QP, Dorrington KL, Gale DP, Robbins PA, 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; 25:2001-11.
Hofherr, A., et al, HIF-1α drives cyst growth in advanced stages of autosomal dominant 
polycystic kidney disease; Kidney International (2018) 94, 849–851.
Kraus, A., et al, HIF-1α promotes cyst progression in a mouse model of autosomal 
dominant polycystic kidney disease; Kidney International, 2018.
Muz B, Khan MN, Kiriakidis S, Paleolog EM.  Hypoxia. The role of hypoxia and HIF-
dependent signalling events in rheumatoid arthritis.  Arthritis Res Ther. 2009; 11:201.
Navaneethan SD, for CRIC investigators: Prevalence, Predictors, and Outcomes of 
Pulmonary Hypertension in CKD. J Am Soc Nephrol 2016, 27:877–886. 
Ohnhaus EE, Breckenridge AM, Park BK.  Urinary excretion of 6β-hydrocortisol and the 
time course measurement of enzyme induction in man. Eur J Clin Pharmacol. 1989; 
36:39-46.
Smith TG, Brooks JT, Balanos GM, Lappin TR, Layton DM, Robbins PA. et al.  
Mutation of von Hippel-Lindau tumour suppressor and human cardiopulmonary 
physiology. PLoS Med. 2006; :e290.
Westra J, Molema G, Kallenberg CG.  Hypoxia-inducible factor-1 as regulator of 
angiogenesis in rheumatoid arthritis - therapeutic implications. Curr Med Chem. 2010; 
17:254-63.


2016N291495_02
CONFIDENTIAL
205767
88
12.8.
Appendix 8: Non-Contact, Optical Forearm 
Plethysmography (NC-OFP) Sub-Study
12.8.1.
Introduction and Rationale
The purpose of this pilot sub-study is to evaluate and compare the effectiveness of 
measuring FBF via a non-contact, alternative method in participants as compared to 
strain-gauge forearm plethysmography assessment. The proposed method could be a step 
in identifying alternate strategies to safely and effectively evaluate FBF in participants 
undergoing cardiovascular drug studies (Wilkinson, 2001).
12.8.2.
Objectives and Endpoints
Objective
Endpoints
Primary
To compare FBF measurements between non-
contact plethysmography and strain-guage 
plethysmography

Compare the FBF ratio and absolute FBF, as 
measured by non-contact plethymography, to 
FBF ratio and absolute FBF, as measured by 
strain-gauge plethysmography technique
12.8.3.
Study Design
This is a sub-study of the 205767 study in order to compare measurement of forearm 
blood flow by a non-contact optical method to assessment by use of a strain gauge. 
Approximately 6 participants from one to two sites participating in the main study will be 
invited to be part of this sub-study. Every attempt will be made to have equal numbers of 
participants from each study treatment group.  
12.8.4.
Additional Inclusion Criteria
Signed written informed consent prior to beginning sub-study-related procedures (subject 
must understand the aims, procedures, and possible consequences of the sub-study).
Note: Consent to participate in the sub-study is separate from consent to participate in the 
main study.
12.8.5.
Study Assessments
Non-contact plethysmography will be conducted in parallel with the main study FBF 
assessment, using a combination of an infrared camera and Raspberry Pi portable 
computer which will capture high-resolution, subdermal images of the forearm.  The 
device will be placed at approximately 30 cm from participants’ forearm while they are 
also undergoing the venous occlusion strain-gauge plethysmography assessment.  The 
device will capture and store visual information and utilizing proprietary software, extract 
plethysmographic data.
The device will utilize the time of flight data gathered from the infrared camera to obtain 
three dimensional data of the forearm.  The high resolution and high frequency images 


2016N291495_02
CONFIDENTIAL
205767
89
will undergo image processing to allow for the extraction of the vasculature data 
separately from the acquisition (data will be stored and sent to the study team for analysis 
off-site).  The data will be analysed in software to estimate the volume change of the 
vessels and therefore the forearm.  A single-point time of flight sensor placed 
intermittently within the enclosure will measure how long it takes for light to return to the 
sensors, effectively measuring distance.  The sensor will ensure correct placement of the 
system and allow for any variance in distance to be accounted for when making 
calculations.  The combination of the sensors and cameras in the enclosure will allow for 
plethysmographic data to be extracted along with vasculature change data.
12.8.6.
Withdrawal from Non-Contact, Optical Plethysmography Sub-
Study
If a participant in this sub-study withdraws from the sub-study, the reason for the 
withdrawal must be recorded in the eCRF. The participant will remain in the main study 
unless the subject withdraws consent from the main study.
12.8.7.
Sample Size
The target evaluable sample size is 6.  The sample size is based on feasibility.
12.8.8.
Analyses Plan
All participants with a minimum baseline FBF assessed via non-contact and strain-gauge 
method will be evaluated in the sub-study. Additional details regarding the analysis plan 
will be provided in the RAP of the main study.


2016N291495_02
CONFIDENTIAL
205767
90
12.9.
Appendix 9: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Previous Amendment:
Amendment 1 29-JAN-2018
Overall Rationale for the Amendment: The study team was required per regulatory 
agencies to change the protocol to include a serum pregnancy testing at screening.  
During the amendment process, minor updates were made for study optimization. 


2016N291495_02
CONFIDENTIAL
205767
91
Section # and 
Name
Description of Change
Brief Rationale
1 and 4 
Objectives and 
Endpoints
The first secondary endpoint was 
designated as the Principle 
Secondary endpoint.
For emphasis of the aim of the study.
2 Schedule of 
Activities
The word “examinations” was 
added to the Physical.
To be more consistent with wording later 
in the protocol.
2 Schedule of 
Activities
Serum pregnancy test [FRP only] 
was added to the table and 
indicated to be done at screening 
by an X in that column. The urine 
pregnancy test for that time point 
was deleted.
Required to amend this by regulatory 
agency. 
6.3.2 Caffeine, 
Alcohol and 
Tobacco
Added in text regarding participant 
instruction on caffeine avoidance 
prior to certain study visits. 
To have more consistency across sites on 
the participant preparation prior to 
procedures. 
9.4.1 Physical 
Examinations
Height and weight was added to 
the the physical exam at 
screening.
Added for more complete assessment of 
the participant. 
9.4.2 Vital Signs
Weight was added as a parameter 
to the vital signs.
Added for more complete assessment of 
the participant.
9.6.1 Venous 
Occlusion 
Plethysmography 
to Measure 
Forearm Blood 
Flow (FBF)
Minor wording changes to indicate 
the subject is not fasting during 
the procedures, but can have a 
light breakfast.
Added for clarity.
12.2 Appendix 2
Serum pregnancy test was added 
to Table 4: Protocol Required 
Laboratory Assessments
For consistency with the Schedule of 
Activities table.
Throughout
Minor editorial and grammatical 
revisions
Minor, therefore have not been 
summarized.

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205767 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan for a randomized, repeat dose, 
open label, parallel group, multi-center study to evaluate the 
effect of daprodustat compared to darbepoetin alfa on 
forearm blood flow in participants with anemia of chronic 
kidney disease that are not dialysis dependent 
Compound Number  : GSK1278863 
Effective Date  
: Refer to Document Date 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol GlaxoSmithKline Document 
Number 2016N291495_02. 
• 
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable. 
 
RAP Author(s): 
Author 
Date 
Lead 
 
 
Manager-Statistics (Speciality), Development Biostatistics 
India Stats 
Refer to Document 
Date 
 
Co-Authors 
 
 
Statistician (Speciality), Development Biostatistics 
02-NOV-2020 
 
 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0
PPD
PPD


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205767 
 
2 
 
RAP Team Review Confirmations  
(Method: E-mail) 
Reviewer 
Date 
 
 
31-OCT-2020 
Lead Programmer (Speciality), Development Biostatistics India 
Prog 
 
 
02-NOV-2020 
Director Clinical Development (Clinical Science Nephrology) 
Clinical Sciences Respiratory and Specialty 
 
Statistics Director (Speciality), Development Biostatistics 
 
31-OCT-2020 
 
 
31-OCT-2020 
Global Clinical Development Manager (R&D GCSD), 
Development Global Clinical Operations 
 
 
02-NOV-2020 
Principal Clinical Data Manager (RD PCPS GCDO DM FPD), 
Development Global Clinical Operations  
 
 
Clinical Statistics & Clinical Programming Line Approvals  
(Method: Pharma TMF eSignature) 
Approver 
Date 
Approval 
Method 
 
 
Refer to 
Document Date 
E-signature, 
eTMF 
Manager- Statistics (Speciality), Development 
Biostatistics India Stats 
 
 
Refer to 
Document Date 
E-signature, 
eTMF 
Senior Manager - Programming (Speciality), 
Development Biostatistics India Prog 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
 
