Conditions: Anaemia
Keywords: GSK1278863 pharmacokinetics mass balance daprodustat
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: yes

Brief summary:
Absorption, metabolism and excretion of daprodustat (GSK1278863) have been studied in previous clinical trials; however, the elimination routes and metabolic pathways of daprodustat have not been fully elucidated in humans. This is an open-label, single-center, non-randomized, 2-period, single-sequence, crossover, mass balance study in 6 healthy male participants. The aim of the study is to assess the excretion balance of daprodustat using \[14C\]-radiolabeled drug substance administered orally, and as an intravenous (IV) infusion, administered as a microtracer dose (concomitant with an oral, non-radiolabeled dose). Absolute bioavailability of an oral dose will also be assessed. Each participant will be involved in the study for up to 10 weeks which include a screening visit, two treatment periods (treatment periods 1 and 2), separated by about 7 days (at least 14 days between oral doses), and a follow up visit 1-2 weeks after the last assessment in treatment period 2. The primary objective of the study is to gain a better understanding of the compound's excretory and metabolic profile. This study will include sampling of duodenal bile to conduct qualitative assessment of drug metabolites in this matrix in order to characterize biliary elimination pathways.

Detailed description:

Arms:
arm 1: Each participant will receive a single 6 milligram (mg) oral dose of daprodustat on Day 1 of period 1. After approximately 1 hour, participants will receive 50 microgram (µg) of \[14C\]-GSK1278863 by IV infusion over 1 hour. On Day 1 of period 2, each participant will receive 25 mg \[14C\]-GSK1278863 as an oral solution.

Interventions: intervention 1: [14C]-GSK1278863 solution for IV infusion intervention 2: [14C]-GSK1278863 oral solution intervention 3: Daprodustat 6 mg oral tablet
Intervention descriptions: intervention 1: It is a clear, colorless solution free from visible particulate matter. Participants will receive 10 mL of 5 µg/mL of \[14C\]-GSK1278863 IV solution (total dose: 50 µg) by IV infusion over 1 hour. intervention 2: It is a clear, colorless solution. Participants will receive 125 mL of 200 µg/mL of \[14C\]-GSK1278863 oral solution (total dose: 25 mg). intervention 3: It is a 9.0 millimeter (mm) round, white film coated tablet.

Protocol document:
Prot_000.pdf: 
2017N310967_01
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200232
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TITLE PAGE
Protocol Title: An open-label study in healthy male participants to determine the mass 
balance, absolute bioavailability and pharmacokinetics of daprodustat, administered as a 
single intravenous microtracer (concomitant with an oral dose of non-radiolabelled 
daprodustat) and a single, oral radiolabelled dose
Protocol Number: 200232
Short Title: Absorption and elimination of radiolabelled daprodustat
Compound Number:
GSK1278863 (daprodustat)
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
GSK Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual (SRM).
HMR Physician Name and Emergency Contact Number:
Dr 
(mobile)
Regulatory Agency Identifying Number(s):
IND number: 101,291
EudraCT number: 2017-001729-42
Approval Date: 01-SEP-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
01-Sep-2017
Original Protocol
30-May-2017
Amendment 01 01-SEP-2017
Overall Rationale for the Amendment: This amendment is required by regulatory 
authority. 
Section # 
and Name
Description of Change
Brief Rationale
9.2.1. Time 
Period and 
Frequency for 
Collecting AE 
and SAE 
Information
“Promptly” has been changed to 
“within 24 hours following 
knowledge of the SAE.”
Clarification of “promptly.”
9.2.5. 
Regulatory 
Reporting 
Requirements 
for SAEs
“Prompt” has been changed to 
“within 24 hours following 
knowledge of an SAE.”
Clarification of “prompt.”