 
205767 
 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 5 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 5 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 5 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 6 
2.3. 
Study Design ................................................................................................ 8 
2.4. 
Statistical Hypotheses................................................................................... 9 
3. 
PLANNED ANALYSES ............................................................................................ 9 
3.1. 
Interim Analyses ........................................................................................... 9 
3.2. 
Final Analyses .............................................................................................. 9 
4. 
ANALYSIS POPULATIONS ..................................................................................... 9 
4.1. 
Protocol Deviations ..................................................................................... 10 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 10 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 10 
5.2. 
Baseline Definitions .................................................................................... 11 
5.3. 
Multicentre Studies ..................................................................................... 11 
5.4. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 11 
6. 
STUDY POPULATION ANALYSES ....................................................................... 12 
6.1. 
Overview of Planned Study Population Analyses ........................................ 12 
6.2. 
Display Details ............................................................................................ 12 
6.2.1. 
Study Disposition ......................................................................... 12 
6.2.2. 
Protocol Deviations ...................................................................... 12 
6.2.3. 
Demographic and Baseline Characteristics .................................. 13 
6.2.4. 
Medical Conditions, Prior and Concomitant Medications .............. 13 
6.2.5. 
Exposure ..................................................................................... 13 
7. 
SAFETY ANALYSES ............................................................................................. 14 
7.1. 
Adverse Events Analyses ........................................................................... 14 
7.2. 
Clinical Laboratory Analyses ....................................................................... 14 
7.3. 
Other Safety Analyses ................................................................................ 15 
8. 
PHARMACODYNAMIC ANALYSES....................................................................... 15 
8.1. 
Primary Pharmacodynamic Analyses .......................................................... 15 
8.1.1. 
Endpoint / Variables ..................................................................... 15 
8.1.2. 
Summary Measure ...................................................................... 16 
8.1.3. 
Population of Interest ................................................................... 16 
8.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 16 
8.1.5. 
Statistical Analyses / Methods ..................................................... 16 
8.2. 
Secondary Pharmacodynamic Analyses ..................................................... 16 
8.2.1. 
Endpoint / Variables ..................................................................... 16 
8.2.2. 
Summary Measure ...................................................................... 17 
8.2.3. 
Population of Interest ................................................................... 17 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
4 
 
8.2.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 17 
8.2.5. 
Statistical Analyses / Methods ..................................................... 17 
9. 
REFERENCES ....................................................................................................... 18 
10. APPENDICES ........................................................................................................ 19 
10.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 19 
10.1.1. 
Exclusions from Per Protocol Population ..................................... 19 
10.2. 
Appendix 2: Schedule of Activities .............................................................. 20 
10.2.1. 
Protocol Defined Schedule of Activities ........................................ 20 
10.3. 
Appendix 3: Assessment Windows ............................................................. 23 
10.3.1. 
Definitions of Assessment Windows for Analyses ........................ 23 
10.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 24 
10.4.1. 
Study Phases .............................................................................. 24 
10.4.1.1. Study Phases for Concomitant Medication ................. 24 
10.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 24 
10.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 25 
10.5.1. 
Reporting Process ....................................................................... 25 
10.5.2. 
Reporting Standards .................................................................... 25 
10.6. 
Appendix 6: Derived and Transformed Data ............................................... 27 
10.6.1. 
General ........................................................................................ 27 
10.6.2. 
Study Population .......................................................................... 27 
10.6.3. 
Safety .......................................................................................... 27 
10.6.4. 
Pharmacodynamic ....................................................................... 28 
10.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 30 
10.7.1. 
Premature Withdrawals ................................................................ 30 
10.7.2. 
Handling of Missing Data ............................................................. 30 
10.7.2.1. Handling of Missing and Partial Dates ........................ 30 
10.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 32 
10.8.1. 
Laboratory Values ........................................................................ 32 
10.8.2. 
Vital Signs ....................................................................................... 32 
10.8.3. 
FBF ............................................................................................... 33 
10.8.4. 
PWV .............................................................................................. 33 
10.9. 
Appendix 9: Abbreviations & Trademarks ................................................... 34 
10.9.1. 
Abbreviations ............................................................................... 34 
10.9.2. 
Trademarks ................................................................................. 34 
10.10. Appendix 10: List of Data Displays.............................................................. 35 
10.10.1. Data Display Numbering .............................................................. 35 
10.10.2. Mock Example Shell Referencing ................................................ 35 
10.10.3. Deliverables ................................................................................. 35 
10.10.4. Study Population Tables .............................................................. 36 
10.10.5. Safety Tables ............................................................................... 36 
10.10.6. Pharmacodynamic Tables ........................................................... 37 
10.10.7. ICH Listings ................................................................................. 38 
10.10.8. Non-ICH Listings .......................................................................... 40 
10.11. Appendix 11: Example Mock Shells for Data Displays ................................ 41 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
5 
 
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  
2016N291495_02. 
Revision Chronology: 
Protocol number: 
Date: 
Version: 
2016N291495_00 
17/Nov/2017 
Original Protocol 
2016N291495_01 
28/Jan/2018 
Protocol Amendment 1 
This protocol amendment was written as the study team was required per regulatory 
agencies to change the protocol to include serum pregnancy testing at screening. 
During the amendment process, minor updates were made for study optimization. 
2016N291495_02 
07/Aug/2019 
Protocol Amendment 2 
This protocol amendment was written becase a challenge agent suddenly became 
commercially unavailable with no immediate ability to reobtain this. The study has 
been modified to allow flexibility for the forearm blood flow testing to be performed 
with this agent if it becomes available again, and to be performed without it if not. 
During this time the safety language was updated as well. 
 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1. 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
10.1.2 Sample Size Re-
estimation 
• 
Sample size re-estimation 
will not be performed 
• 
The study was terminated 
• 
10.3.3 Other Analyses 
(Pharmacodynamic) 
• 
No statistical analyses will 
be performed;  only 
summary statistics will be 
reported. We will not 
perform exploratory 
analyses and sensitivity 
analysis. 
• 
Since the study was 
terminated and we have 
only 4 completed subjects 
to report. Therefore, 
statistical analysis will not 
be performed. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
6 
 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
10.3.4 Interim Analyses 
• 
Interim analyses will not be 
performed 
• 
The study was terminated 
• 
Enrolled population is not 
defined in the protocol 
• 
Enrolled population added 
in the RAP with the below 
definition. 
“All Randomized 
Participants” 
• 
This population is required 
for data disclosure displays 
• 
10.2. Pharmacodynamic Per-
Protocol (PDPP) Population: 
“All randomized participants 
who provide pharmacodynamic 
(PD) data at Day 1 and Day 42 
that meets the QC criteria (See 
Section 9.6.1.3 of Protocol) and 
completes the protocol without 
important deviations will be 
included in the PDPP 
population. This population will 
be used in the evaluation of all 
endpoints with the exception of 
safety endpoints.” 
 
• 
PDPP definition updated 
with adding RAP section 
number of exclusions of 
per proptocol population. 
“All randomized 
participants who provide 
pharmacodynamic (PD) 
data at Day 1 and Day 42 
that meets the QC criteria 
(See Section 9.6.1.3 of 
Protocol) and completes 
the protocol without 
important deviations 
(exclusions are 
populated under Section 
10.1.1 of RAP) will be 
included in the PDPP 
population. This population 
will be used in the 
evaluation of all endpoints 
with the exception of safety 
endpoints.” 
 
• 
To exclude all participants 
based on the Protocol 
Deviation Management 
Plan (PDMP) definitions, 
as not all important 
deviations are criticial for 
analysis population 
exclusion. In efforts to 
maximize the number of 
participants in the analysis, 
only the important 
deviations (exclusions are 
populated under Section 
10.1.1 of RAP) will be 
considered exclusionary 
for the analysis. 
• 
Non-Contact, Optical Forearm 
Plethysmography (NC-OFP) 
Sub-Study 
• 
Sub-study will not be 
performed 
• 
The study was terminated, 
and no subjects recruited 
for sub-study 
 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objective 
Primary Endpoint 
To compare the effect of daprodustat to 
darbepoetin alfa on endothelial function 
- 
Change in FBF ratio from Day 1 to Day 42 in 
response to acetylcholine 
Principle Secondary 
Principle Secondary Endpoint 
To further compare the effect of 
daprodustat to darbepoetin alfa on 
endothelial function 
- 
Change in the absolute FBF from Day 1 to Day 42 
in response to acetylcholine 
Secondary Objectives 
Secondary Endpoints 
To compare the effect of daprodustat to 
darbepoetin alfa on endothelium-
independent vasodilation 
- 
Change in FBF ratio from Day 1 to 42 in response 
to sodium nitroprusside (SNP) 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
7 
 
Objectives 
Endpoints 
- 
Change in the absolute FBF from Day 1 to Day 42 
in response to SNP 
To compare the effect of daprodustat to 
darbepoetin alfa on basal endothelial NO 
synthesis 
- 
Change in FBF ratio from Day 1 to Day 42 in 
response to L-NG-monomethyl arginine citrate (L-
NMMA) 
- 
Change in the absolute FBF from Day 1 to Day 42 
in response to L-NMMA 
To compare the effect of daprodustat on 
the FBF response to acetylcholine, SNP 
and L-NMMA between Day 42 and Day 1 
- 
Change in FBF ratio in response to each individual 
challenge agent at Day 42 vs Day 1 in participants 
treated with daprodustat 
- 
Change in the absolute FBF in response to each 
individual challenge agent at Day 42 vs Day 1 in 
participants treated with daprodustat 
To compare the effect of darbepoetin alfa 
on the FBF response to acetylcholine, 
SNP and L-NMMA between Day 42 and 
Day 1 
- 
Change in FBF ratio in response to each individual 
challenge agent at Day 42 vs Day 1 in participants 
treated with darbepoetin alfa 
- 
Change in the absolute FBF in response to each 
individual challenge agent at Day 42 vs Day 1 in 
participants treated with darbepoetin alfa 
To compare the effect of daprodustat to 
darbepoetin alfa on vascular compliance 
- 
Change in Augmentation Index (an indicator of 
arterial stiffness) as estimated by radial arterial 
pulse contours from Day 1 to 42 
- 
Change in pulse wave velocity (PWV) from Day 1 
to Day 42 
Safety 
Safety Endpoints 
Assess safety and tolerability 
- 
Incidence and severity of adverse events (AEs) and 
serious adverse events (SAEs) including AEs of 
special interest 
- 
Reasons for discontinuation of randomized study 
treatment 
- 
Absolute values and changes from baseline in 
clinical laboratory parameters, ECG parameters, 
blood pressure (BP) and heart rate (HR) 
Exploratory Objective 
Exploratory Endpoint 
To explore the relationship between 
diabetes status and endothelial function 
- 
FBF response to each individual challenge agent in 
relation to diabetes status 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
8 
 
2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• 
This study will use a randomized, repeat dose, open label, parallel group design, in 
adult, ND, male and female participants with anemia of CKD that are currently not 
treated with rhEPOs (i.e. no rhEPO use within the 12 weeks prior to the screening 
visit and through Day 1). 
• 
The study will comprise three study periods: a screening period starting up to 30 
days prior to Day 1, a Day 42 (6 week) treatment period with 4 visits starting at Day 
1, and a follow-up visit up to 14 days later. The total duration of participant 
involvement is up to 14 weeks. 
• 
Participants will be randomized to either daprodustat or darbepoetin alfa. A central 
randomization approach will be used with stratification by center. 
• 
All participants will be treated with the goal of achieving a Hgb level within the range 
of 10.0 to 12.0 g/dL, consistent with national guidelines (Medicines and Healthcare 
Products Regulatory Agency, 2007). 
• 
FBF and PWV will be conducted at the beginning (Day 1) and end (Day 42) of the 
treatment period. 
Number of 
Participants 
• 
As defined in the protocol a sufficient number of participants will be enrolled such 
that at least 50 evaluable participants comprise the Pharmacodynamic Per-Protocol 
(PDPP) Population. Since, the study was terminated the number of evaluable 
participants is not applicable here. 
Dosing 
• 
The dose of darbepoetin and daprodustat is administered using a dosing steps 
algorithm which is based on the HemoCue Hgb value to ensure consistency of 
treatment across the study. The doses of each treatment including starting dose 
and criteria for dose adjustments are detailed in the protocol (Section 7, protocol). 
Time & 
Events 
• 
[Refer to Appendix 2: Schedule of Activities] 
Treatment 
Assignment 
• 
Study treatments (darbepoetin and daprodustat) are randomized to participants 
using a pre-planned randomization schedule stratified by center 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
9 
 
2.4. 
Statistical Hypotheses  
The primary endpoint is to compare the effect of daprodustat to darbepoetin alfa on 
change in FBF ratio from Day 1 to Day 42 in response to acetylcholine. The estimand of 
interest is the effect of 6 weeks of randomized treatment on the primary endpoint. 
Null: The difference between daprodustat and darbepoetin alfa on the acetylcholine-
induced change (from Day 1) in FBF ratio at Day 42 is 0. 
Alternative: The difference between daprodustat and darbepoetin alfa on the 
acetylcholine-induced change (from Day 1) in FBF ratio at Day 42 is not 0. 
 
3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
The study was terminated, hence no interim analysis will be performed.  
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. 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who signed an ICF to participate in 
the clinical trial. This population will be used for 
summarizing screening failure rates and reasons for 
screening failure. 
• 
Screen Failures 
Safety 
• 
All randomized participants who receive at least 
one dose of study treatment will be included in the 
safety population. 
• 
This population will be used in the evaluation of all 
safety analyses 
• 
Particpants will be analyzed according to the 
treatment received.1 
• 
Study population 
• 
Safety and 
tolerability 
Pharmacodynamic 
Per-Protocol 
(PDPP) 
Population 
• 
All randomized participants who provide 
pharmacodynamic (PD) data at Day 1 and Day 42 
that meets the QC criteria (See Section 9.6.1.3 of 
Protocol) and completes the protocol without 
important deviations (exclusion are populated under 
• 
Primary, 
secondary 
endpoints 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
10 
 
Population 
Definition / Criteria 
Analyses Evaluated 
Section 10.1.1 of RAP) will be included in the PDPP 
population.  
• 
This population will be used in the evaluation of all 
endpoints with the exception of safety endpoints. 
• 
Participants will be analyzed according to the 
treatment received.1 
Enrolled 
• 
 All randomized participants 
• 
Study population 
[1]: Only participants receiving incorrect randomized treatment for the duration of their study participation will be 
analysed according to the treatment received. Otherwise, participants will be analyzed according to the 
treatment to which they were randomized. 
Refer to Appendix 10: List of Data Displays which details the population used for each display. 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, subject management or subject assessment) will be listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [28Aug2018 V2.0]. 
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided.  
 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
RandAll NG System 
Data Displays for Reporting  
Code 
Description 
Description 
Order in TLF  
A 
Darbepoetin alfa 
rhEPO 
2 
B 
Daprodustat 
Dapro  
1 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
11 
 
5.2. 
Baseline Definitions 
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) 
Primary Endpoint 
FBF ratio 
 
 
X 
Day 1/Repeat Day 11 
Secondary Endpoints 
FBF ratio 
 
 
X 
Day 1/Repeat Day 11 
Absolute FBF 
 
 
X 
Day 1/Repeat Day 11 
Augmentation index 
 
 
X 
Day 1/Repeat Day 11 
PWV 
 
 
X 
Day 1/Repeat Day 11 
Clinical laboratory 
parameters, ECG 
parameters, blood 
pressure (BP) and 
heart rate (HR) 
X 
 
X 
Screening/Day 1 
1Repeat Day 1 values are only used if a repeat visit was deemed necessary 
Unless otherwise stated, if baseline data is missing, no derivation will be performed, and 
baseline will be set to missing. If a Repeat Day 1 visit is required, then this value will be 
used as the baseline measurement instead. 
5.3. 
Multicentre Studies 
Participants will be recruited from 3 centers and will be randomised stratifying by centre. 
Enrolment will be presented by investigative site. 
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 
10.3 
Appendix 3: Assessment Windows 
10.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
10.5 
Appendix 5: Data Display Standards & Handling Conventions 
10.6 
Appendix 6: Derived and Transformed Data 
10.7 
Appendix 7: Reporting Standards for Missing Data 
10.8 
Appendix 8: Values of Potential Clinical Importance 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
12 
 
6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the Screened/Enrolled/Safety population, 
unless otherwise specified. The study population analyses will include a total column, 
unless otherwise specified. 
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure will be based on GSK Core Data Standards. 
Details of the planned displays are presented in Appendix 10 List of Data Displays. 
6.2. 
Display Details 
6.2.1. 
Study Disposition 
Participant Status and Reason for Study Withdrawal 
The number and percentage of subjects who completed the study as well as participants 
who withdrew from the study will be summarized by participant status and reason for 
withdrawal. Also, a summary of number of subjects by country and site id by treatment 
group and overall total. 
 
A listing of reasons for study withdrawal will be provided for all participants who were 
withdrawn from the study. 
 
Screening Status and Reasons for Screen Failure 
The number and percentage of participants who passed screening (i.e. enrolled) 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 participants who failed 
screening. If a subject has been screened multiple times, the subject’s latest screening 
information will be displayed. (Note that the reasons for rescreened participants who 
initially failed but subsequently enrolled are not included in the display.) 
 
A listing of the screen failure record for all participants who failed screening and were 
not enrolled in the study will be produced. This listing will include site ID, unique subject 
ID, date of screen failure, reason term(s) for screen failure (including the specify text, if 
any).  
6.2.2. 
Protocol Deviations 
A listing of important protocol deviations will be provided. The listing will include 
treatment, site ID, unique subject ID, date of deviation, study day of deviation, protocol 
deviation category, protocol deviation coded term, and protocol deviation description. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
13 
 
A listing of participants with inclusion/exclusion criteria deviations will be provided. The 
listing will include treatment, site ID, unique subject ID, inclusion/exclusion type, and 
criteria description. 
 
6.2.3. 
Demographic and Baseline Characteristics 
Demographic Characteristics 
Demographic data will be summarized by treatment group and overall. 
 
A listing of demographic and baseline characteristics will also be produced. This listing 
will include treatment, site ID, unique subject ID, year of birth, age, sex, ethnicity, height, 
weight, and other demographic and baseline characteristics. 
 
Age Ranges 
A summary of age ranges will be produced for each treatment group and overall total. 
 
Race and Racial Combinations 
A summary of race and racial combinations will be produced for each treatment group 
and overall total.  
 