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................7
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................10
3.
INTRODUCTION....................................................................................................15
3.1.
Study Rationale ..........................................................................................15
3.2.
Background ................................................................................................15
3.2.1.
Anaemia of CKD..........................................................................15
3.2.2.
Daprodustat (GSK1278863).........................................................16
3.3.
Benefit/Risk Assessment ............................................................................16
3.3.1.
Benefit Assessment.....................................................................16
3.3.2.
Overall Benefit:Risk Conclusion...................................................17
4.
OBJECTIVES AND ENDPOINTS...........................................................................18
5.
STUDY DESIGN ....................................................................................................19
5.1.
Overall Design ............................................................................................19
5.2.
Number of Participants ...............................................................................21
5.3.
Participant and Study Completion...............................................................21
5.4.
Scientific Rationale for Study Design ..........................................................21
5.5.
Dose Justification........................................................................................22
6.
STUDY POPULATION...........................................................................................23
6.1.
Inclusion Criteria.........................................................................................23
6.2.
Exclusion Criteria........................................................................................24
6.3.
Lifestyle Restrictions...................................................................................27
6.3.1.
Meals and Dietary Restrictions ....................................................27
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................27
6.3.3.
Activity .........................................................................................28
6.4.
Screen Failures...........................................................................................28
7.
TREATMENTS.......................................................................................................28
7.1.
Treatments Administered............................................................................29
7.2.
Dose Modification .......................................................................................29
7.3.
Method of Treatment Assignment ...............................................................29
7.4.
Blinding.......................................................................................................29
7.5.
Preparation/Handling/Storage/Accountability..............................................30
7.6.
Treatment Compliance................................................................................30
7.7.
Concomitant Therapy..................................................................................31
7.8.
Treatment of Study Treatment Overdose....................................................31
7.9.
Treatment after the End of the Study ..........................................................31
8.
DISCONTINUATION CRITERIA.............................................................................32
8.1.
Discontinuation of Study Treatment ............................................................32
8.1.1.
Liver Chemistry Stopping Criteria ................................................32
8.2.
Withdrawal from the Study..........................................................................33
8.3.
Lost to Follow Up........................................................................................33


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8.4.
Study Stopping Criteria...............................................................................34
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................34
9.1.
Screening and Critical Baseline Assessments ............................................35
9.2.
Adverse Events...........................................................................................35
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................35
9.2.2.
Method of Detecting AEs and SAEs.............................................36
9.2.3.
Follow-up of AEs and SAEs.........................................................36
9.2.4.
Adverse Events of Special Interest (AESI)...................................36
9.2.5.
Regulatory Reporting Requirements for SAEs .............................37
9.2.6.
Pregnancy ...................................................................................37
9.3.
Safety Assessments ...................................................................................37
9.3.1.
Physical Examinations.................................................................37
9.3.2.
Vital Signs....................................................................................38
9.3.3.
Electrocardiograms......................................................................38
9.3.4.
Clinical Safety Laboratory Assessments ......................................38
9.4.
Pharmacokinetics .......................................................................................39
9.5.
Urine Sample collection ..............................................................................39
9.6.
Faecal Sample Collection ...........................................................................39
9.7.
Bile Sample Collection................................................................................40
9.8.
Sample Analysis .........................................................................................40
9.9.
Pharmacodynamics ....................................................................................40
9.10.
Genetics .....................................................................................................40
9.11.
Biomarkers .................................................................................................40
10. DATA MANAGEMENT ...........................................................................................41
11. STATISTICAL CONSIDERATIONS........................................................................41
11.1.
Sample Size Assumptions ..........................................................................41
11.1.1.
Sample Size Sensitivity................................................................41
11.1.2.
Sample Size Re-estimation or Adjustment...................................41
11.2.
Data Analysis Considerations .....................................................................41
11.2.1.
Analysis Populations....................................................................41
11.2.1.1.
Screened Population ..................................................41
11.2.1.2.
All Subjects Population...............................................42
11.2.1.3.
Pharmacokinetic Population .......................................42
11.2.2.
Interim Analysis ...........................................................................42
11.3.
Key Elements of Analysis Plan ...................................................................42
11.3.1.
Pharmacokinetic Analyses...........................................................42
11.3.2.
Metabolite profiling.......................................................................43
11.3.3.
Safety Analyses...........................................................................43
12. REFERENCES.......................................................................................................44
13. APPENDICES........................................................................................................45
13.1.
Appendix 1: Abbreviations and Trademarks................................................45
13.2.
Appendix 2: Risk Assessment.....................................................................48
13.3.
Appendix 3: An assessment of the radiation dose to male 
volunteers from the oral and IV administration of the study treatment.........57
13.4.
Appendix 4:  Clinical Laboratory Tests........................................................67
13.5.
Appendix 5: Study Governance Considerations..........................................69


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13.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................73
13.7.
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................78
13.8.
Appendix 8: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................79
13.9.
Appendix 9: Protocol Amendment 01..........................................................82