6.2.4. 
Medical Conditions, Prior and Concomitant Medications 
Medical Conditions 
A listing of medical conditions will be produced, which will capture both pre-specified 
medical conditions and other medical conditions collected on the eCRF.  
Concomitant Medications 
A listing of all medications taken by participants, including any of which are pre, on and 
post-treatment, will be produced. The relationship between ATC level 1, 2, 3, and 
ingredients and verbatim text for all medications in the study will be listed. 
6.2.5. 
Exposure  
A listing of exposure data will be provided. This listing will include treatment, site ID, 
unique subject ID, dose start date, duration of time on dose, dose and dose units. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
14 
 
7. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population, unless otherwise specified. 
Objectives 
Endpoints 
Safety 
 
• 
Assess safety and tolerability 
• 
Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs) 
including AEs of special interest 
• 
Reasons for discontinuation of randomized 
study treatment 
• 
Absolute values and changes from baseline 
in clinical laboratory parameters, ECG 
parameters, blood pressure (BP) and heart 
rate (HR) 
 
7.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs) and Serious 
(SAEs) will be based on GSK Core Data Standards. The details of the planned displays 
are provided in Appendix 10: List of Data Displays. 
Adverse Events 
A listing of AE records for all participants who reported AEs will be produced. 
7.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of chemistry laboratory tests, hematology 
laboratory tests, and liver function tests will be based on GSK Core Data Standards. The 
details of the planned displays are in Appendix 10: List of Data Displays and include the 
following tests: 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
15 
 
  
 
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 10: List of Data Displays. 
 
8. 
PHARMACODYNAMIC ANALYSES 
8.1. 
Primary Pharmacodynamic Analyses 
8.1.1. 
Endpoint / Variables 
The endpoint of interest is FBF ratio. 
 
FBF ratio is calculated as the FBF of the subject’s treatment arm divided by the subject’s 
non-treatment arm. The treatment arm is given either saline or the challenge agent. The 
non-treatment arm is given nothing.  
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
16 
 
The FBF measurement is calculated from the average of 5 values as recorded on the 
LabChart file. The 5 values of FBF are recorded manually from a blinded central reader 
reviewing the subject’s FBF LabChart file. 
8.1.2. 
Summary Measure 
The summary measure of interest is the change in FBF ratio from Day 1 to Day 42 in 
response to acetylcholine. 
If FBF procedure is repeated for Day 1 and/or Day 42, this data will take the place of the 
original Day 1 and Day 42 data respectively. A quality control (QC) check will be 
performed on the FBF data before the final analyses. The QC check will be to assess 
negative and extreme values for FBF (FBF). 
Descriptive statistics (n, arithmetic mean, standard deviation (SD), minimum, median, 
maximum) will be calculated by treatment group for change in FBF ratio endpoints. 
 
8.1.3. 
Population of Interest 
The primary pharmacodynamics analyses will be based on the PDPP population, unless 
otherwise specified. 
8.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Due to the design of the PDPP population, only subjects who have FBF measurements 
for both Day 1 and Day 42 are included, and it is not possible to have missing FBF data. 
Therefore, no FBF data will be imputed. 
8.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarised using descriptive statistics and listed. 
8.2. 
Secondary Pharmacodynamic Analyses 
8.2.1. 
Endpoint / Variables 
• Principle secondary endpoint: change in the absolute FBF 
• Secondary endpoints: 
o  FBF ratio, absolute FBF of Sodium nitroprusside and L-NMMA 
o Augmentation index 
o PWV 
Absolute FBF is defined as only including the FBF value from the subject’s treatment 
arm which is infused with either saline or challenge agents. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
17 
 
8.2.2. 
Summary Measure 
Principle secondary endpoint: Change in the absolute FBF from Day 1 to Day 42 in 
response to acetylcholine 
 
Secondary endpoints: Change in FBF ratio from Day 1 to Day 42 in response to sodium 
nitroprusside and L-NMMA. 
Change in absolute FBF from Day 1 to Day 42 in response to sodium nitroprusside and 
L-NMMA. 
Change in Augmentation Index (AIX, an indicator of arterial stiffness) as estimated by 
radial arterial pulse contours from Day 1 to Day 42. 
 
Change in pulse wave velocity (PWV) from Day 1 to Day 42. 
 
For the PWV dataset, there are two recorded values for each variable per day, with the 
option to collect a third value if the first two values varied (Refer: SRM) too much from 
each other. The average of the two closest absolute values will be used for analysis 
purposes. 
 
If for any of these measures mentioned above, the respective procedures are repeated for 
Day 1 and/or Day 42, the data from the repeat visit will take place of the original Day 1 
and Day 42 data respectively. Like the FBF data, a QC check will be performed for the 
PWV data before the final analyses.  The QC check will be to assess negative and 
extreme values for PWV (PWV).  
 
Descriptive statistics (n, mean, standard deviation (SD), minimum, median, maximum) 
will be calculated by treatment group.   
 
8.2.3. 
Population of Interest  
The secondary pharmacodynamics analyses will be based on the PDPP population, unless 
otherwise specified. 
8.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Augmentation index and PWV data is expected to have minimal missing data, therefore 
these data points will not be imputed if missing. 
8.2.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10 List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 8.2.1 will be 
summarised using descriptive statistics and listed. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
18 
 
9. 
REFERENCES 
• GlaxoSmithKline Document Number 2016N291495_02. A randomized, repeat dose, 
open label, parallel group, multi-center study to evaluate the effect of daprodustat 
compared to darbepoetin alfa on forearm blood flow in participants with anemia of 
chronic kidney disease that are not dialysis dependent; 07-Aug-2019. 
• GUI_137354: Information for Authors – Reporting and Analysis Plan, Global; GSK. 
• Iverson C, Christiansen S, Flanagin A, et al. AMA Manual of Style: A Guide for 
Authors and Editors. 10th ed. New York, NY: Oxford University Press; 2007. 
• Medicines and Healthcare Products Regulatory Agency. Recombinant human 
erythropoietins: New advice for prescribing. Drug Safety Update. 2007; 1:2. 
• SOP_54838: Development, Review & Approval of Reporting & Analysis Plan, 
Global; GSK. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
19 
 
10. 
APPENDICES 
10.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
10.1.1. 
Exclusions from Per Protocol Population 
There is no important protocol deviation identified in the study, hence no exclusions for 
per protocol population. 
 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
20 
 
10.2. 
Appendix 2: Schedule of Activities 
10.2.1. 
Protocol Defined Schedule of Activities 
Procedure 
Screening1 
Treatment Period2 
Follow-up3 
Up to 30 Days 
Day 1 
Repeat 
Day 117 
Day 14 
Day 28 
Day 42 
Repeat 
Day 4217 
 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X4 
 
 
 
 
 
 
Physical examinations, Medical 
History, Demographics 
X 
X5 
 
 
 
 
 
 
HemoCue Hgb 
X 
X6 
X 
X 
X 
X 
X 
 
eGFR 
X 
 
 
 
 
 
 
 
Vital signs 
X 
X6 
X 
X 
X 
X 
X 
X 
Clinical chemistry7  
X 
 
 
 
 
X 
 
X 
Hematology7 
X 
X 
 
X 
X 
X 
 
X 
Serum pregnancy test (FRP only) 
X 
 
 
 
 
 
 
 
Urine pregnancy test (FRP only)8 
 
X 
X 
X 
X 
X 
X 
X 
Folate & Vitamin B12 
X 
 
 
 
 
 
 
 
12 Lead ECG 
X 
X6 
 
 
 
X 
 
X 
Ferritin & TSAT 
X 
 
 
 
 
 
 
 
hs-CRP 
X 
X 
 
 
 
X 
 
 
Females only: FSH9 
X 
 
 
 
 
 
 
 
5Brachial artery palpation 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Daprodustat administration10 
 
<====================================================> 
 
Darbepoetin alfa administration10 
 
X10 
X 
X 
See 
footnote 
18 
 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
21 
 
Procedure 
Screening1 
Treatment Period2 
Follow-up3 
Up to 30 Days 
Day 1 
Repeat 
Day 117 
Day 14 
Day 28 
Day 42 
Repeat 
Day 4217 
 
Study treatment adjustment11 
 
 
 
 
X 
 
 
 
Liver chemistry monitoring 
 
 
 
X 
X 
 
 
 
International Normalized Ratio (INR)12 
X 
X 
X 
 
 
X 
X 
 
Hepatitis B and C screening13 
X 
 
 
 
 
 
 
 
HbA1c, lipids7 
 
X 
 
 
 
 
 
 
Forearm Blood Flow (FBF)14 
 
X 
X 
 
 
X 
X 
 
Pulse Wave Velocity (PWV)14 
 
X 
X 
 
 
X 
X 
 
AE and SAE Assessment 
X15 
X 
X 
X 
X 
X 
X 
X 
Blood draw for storage biomarkers16 
 
X 
 
 
 
X 
 
 
Review concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
1 All participants will undergo screening assessments within 30 days of enrolment. 
2 Allowable time window  2 days except for the forearm blood flow (FBF) & pulse wave velocity (PWV) as noted. 
3 Allowable time window  3 days. Follow up will occur 7-14 days ± 3 following completion of the last FBF procedure. See Section 8.2 for guidance regarding EW 
participants.  
4 Eligibility criteria to be assessed prior to performance of the FBF procedure include HemoCue hemoglobin (Hgb), vital signs & 12-lead electrocardiogram (ECG). 
5 Only a brief physical exam on Day 1. 
6 As detailed in Exclusion Criteria (Section 6.2). 
7 Clinical chemistry, hematology and other laboratory tests as listed in Appendix 2. 
8 Local urine pregnancy testing will be standard for protocol unless serum testing is required by local regulations or Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC). 
9 As detailed in Inclusion Criteria (Section 6.1). 
10 The initial dose of study treatment will be after the Day 1/Repeat Day 1 FBF & PWV procedures.  Participants will receive EITHER daprodustat OR darbepoetin alfa.  
The final dose of daprodustat will be Day 41 (i.e., the day prior to the FBF & PWV procedures), while the final dose of darbepoetin alfa will be Day 28. If repeat procedures 
are needed the dosing will be extended (See Section 9.6.1.4). 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
22 
 
11 See Section 7.2 for details on study treatment adjustment 
12 Applies only to participants on anti-coagulant therapy; further details concerning measurement of the international normalised ratio (INR) and subsequent actions can be 
found in the study reference manual (SRM). 
13 If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required 
14 The FBF & PWV assessments are to be performed following confirmation of INR < 3.0 for participants on anticoagulant therapy.  The Day 42 FBF & PWV assessments 
can be delayed up to 1 week (i.e., Day 49)., while randomization (Day 1) should be delayed until the participant’s INR < 3.0 (Section 9.6.1.1). 
15 Only serious adverse events (SAEs) assessed as related to study participation are collected at this visit.  See Appendix 4 for additional details. 
16 As described in Section 9.8 
17Indicates the procedures to be performed on the repeat visits only if the visit is deemed necessary. See Section 9.6.1.4. 
18Darbepoetin is only to be given on Day 42 if a Repeat Day 42 is needed. 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
23 
 
10.3. 
Appendix 3: Assessment Windows 
10.3.1. 
Definitions of Assessment Windows for Analyses 
Data for continuous variables will be summarized according to the scheduled visit time 
period for which they were recorded in the eCRF. Unscheduled assessments will not be 
slotted to a particular time point but will remain as unscheduled if they are either 
summarized or listed unless otherwise specified. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
24 
 
10.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
10.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
study treatment start and stop dates. 
Study Phase 
Definition 
Pre-Treatment  
Date < Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date ≤ Date ≤ Study Treatment Stop Date + 1 day 
Post-Treatment 
Date > Study Treatment Stop Date + 1 day 
• 
If the treatment stop date is missing and the treatment start date is non-missing, then the assessment will be 
considered On-Treatment. 
10.4.1.1. Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before 28 days prior to screening visit 
Concomitant 
Any medication that is not a prior 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
10.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• 
If AE onset date is on or after treatment start date & on or before treatment stop 
date + 1 day  
• 
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 1 
day. 
NOTES:  
• 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
• 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
25 
 
10.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
10.5.1. 
Reporting Process 
Software 
• 
The SAS Version 9.4 or above will be used. 
Reporting Area 
HARP Server 
: US1SALX00259 
HARP Compound 
: arenv/arprod/ GSK1278863/mid205767/final_01 
Analysis Datasets  
• 
Analysis datasets will be created according to Clinical Data Interchange Standards Consortium 
(CDISC) standards: Study Data Tabulation Model (SDTM) implementation guide (IG) Version 3.1.3 
with some updates from Version 3.2, Analysis data model (ADaM) IG Version 1.1, and GSK ADaM 
specification template. 
• 
For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from system independent (SI) to SDTM. 
Generation of RTF Files 
• 
Rich text format (RTF) files will be generated for Tables 
10.5.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
• 
Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject 
level listings should be located in the modular appendices as ICH or non-ICH listings 
• 
In all displays (TFLs) the term “Subjects” will be used to refer to the “Participants”. 
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:  
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
26 
 
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the subject’s listings.  
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables and/or figures. 
• 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
Note 
• 
All displays (TFL) will use the term 'Subjects' (i.e. reflect GSK Display Standards and CDISC 
SDTM/ADaM standards) 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
27 
 
10.6. 
Appendix 6: Derived and Transformed Data 
10.6.1. 
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. 
• 
If there are two values for time points other than the baseline within a time window (as per Section 
10.3.1), the value closest to the target day for that window will be used. If values are the same 
distance from the target, then the mean will be taken. 
Study Day 
• 
Calculated as the number of days from First Dose Date: 
• 
Ref Date = Missing              → Study Day = Missing  
• 
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
• 
Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
Screening and Washout visits 
• 
Rescreened subject’s data will only be counted once, the latest visit will only be summarized. 
 
10.6.2. 
Study Population 
Demographics 
Body Mass Index (BMI) 
• 
Calculated as Weight (kg) / [Height (m)]2 
Extent of Exposure 
• 
Number of days of exposure to study drug will be calculated based on the formula:  The study 
duration will be assigned based on exposure date and by default will assign as 1 day for each date (if 
there is any repetation in the date we will consider only one record). Since there is no exposure end 
date collected for the study, we will be assigning by default value as 1 day. However, we are 
checking duplication in the bakend. 
• 
Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure.  
• 
The cumulative dose will be based on the formula: Sum of each record in incremental order on all 
previous records and current record value get added as cumulative. 
• 
If there are any treatment breaks during the study, exposure data will be adjusted accordingly. 
10.6.3. 
Safety 
Laboratory Parameters 
• 
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a 
character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment 
field) is present, the number of significant digits in the observed values will be used to determine how 
much to add or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 Significant Digits = ‘< x’ becomes x – 0.01 
o Example 2: 1 Significant Digit = ‘> x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
28 
 
Laboratory Parameters 
• 
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a 
character value starting with ‘x’ or ‘x’ is present, then the corresponding numeric value will be set 
equal to x. 
• 
If there is more than one laboratory value on the same date for the same laboratory test, then the 
laboratory values associated with scheduled visits will be used. 
• 
The following will be used to convert laboratory values from SI units to conventional units if the 
specific lab value is not already in this format. [Iverson, 2007]: 
• 
Hemoglobin and MCHC: Divide the g/L value by 10 to get the g/dL value. 
• 
TSAT: If unit is not percentage then multiply with 100 to get the % value. 
• 
Lab values that are converted will be reported in place of original value 
• 
Heart rate and pulse rate can be used interchangeably 
• 
Total calcium and calcium can be used interchangeably 
• 
Total protein and protein can be used interchangeably 
• 
Total bilirubin and bilirubin can be used interchangeably 
• 
TSAT and transferrin saturation can be used interchangeably 
• 
Folate and Vitamin B9 can be used interchangeably 
• 
Baseline HGB will be based either on the pre-dose value on Day 1 or screening value. Any 
unscheduled HGB values taken after the pre-dose value on Day 1 will not be used. 
• 
Scheduled central laboratory HGB values and HemoCue HGB value will be used for report. 
Conversion values (g/L value g/dL) also will be reported.  
PCI Criteria Categories  
• 
PCI criteria categories are: To Low, To w/in Range or No Change, To High 
• 
Subjects with a missing baseline value are to be assumed to have a normal/within range baseline 
value. 
 
10.6.4. 
Pharmacodynamic  
Primary/Principle Secondary/Secondary/Exploratory Endpoints 
FBF Ratio/Absolute FBF 
• 
If either a Day 1 Repeat or Day 42 Repeat measurement is available for forearm blood flow, the 
repeat value will be used instead. 
• 
Forearm blood flow for a given challenge agent dose (infused arm), or for values from the non-
infused arm, will be the mean of 5 continuous time point values. 
• 
Forearm blood flow ratio is defined as the ratio of a subject’s treatment (infused) arm value divided 
by the non-treatment (non-infused) arm value 
o First, the mean of both the infused and non-infused arm will be taken separately for the 
given five measurements before going into the ratio calculation. An example of this is 
shown in the table below: 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
29 
 
Primary/Principle Secondary/Secondary/Exploratory Endpoints 
 
• 
Absolute forearm blood flow is defined as the infused arm value. 
 
Secondary Endpoint 
PWV Dataset 
For the PWV dataset, there are two recorded values for each variable per day, with the option to collect a 
third value if the first two values varied (Refer: SRM) too much from each other. The average of the two 
closest absolute values will be used for analysis purposes. 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
30 
 
10.7. 
Appendix 7: Reporting Standards for Missing Data 
10.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Participant study completion (i.e. as specified in the protocol) was defined as a 
participant who has completed all phases of the study including the last visit or the 
last scheduled procedure 
• 
Withdrawn subjects were not replaced in the study. 
• 
All available data from participants 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.  
• 
Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be 
summarised as withdrawal visits. 
10.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
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. 
10.7.2.1. Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in subject listing displays. 
Adverse Events 
• 
The eCRF allows for the possibility of partial dates (i.e., only month and year) 
to be recorded for AE start and end dates; that is, the day of the month may 
be missing. In such a case, the following conventions will be applied for 
calculating the time to onset and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before 
the start date of study treatment; in this case the study treatment start 
date will be used and hence the event is considered On-treatment as per 
Appendix 4: Study Phases and Treatment Emergent Adverse Events. 
o Missing Stop Day: Last day of the month will be used, unless this is after 
the stop date of study treatment; in this case the study treatment stop 
date will be used. 
o Missing Start Month: ‘January’ will be used unless this makes the start 
date before the month of start of study treatment; in this case the month 
of study treatment start will be used. 
o Missing Stop Month: ‘December’ will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be 
used. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
31 
 
Element 
Reporting Detail 
• 
Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing. 
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 recorded partial date will be displayed in listings. 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
32 
 
10.8. 
Appendix 8: Values of Potential Clinical Importance 
10.8.1. 
Laboratory Values 
Hematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hemoglobin 
g/dL 
 