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1.
SYNOPSIS
Protocol Title: An open-label study in healthy male participants to determine the mass 
balance, absolute bioavailability and pharmacokinetics of daprodustat, administered as a 
single intravenous microtracer (concomitant with an oral dose of non-radiolabelled 
daprodustat) and a single, oral radiolabelled dose.
Short Title: Absorption and elimination of radiolabelled daprodustat
Rationale:
Absorption, metabolism and excretion of daprodustat (GSK1278863) have been studied 
in pre-clinical animals models, in vitro, and in previous clinical trials; however, the 
elimination routes and metabolic pathways of daprodustat have not been fully elucidated 
in humans. The absorption, metabolism and excretion of daprodustat must be adequately 
described in human subjects as part of the clinical development of this compound.
This study will use the Entero-Test (HDC Corp., Mountain View, CA; or alternative 
source, subject to commercial availability) for sampling of duodenal bile to conduct 
qualitative assessment of drug metabolites in this matrix in order to characterise biliary 
elimination pathways. Samples from this study will also be transferred to a separate 
study to characterise and quantify the metabolites of daprodustat in plasma, urine, faeces, 
and duodenal bile.
Objectives and Endpoints:
Objectives
Endpoints1
Primary

To determine total radioactivity (drug related 
material) in blood and plasma following a 
single IV microtracer dose of 
[14C]-GSK12788631 (concomitant with an oral 
dose of non-radiolabelled daprodustat1) and a 
single, oral dose of [14C]-GSK1278863.

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2 of total 
drug-related material (radioactivity) in blood 
and plasma.

Volume (Vss) and clearance (CL) of total drug-
related material (radioactivity) after IV dose 
only (Period 1).

To determine the rate and extent of excretion 
of total radioactivity in urine and faeces and the 
total recovery of radioactivity following a single, 
oral dose of [14C]-GSK1278863.

Urinary and faecal cumulative excretion as a 
percentage of the total radioactive dose 
administered over time (Treatment Period 2 
only).


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Objectives
Endpoints1
Secondary

To determine parent daprodustat and 
metabolite concentrations in plasma following 
a single IV microtracer dose of [14C]-
GSK1278863 and both oral doses of 
daprodustat.

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2 of
daprodustat parent and metabolite in plasma 
from the IV dose and both oral doses.

Volume (Vss) and clearance (CL) of 
daprodustat parent and metabolite (if possible) 
after IV dose only (Period 1).

To estimate the absolute bioavailability of 
daprodustat following oral administration.

F (absolute bioavailability) after oral dosing.

To generate samples that will be used to 
characterize the metabolite profile of 
daprodustat following a single IV microtracer 
dose of [14C]-GSK1278863 concomitant with 
an oral dose of non-radiolabelled daprodustat 
(plasma and duodenal bile) and a single, oral 
dose of [14C]-GSK1278863 (plasma, urine and 
faeces).

Characterization and quantification of 
metabolites in plasma, urine, faeces, and 
duodenal bile (these analytical investigations 
will be conducted and the results reported 
under a separate GSK protocol).

To evaluate the safety and tolerability of 
daprodustat after single IV and oral doses in 
healthy participants.

Incidence and severity of adverse events.

Laboratory safety, 12-lead ECG, and vital 
signs parameters.
1 For measured concentrations of daprodustat in blood and plasma, the nomenclature [14C]-GSK1278863 
describes the parent daprodustat concentration derived via analysis by liquid chromatography (LC) + 
Accelerator Mass Spectrometry (AMS), whereas daprodustat describes the parent daprodustat 
concentration derived via liquid chromatography-tandem mass spectrometry (LC/MS).
Overall Design:
This is an open-label, single-centre, non-randomised, 2-period, single-sequence, 
crossover, mass balance study in 6 healthy male participants. The aim of the study is to 
assess the excretion balance of daprodustat (GSK1278863) using [14C]-radiolabelled drug 
substance administered orally, and as an IV infusion, administered as a microtracer dose 
(concomitant with an oral, non-radiolabelled dose). Absolute bioavailability of an oral 
dose will also be assessed.
Safety data will include AE reporting, 12-lead ECG, vital signs, and laboratory safety
tests. Blood will be sampled extensively on the day of dosing, and daily until Day 7, for 
assessing the PK of daprodustat and metabolites.
Number of Participants:
6 healthy male participants will be enrolled.
If one or more participants prematurely discontinue the study, replacement participants 
may be enrolled at the discretion of the sponsor and in consultation with the investigator.


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Replacement subjects may be required to complete one or both treatment periods, at the 
discretion of the sponsor.
Treatment Periods and Duration:
Each participant will be involved in the study for up to 10 weeks. He will have a 
screening visit, two treatment periods (Treatment Periods 1 and 2), separated by about 
7 days (at least 14 days between oral doses), and a follow up visit 1-2 weeks after the last 
assessment in Treatment Period 2. During both treatment periods, participants will reside 
in the unit from the afternoon before Day 1 (Day -1) until all procedures are completed 
on Day 7. Participants may be asked to stay for up to 1 week longer in Treatment 
Period 2, if excretion of drug-related material takes longer than anticipated.
Treatment Period 1 (oral tablet and intravenous infusion)
On Day 1 of Treatment Period 1, after an overnight fast of at least 8 h, each participant 
will take a single 6 mg oral dose of daprodustat; participants will continue to fast for 4 h 
after dosing.  After approximately 1 h, participants will receive 50 µg of [14C]-
GSK1278863 (approximately 4.63 kBq; 125 nCi) by IV infusion over 1 h.  Blood
samples will be collected for 144 h after oral dosing (until Day 7), while duodenal bile 
will be collected by Entero-Test as described below.  Participants will be discharged on 
study Day 7 after completion of the 144 h sample collection.
The Entero-Test to collect duodenal bile will be used only in Treatment Period 1. The 
Entero-Test will be swallowed about 3.5 h before the oral dose, a duration recommended 
to allow transit of the Entero-Test to the duodenum, while participants are in a fasted 
state. It will be removed about 3 h after the oral dose (about 1 h after the end of the IV 
infusion), a time when the oral dose is expected to have transitioned from the stomach to
the duodenum. At about 0.5 h after the start of IV infusion (i.e., 1.5 h before string 
withdrawal) a food cue will be used to stimulate gall bladder emptying.
Treatment Period 2 (oral solution)
On Day 1 of Treatment Period 2, after an overnight fast of at least 8 h, each participant 
will receive 25 mg [14C]-GSK1278863 (approximately 2.31 MBq; 62.5 µCi) as an oral 
solution; participants will continue to fast for 4 h after dosing.  Blood, urine and faecal 
samples will be collected for a minimum of 144 h (up to Day 7) after dosing, depending 
on the amount of radioactivity excreted by each participant.  Radioactivity quantification 
using liquid scintillation counting (LSC) will be performed daily on the 24-h urine 
collections and 24-h faecal homogenates on Day 6 (96–120 h) and Day 7 (120–144 h).
Based on the radioquantitification results on Days 6 and 7, participants will be asked to 
do the following:

If  ≥ 90% of the administered radioactivity has been recovered and less than 1% 
of the dose is excreted on both Day 6 (96–120 h) and Day 7 (120–144 h) for a 
given participant, he may be discharged on Day 8 (after the LSC results are 
available), and no further samples will be collected.  Drug Metabolism and 


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Pharmacokinetics (DMPK) at GSK should be consulted to agree with release of a 
participant.

If excretion is higher than 1% in the 96–144 h (Day 6–7) collection period, or if 
the results are inconclusive, the participant will remain at the unit, and urine and 
faecal collections will continue at 24-h intervals for up to 7 additional days (until 
the morning of Day 14).  Once less than 1% of the dose is excreted in 
2 consecutive 24-h periods where samples are provided, or ≥ 90% of the 
radioactivity has been recovered, the participant will be discharged.  All 
remaining participants will be discharged from the unit no later than Day 15.

In the unlikely event that excretion is still higher than 1% in the 24-h collection 
period prior to discharge on Day 15, the participant will continue to collect faecal 
samples only, at home, at 24-h intervals.  Samples will be returned to the unit 
every 2 to 3 days for analysis.
2.
SCHEDULE OF ACTIVITIES (SOA)
The SoA for Treatment Period 1 and Treatment Period 2 is presented in Table 1 and 
Table 2, respectively.
The timing and number of planned study assessments, including safety and 
pharmacokinetic 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 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment 
of the Informed Consent (ICF).