< 8 g/dL 
> 13 g/dL 
Platelet Count 
GI/L or x109/ L 
 
< 80 GI/L 
> 500 GI/L 
WBC Count  
GI/L or x109/ L 
 
< LLRR 
> 5x ULRR 
Neutrophils 
GI/L or x109/ L 
 
< 0.5 GI/L 
  
Lymphocytes 
GI/L or x109/ L 
 
< 0.5x LLRR 
  
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin 
g/L 
 
< 30 g/L 
> 55 g/L 
AST (SGOT) 
U/L 
 
  
>= 3x ULRR 
ALT (SGPT) 
U/L 
 
  
>= 3x ULRR 
Total billirubin 
Umol/L 
 
  
>= 2x ULRR 
Potassium 
mmol/L 
 
> 0.5 mmol/L below 
LLRR 
> 1.0 mmol/L above 
ULRR 
Sodium (serum) 
mmol/L 
 
< 130 mmol/L 
> 150 mmol/L 
 
Iron Parameters 
Test Analyte 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Serum ferritin 
ug/l 
 
< 100 ug/l 
> 800 ug/l 
TSAT 
Percent 
 
<15% 
> 40% 
 
10.8.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
<= 80 mmHg 
>= 160 mmHg 
Diastolic Blood Pressure 
mmHg 
<= 50 mmHg 
>= 100 mmHg 
Heart Rate 
bpm 
<= 40 bpm 
>= 110 bpm 
Note: 
At visits where BP and HR are assessed in triplicate, the average of the 3 values will be used to assess PCI criteria. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
33 
 
10.8.3. 
FBF 
Agent 
Units 
Clinical Concern Range 
FBF Infused Arm 
FBF Non-Infused Arm 
Lower 
Upper 
Lower 
Upper 
Saline 
mL/min 
0.01 
15.0 
0.01 
15.0 
ACH 
µg/min 
0.01 
150.0 
0.01 
30.0 
SNP 
µg/min 
0.01 
150.0 
0.01 
30.0 
LNMMA 
µmol/min 
0.01 
15.0 
0.01 
15.0 
 
10.8.4. 
PWV 
PWV Parameter 
 
Units 
Clinical Concern Range 
Lower 
Upper 
Average Systolic BP (Seated & Supine) 
mmHg 
<= 80 mmHg 
>= 160 mmHg 
Average Diastolic BP (Seated & Supine) 
mmHg 
<= 50 mmHg 
>= 100 mmHg 
Central Systolic Pressure               
mmHg 
<= 80 mmHg 
>= 160 mmHg 
Central Diastolic Pressure             
mmHg 
<= 50 mmHg 
>= 100 mmHg 
Mean Arterial Pressure                  
mmHg 
<= 40 mmHg 
>= 200 mmHg 
Central Pulse Pressure                  
mmHg 
<= 10 mmHg 
>= 200 mmHg 
Peripheral Pulse Pressure 
mmHg 
<= 10 mmHg 
>= 200 mmHg 
Central Augmentation Pressure     
mmHg 
<= -50 mmHg 
>= 100 mmHg 
Central Augmentation Index          
% 
-30 
60 
Heart Rate 
bpm 
<= 40 bpm 
>= 110 bpm 
Aortic Tr 
msec 
<=0 msec 
>=1000 msec 
Carotid to Femoral Distance 
mm 
<= 200 mm 
>= 1500 mm 
Pulse Wave Velocity 
msec 
<= 2 msec 
>= 35 msec 
Notch to Carotid Distance 
mm 
<= 10 mm 
>= 200 mm 
Notch to Femoral Distance 
mm 
<= 200 mm 
>= 1500 mm 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
34 
 
10.9. 
Appendix 9: Abbreviations & Trademarks 
10.9.1. 
Abbreviations 
Abbreviation 
Description 
ACH 
Acetylcholine, 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIX 
Augmentation Index 
BP 
Blood Pressure 
CDISC 
Clinical Data Interchange Standards Consortium 
CKD 
Chronic Kidney Disease 
DBF 
Database Freeze 
DBR 
Database Release 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
FBF 
Forearm Blood Flow 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
FPD 
Future Pipeline Discovery 
GSK 
GlaxoSmithKline 
HR 
Heart Rate 
ICH 
International Conference on Harmonization 
IDSL 
Integrated Data Standards Library 
L-NMMA 
L-NG-monomethyl arginine citrate 
PCI 
Potential Clinical Importance  
PCPS 
Projects, Clinical Platforms, and Sciences 
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PDPP 
Pharmacodynamic Per Protocol 
PP 
Per Protocol 
PWV 
Pulse Wave Velocity 
QC 
Quality Control 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
rhEPO 
Recombinant Human Erythropoietin 
SAC 
Statistical Analysis Complete 
SDTM 
Study Data Tabulation Model 
SNP 
Sodium Nitroprusside 
SOP 
Standard Operation Procedure 
SRM 
Study Reference Manual 
TFL 
Tables, Figures & Listings  
10.9.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
SAS 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
35 
 
10.10. 
Appendix 10: List of Data Displays 
10.10.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Study Population 
1.1 to 1.6 
Safety 
2.1 to 2.9 
Pharmacodynamic 
3.1 to 3.10 
Section 
Listings 
ICH Listings 
1 to 16 
Other Listings 
17 to 20 
 
10.10.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays. 
Section 
Table 
Listing 
Safety 
SAFE1 
- 
Pharmacodynamic 
PD_T1 to PD_T5 
PD_L1 to PD_L2 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
10.10.3. 
Deliverables 
Delivery 
Description 
SAC 
Final Statistical Analysis Complete 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
36 
 
10.10.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
Safety 
ES1  
Summary of Subject Status and Subject Disposition for the 
Study Conclusion Record 
ICH E3, FDAAA, EudraCT 
SAC 
1.2. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements 
SAC 
1.3. 
Enrolled 
NS1 
Summary of Number of Participant by Country and Site ID 
EudraCT/Clinical Operations 
SAC 
Demographic and Baseline Characteristics 
1.4. 
Safety 
DM1 
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
SAC 
1.5. 
Enrolled 
DM11 
Summary of Age Ranges 
EudraCT 
SAC 
1.6. 
Safety 
DM6 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT 
SAC 
 
10.10.5. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Chemistry  
2.1.  
Safety 
SAFE1 
Summary of Chemistry lab values 
ICH E3 
SAC 
2.2.  
Safety 
LB1 
Summary of Chemistry Changes from Baseline  
ICH E3 
SAC 
Laboratory: Hematology 
2.3.  
Safety 
SAFE1 
Summary of Hematology Values 
ICH E3 
SAC 
2.4.  
Safety 
LB1 
Summary of Hematology Changes from Baseline 
ICH E3 
SAC 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
37 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Other Screening Tests 
2.5.  
Safety 
SAFE1 
Summary of other screen test lab values 
ICH E3 
SAC 
ECG 
2.6.  
Safety 
SAFE1 
Summary of ECG Values 
IDSL 
SAC 
2.7.  
Safety 
EG2 
Summary of Change from Baseline in ECG Values 
IDSL 
SAC 
Vital Signs 
2.8.  
Safety 
SAFE1 
Summary of Vital Signs 
ICH E3 
SAC 
2.9.  
Safety 
VS1 
Summary of Change from Baseline in Vital Signs 
ICH E3 
SAC 
 
10.10.6. 
Pharmacodynamic Tables 
Pharmacodynamic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Primary Endpoint 
3.1.  
PDPP 
PD_T1 
Summary of Forearm Blood Flow Ratio in Response to 
Acetylcholine  
 
SAC  
3.2.  
PDPP 
PD_T2 
Summary of Change in Forearm Blood Flow Ratio (Day 1 to 
Day 42), Acetylcholine 
 
SAC  
Principle Secondary Endpoint 
3.3.  
PDPP 
PD_T3 
Summary of Change in Absolute Forearm Blood Flow (Day 1 to 
Day 42), Acetylcholine 
 
SAC  
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
38 
 
Pharmacodynamic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Secondary Endpoints 
3.4.  
PDPP 
PD_T2 
Summmary of Change in Forearm Blood Flow Ratio (Day 1 to 
Day 42), Sodium Nitroprusside 
 
SAC  
3.5.  
PDPP 
PD_T3 
Summary of Change in Absolute Forearm Blood Flow (Day 1 to 
Day 42), Sodium Nitroprusside 
 
SAC  
3.6.  
PDPP 
PD_T2 
Summary of Change in Forearm Blood Flow Ratio (Day 1 to 
Day 42), L-NMMA 
 
SAC 
3.7.  
PDPP 
PD_T3 
Summary of Change in Absolute Forearm Blood Flow (Day 1 to 
Day 42), L-NMMA 
 
SAC 
3.8.  
PDPP 
PD_T4 
Summary of Augmentation Index and Pulse Wave Velocity  
 
SAC  
3.9.  
PDPP 
PD_T5 
Summary of Change in Augmentation Index (Day 1 to Day 42) 
 
SAC  
3.10. 
PDPP 
PD_T5 
Summary of Change in Pulse Wave Velocity (Day 1 to Day 42) 
 