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Table 1
SoA: Treatment Period 1 (oral tablet and intravenous infusion)
Visit
Screening1
Treatment Period 1
Day
Procedure
-30 to -1
-1
1
2
3
4
5
6
7
hour
Pre-
dose
0
0.5
1
1.25
1.5
2
3
4
6
8
10
12
24
36
48
72
96
120
144
Informed consent
X
Medical history 
(including drug/alcohol 
use)
X
Demography
X
Admission to unit
X
Discharge from unit2
X
Full physical exam, 
including height,weight
and BMI
X
Brief physical exam 
X
X
Drugs of abuse screen 
X
X
Alcohol and cotinine 
tests, CO breath tests 
X
X
HIV and hepatitis B and 
C screen
X
Laboratory safety tests 
(including LFTs)
X
X
X
12-lead ECG3
X
X
Vital signs3,4
X
X
X
X
[14C]-GSK1278863 IV 
infusion 
Oral daprodustat5
X
Blood samples for drug 
assay and radioactivity6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine collection7
X


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Visit
Screening1
Treatment Period 1
Day
Procedure
-30 to -1
-1
1
2
3
4
5
6
7
hour
Pre-
dose
0
0.5
1
1.25
1.5
2
3
4
6
8
10
12
24
36
48
72
96
120
144
Faecal collection7
X
Entero-Test (duodenal 
bile)8
Meals8,9
X
X
X
AE/SAE/concomitant 
medication review10
Abbreviations: AE: adverse event; ECG: electrocardiogram; HIV: human immunodeficiency virus; IV: intravenous; LFTs: liver function tests; SAE: serious adverse event.
Notes:
1 Screening will be within 30 days before Day 1.
2 Participants will be discharged for a washout period prior to dosing in Treatment Period 2; there will be at least 14 days between a participant’s oral doses. Participants who withdraw from the study early 
should be subject to those assessments that would be required at discharge in that treatment period, if participants agree to that.
3 Single ECG measurements will be taken at at all time points. If any measurement is considered abnormal, triplicate measurements will be taken and the mean of the triplicate measurements used.  The
pre-dose measurement on Day 1 will be used as baseline.
4 Triplicate measurements of systolic and diastolic blood pressure; single measurements of oral temperature and respiratory rate.
5 Participants will fast for at least 8 h before oral dosing.
6 Samples will be taken for background radiation at screening, Day –1 and pre-dose only, while total radioactivity, [14C]-GSK1278863 analysis, cold daprodustat analysis, and metabolite profiling will 
include predose and all post-dosing samples. Sampling times are relative to the oral dose on Day 1, unless otherwise indicated.
7 Urine and faeces will be collected at pre-dose (up to 3 h pre-dose for the urine sample; up to 48 h pre-dose for the faecal sample).
8 The Entero-Test will be swallowed about 3.5 h before the oral dose, while participants are in a fasted state. It will be removed 3 h after the oral dose (about 1 h after the end of the IV infusion). At about 
0.5 h after the start of IV infusion (i.e., 1.5 h before string withdrawal) a food cue will be used to stimulate gall bladder emptying.
9 Meal times are specified for Day 1 only. On all other days, meals will be served at the unit’s standard times.
10 AEs and SAEs will be collected from the start of oral dosing until the final follow-up visit. However, any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product will be recorded from the time a subject consents to participate in the study.
If assessments are scheduled for the same nominal time, the assessments should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws
4. other assessments
Note: The timing of the assessments should allow the blood draw to occur at the exact nominal time.


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Table 2
SoA: Treatment Period 2 (oral solution)
Visit
Treatment Period 2
FU1
Day
Procedure
-1
1
2
3
4
5
6
72
8–152,3
hour
Pre-
dose
0
0.5
1
1.5
2
3
4
6
8
10
12
24
36
48
72
96
120
144
Admission to unit
X
Discharge from unit4
X
X
Brief physical exam 
X
X
X
X
Drugs of abuse screen 
X
Alcohol and cotinine 
tests, CO breath tests
X
Laboratory safety tests 
(including LFTs)
X
X
X
X
12-lead ECG5
X
X
X
Vital signs5,6
X
X
X
X
X
[14C]-GSK1278863 oral 
solution7
X
Blood samples for drug 
assay and radioactivity8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine collection9
X
Faecal collection9
X
Meals10
X
X
AE/SAE/concomitant 
medication review11


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Abbreviations: AE: adverse event; ECG: electrocardiogram; FU: follow-up; HIV: human immunodeficiency virus; LFTs: liver function tests; SAE: serious adverse event.
Notes:
1 Follow-up will be 7–14 days after the participant’s last assessment.
2 Urine and faecal samples will be collected for a minimum of 144 h (up to Day 7) after dosing, depending on the amount of radioactivity excreted by each participant. Liquid scintillation 
counting (LSC) will be performed daily on 24-h urine collections and 24-h faecal homogenates on Day 6 (96–120 h) and Day 7 (120–144 h). If less than 1% of the dose is excreted in 
each of those 24-h periods for a given participant, he may be discharged on Day 8 (after the LSC results from Days 6 and 7 are available), and no further samples will be collected. If 
excretion is higher than 1% in the 96–144 h (Day 6–7) collection period, or if the results are inconclusive, the participant will remain at the unit, and urine and faecal collections will 
continue at 24-h intervals, for up to 7 additional days (until the morning of Day 14). Once less than 1% of the dose is excreted in a 24-h period, or ≥ 90% of the radioactivity has been 
recovered, that participant will be discharged. Any remaining participants will be discharged from the unit on Day 15. In the unlikely event that excretion is still higher than 1% in the 
24-h collection period prior to discharge on Day 15, the participant will continue to collect faecal samples only, at home, at 24-h intervals. Samples will be returned to the unit every 2 to 
3 days for analysis.
3 Brief physical exam, laboratory safety tests, 12-lead ECG and vital signs to be done only on the day of discharge. Blood samples for drug assay and radioactivity to be taken each 
morning (at the time of dosing on Day 1) until Day 7.
4 Participants withdrawing from the study early should be subject to those assessments that would be required at discharge.
5 Single ECG measurements will be taken at at all time points.  If any measurement is considered abnormal, triplicate measurements will be taken and the mean of the triplicate 
measurmements used.  The pre-dose measurement on Day 1 will be used as baseline.
6 Triplicate measurements of systolic and diastolic blood pressure; single measurements of oral temperature and respiratory rate.
7 Participants will fast for at least 8 h before oral dosing.
8 Samples will be taken for background radiation pre-dose only, while total radioactivity, [14C]-GSK1278863 analysis, cold GSK1278863 analysis, and metabolite profiling will include 
predose and all post-dosing samples.
9 Urine and faeces will be collected at pre-dose (up to 3 h pre-dose for the urine sample; up to 48 h pre-dose for the faecal sample), then over 24 h collection periods as follows: 0–24 h, 
24‒48 h, 48–72 h, 72–96 h, 96–120 h and 120–144 h. If participants are required to stay after Day 7, collections will continue at 24-h intervals. An aliquot from each collection period 
will be taken for metabolic profiling (separate study).
10 Meal times are specified for Day 1 only. On all other days, meals will be served at the unit’s standard times.
11 AEs and SAEs will be collected until the final follow-up visit.
If assessments are scheduled for the same nominal time, the assessments should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws
4. other assessments
Note: The timing of the assessments should allow the blood draw to occur at the exact nominal time.