SAC  
10.10.7. 
ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
Journal Guidelines 
SAC  
2.  
Enrolled 
ES2  
Listing of Reasons for Study Withdrawal 
ICH E3 
SAC  
3.  
Safety 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
SAC  
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
39 
 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Protocol Deviations 
4.  
Safety 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
SAC  
5.  
Safety 
IE3  
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
SAC  
Demographic Characteristics 
6.  
Safety 
DM2 
Listing of Demographic Characteristics 
ICH E3 
SAC  
Prior and Concomitant Medications 
7.  
Safety 
CM10 
Listing of Concomitant Medications 
IDSL 
SAC  
8.  
Safety 
MH2 
Listing of Medical Conditions 
IDSL 
SAC 
Exposure  
9.  
Safety 
EX3  
Listing of Exposure Data 
ICH E3 
SAC  
Adverse Events 
10.  
Safety 
AE8  
Listing of All Adverse Events 
ICH E3 
SAC  
Serious Adverse Events 
11.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3 
SAC  
12.  
Safety 
AE8  
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment 
ICH E3 
SAC  
All Laboratory 
13.  
Safety 
LB5  
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance/Outside Normal Range 
ICH E3 
 
SAC 
14.  
Safety 
LB14 
Listing of Laboratory Data with Character Results 
ICH E3 
SAC  
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
40 
 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ECG 
15.  
Safety 
EG5 
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding 
IDSL 
 
SAC  
Vital Signs 
16.  
Safety 
VS4  
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance 
IDSL 
 
SAC  
 
10.10.8. 
Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Primary Endpoint 
17.  
PDPP 
PD_L1 
Listing of Forearm Blood Flow 
 
SAC  
18.  
PDPP 
PD_L2 
Listing of All Forearm Blood Flow Data for Participants with Any 
Value of Potential Clinical Importance 
 
 
SAC  
Secondary Endpoint 
19.  
PDPP 
PD_L3 
Listing of Pulse Wave Velocity and Augmentation Index 
 
SAC  
20.  
PDPP 
PD_L4 
Listing of All Pulse Wave Velocity and Augmentation Index 
Data for Participants with Any Value of Potential Clinical 
Importance 
 
 
SAC  
 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
41 
 
10.11. 
Appendix 11: Example Mock Shells for Data Displays 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
42 
 
Example:    SAFE1 
 
 
 
 
 
 
 
 
 
                 Page 1 of n 
Protocol: 205767  
 
 
 
 
 
 
 
 
 
 
 
Population: Safety  
Table 2.1 
Summary of Lab Values 
 
 
Parameter 
 
 
Treatment 
 
 
N    
 
Visit  
 
 
n 
 
 
Mean 
 
 
SD 
 
 
Min 
 
 
P25 
 
 
Median 
 
 
P75 
 
 
Max 
 
 
 
 
 
 
 
 
 
 
 
 
HGB 
(g/dL) 
Dapro 
xxxx   Screening [1] 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
  
  
Day 1 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
  
  
Repeat Day 1 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
 
 
Day 14 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
 
 
Day 28 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
 
 
Day 42 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
 
 
Repeat Day 42 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
 
 
Follow-up   
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
rhEPO 
xxxx   Screening [1] 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
  
  
Day 1 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
  
  
Repeat Day 1 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
 
 
Day 14 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
 
 
Day 28 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
 
 
Day 42 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
 
 
Repeat Day 42 
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
 
 
Follow-up   
Xxxx 
xx.x 
xx.xx 
Xx 
xx.x 
xx.x 
xx.x 
Xx 
 
[1] Screening is an average of all screening values. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
43 
 
Example: PD_T1 
 
 
 
 
 
 
 
 
 
 
 
 
        Page 1 of n 
Protocol: 205767 
Population: PDPP 
Table 3.1 
Summary of Forearm Blood Flow Ratio in Response to Acetylcholine  
Treatment: Daprodustat  
 
FBF Control Arm          FBF Infused Arm       Ratio [1] 
                                                                   
        Challenge Agent             
Day 1    Day 42     
 Day 1     Day 42      
       ---------------------------------------------------------------------------------------------- 
        Saline         n              3        3     
 3          3  
3 
                     
 Mean           1.75    1.75    
 1.75       1.75       1.75 
                     
 SD             0.834   0.834    
 0.834      0.834      0.834 
                     
 Median         1.65    1.65    
 1.65       1.65       1.65 
                     
 Min.           1.0     1.0     
 1.0        1.0        1.0 
                    
 Max            1.4     1.4     
 1.4        1.4        1.4 
 
        7.5 ug         n              3        3     
 3          3  
3 
                     
 Mean           1.75    1.75    
 1.75       1.75       1.75 
                     
 SD             0.834   0.834    
 0.834      0.834      0.834 
                     
 Median         1.65    1.65    
 1.65       1.65       1.65 
                     
 Min.           1.0     1.0     
 1.0        1.0        1.0 
                    
 Max            1.4     1.4     
 1.4        1.4        1.4 
 
        15 ug        
 n              3        3     
 3          3  
3 
                     
 Mean           1.75    1.75    
 1.75       1.75       1.75 
                     
 SD             0.834   0.834    
 0.834      0.834      0.834 
                     
 Median         1.65    1.65    
 1.65       1.65       1.65 
                     
 Min.           1.0     1.0     
 1.0        1.0        1.0 
                    
 Max            1.4     1.4     
 1.4        1.4        1.4 
 
 
[1] The Day 42 ratio is calculated by taking the subject’s Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment 
(control) arm value. The Day 1 ratio is calculated by taking the subject’s Day 1 treatment (infused) arm and dividing by the Day 1 non-
treatment (control) arm value. The overall ratio is determined by taking the subject’s Day 42 ratio and dividing by the Day 1 ratio. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
44 
 
Example: PD_T2 
 
 
 
 
 
 
 
 
 
 
 
 
        Page 1 of n 
Protocol: 205767 
Population: PDPP 
Table 3.2 
Summary of Change in Forearm Blood Flow (FBF) Ratio (Day 1 to Day 42), Acetylcholine 
 
          
                                                                   
        Challenge Agent            Daprodustat  
 
rhEPO   
Change in FBF Ratio [2] 
 
 
 
 
    FBF Ratio [1]      
FBF Ratio [1]      
       ---------------------------------------------------------------------------------------------- 
        Saline         n              3        
 
3    
 
 3           
 
                     
 Mean           1.75     
 
1.75      
 1.75             
                     
 SD             0.834    
 
0.834    
 0.834            
                     
 Median         1.65     
 
1.65      
 1.65             
                     
 Min.           1.0      
 
1.0              1.0              
                    
 Max            1.4      
 
1.4       
 1.4            
 
        7.5 ug         n              3        
 
3    
 
 3           
 
                     
 Mean           1.75     
 
1.75      
 1.75             
                     
 SD             0.834    
 
0.834    
 0.834            
                     
 Median         1.65     
 
1.65      
 1.65             
                     
 Min.           1.0      
 
1.0              1.0              
                    
 Max            1.4      
 
1.4       
 1.4            
 
        15 ug        
 n              3        
 
3    
 
 3           
 
                     
 Mean           1.75     
 
1.75      
 1.75             
                     
 SD             0.834    
 
0.834    
 0.834            
                     
 Median         1.65     
 
1.65      
 1.65             
                     
 Min.           1.0      
 
1.0              1.0              
                    
 Max            1.4      
 
1.4       
 1.4            
 
[1] The Day 42 ratio is calculated by taking the subject’s Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment 
(control) arm value. The Day 1 ratio is calculated by taking the subject’s Day 1 treatment (infused) arm and dividing by the Day 1 non-
treatment (control) arm value. The overall ratio is determined by taking the subject’s Day 42 ratio and dividing by the Day 1 ratio. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
45 
 
[2] The FBF ratio difference between Daprodustat and rhEPO. 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
46 
 
Example: PD_T3 
Protocol: 205767                                                                                 Page 1 of n 
Population: PDPP 
                                                 Table 3.3 
                               Summary of Change in Absolute FBF (Day 1 to Day 42), Acetylcholine 
 
                                            
   Treatment          Challenge Agent   N Visit    n  Mean     SD    Median  Min.  Max. 
   ------------------------------------------------------------------------------------------------------ 
   Dapro  
 
     Saline     4  AVG. Day 1               4   1.06   6.695    1.50    0.7   1.7 
                                          AVG. Day 42              4  -0.17   5.722    0.17   -0.6   0.5 
                                            
                            7.5 ug     4  AVG. Day 1               4   1.06   6.695    1.50    0.7   1.7 
                                          AVG. Day 42              4  -0.17   5.722    0.17   -0.6   0.5 
                                            
   
 
 
     15 ug      4  AVG. Day 1               4   1.06   6.695    1.50    0.7   1.7 
                                          AVG. Day 42              4  -0.17   5.722    0.17   -0.6   0.5 
 
                            30 ug      4  AVG. Day 1               4   1.06   6.695    1.50    0.7   1.7 
                                          AVG. Day 42              4  -0.17   5.722    0.17   -0.6   0.5 
 
   rhEPO 
 
    Saline      4  AVG. Day 1               4   1.06   6.695    1.50    0.7   1.7 
                                          AVG. Day 42              4  -0.17   5.722    0.17   -0.6   0.5 
                                            
                            7.5 ug     4  AVG. Day 1               4   1.06   6.695    1.50    0.7   1.7 
                                          AVG. Day 42              4  -0.17   5.722    0.17   -0.6   0.5 
 
   
 
 
     15 ug      4  AVG. Day 1               4   1.06   6.695    1.50    0.7   1.7 
                                           AVG. Day 42             4  -0.17   5.722    0.17   -0.6   0.5 
 