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3.
INTRODUCTION
Daprodustat (GSK1278863) is an orally-available, small molecule which inhibits 
hypoxia-inducible factor (HIF) prolyl-4-hydroxylases (PHDs), and is being studied for 
treatment of anaemia of chronic kidney disease (CKD).
3.1.
Study Rationale
Absorption, metabolism and excretion of daprodustat (GSK1278863) have been studied 
in pre-clinical animals models, in vitro, and in previous clinical trials; however, the 
elimination routes and metabolic pathways of daprodustat have not been fully elucidated 
in humans. The absorption, metabolism and excretion of daprodustat must be adequately 
described in human subjects as part of the clinical development of this compound.
This open-label study in 6 healthy male participants will assess the excretion balance of 
daprodustat in humans using [14C]-radiolabelled drug substance administered as an 
intravenous (IV) infusion and orally. [14C]-GSK1278863 administered by IV infusion 
will be a microtracer; therefore, it will be administered concomitant to an oral non-
radiolabelled dose, to ensure that the pharmacokinetics (PK) are representative of a 
clinically-relevant dose. The study will also provide an assessment of bioavailability of 
daprodustat following administration of a [14C]-radiolabelled oral solution.
Since biliary excretion has been shown as a predominant elimination route in preclinical 
species for daprodustat, this study will use the Entero-Test (HDC Corp., Mountain View, 
CA; or alternative source, subject to commercial availability) for sampling of duodenal 
bile to conduct qualitative assessment of drug metabolites in this matrix in order to 
characterise biliary elimination pathways. Samples from this study will also be 
transferred to a separate study to characterise and quantify the metabolites of daprodustat 
in plasma, urine, faeces, and duodenal bile.
3.2.
Background
3.2.1.
Anaemia of CKD
Anaemia is a common complication of CKD. The causes of anaemia in this population is
multi-factorial, including relative or absolute deficiency of erythropoietin (EPO) and
reduced iron availability related to chronic inflammation.
Current treatments for anaemia of CKD include supplemental iron therapy (IV and/or
oral), the use of recombinant human EPO (rhEPO) and blood transfusions. However, 
each of these treatments has significant limitations, including poor compliance, 
gastrointestinal intolerability and increased risk of cardiovascular (CV) complications
(e.g., stroke and myocardial infarction) and cancer-related morbidity and mortality (FDA 
Drug Safety Communication, 2011).
HIF prolyl hydroxylase inhibitors (PHIs), such as daprodustat, are an emerging new class 
of agent under investigation for the treatment of anaemia of CKD. Both pre-clinical and 
clinical data show that daprodustat can increase endogenous EPO levels and 
erythropoiesis with a resultant increase in haemoglobin (Hgb) levels.


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Daprodustat may present several important advantages over rhEPO. It is an oral 
medication and does not require cold-chain storage as does rhEPO, thus increasing ease 
of use for patients. After administration of daprodustat, data suggest that increases in 
Hgb are achieved with EPO exposures lower than that observed with rhEPO. Treatment 
of anaemia of CKD with rhEPO is associated with increased CV risk which is postulated 
to be related to the associated increases in EPO exposure with rhEPO [Szczech, 2008]; 
therefore, daprodustat has the potential to raise Hgb without increasing CV risk.
3.2.2.
Daprodustat (GSK1278863)
Daprodustat stimulates erythropoiesis through inhibition of HIF-PHDs: PHD1, PHD2 and 
PHD3. This activity results in the accumulation of HIFα transcription factors which 
leads to increased transcription of HIF-responsive genes. This biological activity 
simulates components of the natural response to hypoxia. During hypoxia, the PHDs are 
inhibited, resulting in the accumulation of unhydroxylated HIFα subunits, which dimerize 
with HIFβ subunits to induce transcription of HIF-responsive genes, including EPO and 
others involved in increasing oxygen utilisation (transferrin, haem oxygenase 1 (HO-1)).
Other functions regulated by HIFs include iron metabolism and utilization (haemojuvelin, 
and ferroportin), angiogenesis (VEGF), extracellular matrix metabolism, apoptosis, 
energy and glucose metabolism, vascular tone, cell adhesion, and motility.
To date, a total of eleven Clinical Pharmacology studies have been completed.  In all of 
the completed studies daprodustat has been generally well tolerated and no new safety 
concerns have been identified which would preclude further development.  In the Clinical 
Pharmacology program oral daprodustat has been administered to 332 healthy subjects 
(subjects with normal renal function), and 26 subjects with CKD.  In this program, single 
doses of daprodustat between 2 mg and 500 mg and repeat doses between 5 mg and 
100 mg once daily for up to 15 days have been administered.  Daprodustat has not been 
administered IV to human participants in any study conducted to date.
Detailed information relating to non-clinical pharmacology, safety pharmacology, PK 
and metabolism, toxicology and other pre-clinical data can be found in the daprodustat 
Investigator’s Brochure (IB) and supplements.
3.3.
Benefit/Risk Assessment
The potential risks of study treatment and trial procedures, and their mitigation, are given 
in Appendix 2.
More detailed information about the known and expected benefits and risks of 
daprodustat may be found in the IB and supplements.
3.3.1.
Benefit Assessment
As this is a study in healthy volunteers, they will receive no clinical benefit for 
participation in this study.


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3.3.2.
Overall Benefit:Risk Conclusion
Overall, the available data from non-clinical and clinical studies has not identified 
prohibitive risks associated with daprodustat at the exposures planned for this study.
While there are a number of important potential risks identified for daprodustat and the 
study procedures, these can be addressed in clinical trials with proper participant 
selection, close safety monitoring, and specific risk characterisation and mitigation (see 
Appendix 2).