                            30 ug      4  AVG. Day 1               4   1.06   6.695    1.50    0.7   1.7 
                                          AVG. Day 42              4  -0.17   5.722    0.17   -0.6   0.5 
 
 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
47 
 
Example: PD_T4 
 
 
 
 
 
 
 
 
 
 
 
 
        Page 1 of n 
Protocol: 205767 
Population: PDPP 
Table 3.8 
Summary of Augmentation Index and Pulse Wave Velocity  
 
 
 
 
 
          
        
 
 
 
     
           
                                                                   
        Treatment 
 
             
 
Day 1    Day 42     
       
       -------------------------------------------------------------------------- 
        Dapro 
  
 Augmentation   n              3        3     
         
 
         
 
 Index           Mean          25.0     25.0    
              
                     
  
 
  SD             0.15    0.15    
             
                     
  
 
  Median         25.5    25.5    
            
                     
  
 
  Min.           20      20     
  
                  
                    
  
 
  Max            30      30     
  
                 
 
         
 
Pulse Wave     n              3        3     
            
 
         
 
Velocity       Mean           7.75    7.75    
        
         
 
  
 
 SD             0.834   0.834    
  
                     
  
 
 Median         6.65    6.65    
  
                     
  
 
 Min.           7.0     7.0     
  
                    
  
 
 Max            9.5     9.5     
  
 
       rhEPO 
  
 Augmentation   n              1        1    
         
 
         
 
 Index           Mean          25.0     25.0    
              
                     
  
 
  SD             0.15    0.15    
             
                     
  
 
  Median         25.5    25.5    
            
                     
  
 
  Min.           20      20     
  
                  
                    
  
 
  Max            30      30     
  
                 
 
         
 
 
Example: PD_T5 
Protocol: 205767                                                                                 Page 1 of n 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
48 
 
Population: PDPP 
                                                 Table 3.9 
                               Summary of Change in Augmentation Index and Pulse Wave Velocity (Day 1 to Day 42) 
 
                                            
   Treatment            
 
 N Visit 
 
    n  Mean     SD    Median  Min.  Max. 
   ------------------------------------------------------------------------------------------------------ 
   Dapro  
   Augmentation Index   4  AVG. Day 1              3   24.0   6.69    24.5     20    30 
                                          AVG. Day 42              3   -2.0   5.72     -2.5    -2    -3 
                                            
                  Pulse Wave Velocity  4  AVG. Day 1               3   7.75   6.695    7.50    6.0   9.5 
                                          AVG. Day 42              3  -0.50   5.722    1.50   -0.5   0.5 
                                            
   
 
 
      
   rhEPO 
   Augmentation Index   4  AVG. Day 1               3   24.0   6.69    24.5     20    30 
                                          AVG. Day 42              3   -2.0   5.72     -2.5    -2    -3 
                                            
                  Pulse Wave Velocity  4  AVG. Day 1               3   7.75   6.695    7.50    6.0   9.5 
                                          AVG. Day 42              3  -0.50   5.722    1.50   -0.5   0.5 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
Example  
: PD_L1 
 
 
 
 
 
 
 
 
Page 1 of n 
Protocol 
: 205767 
Population 
: PDPP 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0


 
CONFIDENTIAL 
 
 
 
205767 
 
49 
 
Listing 17 
Listing of Forearm Blood Flow 
 
 
Treatment 
Unique Subject 
Id./ 
Subject Id. 
Age 
(YEARS)/ 
Sex/ 
Race 
Detail 
 
Visit 
Challeng
e Agent 
Challenge 
Agent 
Dose  
Infusion 
Drug Unit 
Avg.Infus
ed Arm 
Avg.Non-
infused 
Arm 
FBF 
Rati
o 
 
 
 
 
 
 
 
 
 
 
Dapro 
65/ 
F/ 
ASIAN - 
JAPANESE 
HERITAGE 
Day1 
1 
1 
mL/min 
1.2 
1.3 
1.22 
 
 
 
 
 
 
POST 
DOSE 
2 
7.5 
µg/min 
1.4 
1.01 
1.33 
 
 
 
rhEPO 
65/ 
F/ 
MIXED 
RACE 
PRE-
DOSE 
1 
1 
mL/min 
1.2 
1.3 
1.22 
 
 
 
 
 
Example  
: PD_L2 
 
 
 
 
 
 
 
 
Page 1 of n 
Protocol 
: 205767 
Population 
: PDPP 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0
PPD
PPD


 
CONFIDENTIAL 
 
 
 
205767 
 
50 
 
Listing 18 
Listing of All Forearm Blood Flow Data for Participants with Any Value of Potential Clinical Importance 
 
 
Treatment 
 
 
 
 
Arm 
Unique Subject 
Id./ 
Subject Id. 
Age 
(YEARS)/ 
Sex/ 
Race 
Detail 
 
Visit/ 
Date[Time] 
Saline 
(mL/min) 
Ach 
(µg/min) 
SNP 
(µg/min) 
LNMMA 
(µmol/min) 
 
Dapro 
 
 
 
 
 
 
 
 
 
 
FBF - infused 
arm 
65/ 
F/ 
ASIAN - 
JAPANESE 
HERITAGE 
PRE-DOSE/ 
2002-01-01 
T14:00 
xx H 
xx L 
xx H 
xx H 
 
  
 
 
 
POST DOSE/ 
2002-01-01 
T14:00 
 
 
xx H 
xx L 
xx H 
xx H 
 
FBF – non 
infused arm 
65/ 
F/ 
ASIAN - 
JAPANESE 
HERITAGE 
PRE-DOSE/ 
2002-01-01 
T14:00 
xx H 
xx L 
xx H 
xx 
H 
 
 
 
 
 
 
 
 
 
rhEPO 
FBF - infused 
arm 
65/ 
F/ 
MIXED 
RACE 
PRE-DOSE/ 
2002-01-01 
T14:00 
xx H 
xx L 
xx H 
xx H 
Note:(PCI) Potential Clinical Importance Flag: L=Low, H=High 
 
Example  
: PD_L3 
 
 
 
 
 
 
 
 
Page 1 of n 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0
PPD
PPD
PPD


 
CONFIDENTIAL 
 
 
 
205767 
 
51 
 
Protocol 
: 205767 
Population 
: PDPP 
Listing 19 
Listing of Pulse Wave Velocity and Augmentation Index 
 
Treatment 
Unique Subject 
Id./ 
Subject Id. 
Age 
(YEARS)/ 
Sex/ 
Race Detail 
 
Visit/Planned 
Time/ 
ECG Date[Time] 
Pulse wave 
velocity test 
(unit) 
Pulse 
wave 
result 
 
 
 
 
 
 
 
 
Dapro 
 
 
65/ 
F/ 
ASIAN - JAPANESE 
HERITAGE 
 
Day1/PRE-
DOSE/ 
2002-01-01 
T14:00 
 
Central 
Diastolic BP 
(mmHg) 
 
xx 
 
 
 
 
 
 
 
 
POST DOSE/ 
2002-01-01 
T14:00 
Central 
Diastolic BP 
(mmHg) 
xx 
 
 
 
 
 
 
 
 
 
rhEPO 
 
 
65/ 
F/ 
MIXED RACE 
 
PRE-DOSE/ 
2002-01-01 
T14:00 
 
Central 
Diastolic BP 
(mmHg) 
 
xx 
 
 
 
 
 
 
 
 
 
 
Example  
: PD_L4 
 
 
 
 
 
 
 
 
Page 1 of n 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0
PPD
PPD


 
CONFIDENTIAL 
 
 
 
205767 
 
52 
 
Protocol 
: 205767 
Population 
: PDPP 
Listing 20 
Listing of All Pulse Wave Velocity and Augmentation Index Data for Participants with Any Value of Potential Clinical Importance 
 
 
Treatment 
Unique Subject 
Id./ 
Subject Id. 
Age 
(YEARS)/ 
Sex/ 
Race 
Detail 
 
Visit/Plan
ned 
relative 
Time/ 
Date[Time] 
Central 
Diastoli
c BP 
(mmHg) 
Central 
Systoli
c BP 
(mmHg) 
Heart 
Rate 
(bpm) 
Pulse 
Wave 
Velocit
y 
 
 
 
.... 
 
Dapro 
 
 
 
 
 
 
 
 
 
 
65/ 
F/ 
ASIAN - 
JAPANESE 
HERITAGE 
Day1/PRE-
DOSE/ 
2002-01-01 
T14:00 
xx H 
xx L 
xx H 
xx H 
 
 
 
 
 
 
 
 
 
rhEPO 
 
POST DOSE/ 
2002-01-01 
T14:00 
xx H 
xx L 
xx H 
xx H  
 
65/ 
F/ 
ASIAN - 
JAPANESE 
HERITAGE 
PRE-DOSE/ 
2002-01-01 
T14:00 
xx H 
xx L 
xx H 
xx 
H 
 
 
 
 
 
 
 
 
 
 
 
 
Note:(PCI) Potential Clinical Importance Flag: L=Low, H=High 
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0
PPD
PPD


Signature Page for  205767 TMF-2204610 v1.0
Signature Page for TMF-2204610 v1.0
Reason for signing: Approved
Name: 
Role: Author
Date of signature: 10-Nov-2020 13:46:45 GMT+0000
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 10-Nov-2020 13:59:49 GMT+0000
205767 | Statistical Analysis Plan  RAP 10 Nov 2020 | TMF-2204610 | 1.0
PPD
PPD