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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints1
Primary

To determine total radioactivity (drug related 
material) in blood and plasma following a 
single IV microtracer dose of 
[14C]-GSK12788631 (concomitant with an oral 
dose of non-radiolabelled daprodustat1) and a 
single, oral dose of [14C]-GSK1278863.

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2 of total 
drug-related material (radioactivity) in blood 
and plasma.

Volume (Vss) and clearance (CL) of total drug-
related material (radioactivity) after IV dose 
only (Treatment Period 1).

To determine the rate and extent of excretion 
of total radioactivity in urine and faeces and the 
total recovery of radioactivity following a single, 
oral dose of [14C]-GSK1278863.

Urinary and faecal cumulative excretion as a 
percentage of the total radioactive dose 
administered over time (Treatment Period 2 
only).
Secondary

To determine parent daprodustat and 
metabolite concentrations in plasma following 
a single IV microtracer dose of [14C]-
GSK1278863 and both oral doses of 
daprodustat.

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2 of
daprodustat parent and metabolite in plasma
from the IV dose and both oral doses.

Volume (Vss) and clearance (CL) of
daprodustat parent and metabolite (if possible) 
after IV dose only (Treatment Period 1).

To estimate the absolute bioavailability of 
daprodustat following oral administration.

F (absolute bioavailability) after oral dosing.

To generate samples that will be used to 
characterise the metabolite profile of 
daprodustat following a single IV microtracer 
dose of [14C]-GSK1278863 concomitant with 
an oral dose of non-radiolabelled daprodustat
(plasma and duodenal bile) and a single, oral 
dose of [14C]-GSK1278863 (plasma, urine and 
faeces).

Characterisation and quantification of 
metabolites in plasma, urine, faeces, and 
duodenal bile (these analytical investigations 
will be conducted and the results reported 
under a separate GSK protocol).

To evaluate the safety and tolerability of 
daprodustat after single IV and oral doses in 
healthy participants.

Incidence and severity of adverse events.

Laboratory safety, 12-lead ECG, and vital sign
parameters.
1 For measured concentrations of daprodustat in blood and plasma, the nomenclature [14C]-GSK1278863 describes the 
parent daprodustat concentration derived via analysis by liquid chromatography (LC) + Accelerator Mass Spectrometry 
(AMS), whereas daprodustat describes the parent daprodustat concentration derived via liquid chromatography-
tandem mass spectrometry (LC/MS).


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5.
STUDY DESIGN
5.1.
Overall Design
This is an open-label, single-centre, non-randomised, 2-period, single-sequence, 
crossover, mass balance study in 6 healthy male participants. The aim of the study is to 
assess the excretion balance of daprodustat (GSK1278863) using [14C]-radiolabelled drug 
substance administered orally, and as an IV infusion, administered as a microtracer dose 
(concomitant with an oral, non-radiolabelled dose). Absolute bioavailability of an oral 
dose will also be assessed.
No formal sample size calculation has been performed for this study; 4 to 6 participants 
are deemed sufficient for this purpose. In order to minimise the number of participants 
exposed to radiation, those participants that discontinue early will not be replaced unless 
the total number of participants who complete dosing and all critical assessments drops 
below 4.
Each participant will be involved in the study for up to 10 weeks. He will have a 
screening visit, two treatment periods (Treatment Periods 1 and 2), separated by about
7 days (at least 14 days between oral doses), and a follow up visit 1-2 weeks after the last 
assessment in Treatment Period 2. During both treatment periods, participants will reside 
in the unit from the afternoon before Day 1 (Day -1) until all procedures are completed 
on Day 7. Participants may be asked to stay for up to 1 week longer in Treatment 
Period 2, if excretion of drug-related material takes longer than anticipated. A schematic 
of the study design is presented in Figure 1.
Safety data will include AE reporting, 12-lead ECG, vital signs, and laboratory safety
tests. Blood will be sampled extensively on the day of dosing, and daily until Day 7, for 
assessing the PK of daprodustat and metabolites.
Figure 1
Study Treatment Schematic
Screening Period
Participants must be screened within 30 days before the first dose of daprodustat, and 
must meet all eligibility criteria.


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Treatment Period 1 (oral tablet and intravenous infusion)
On Day 1 of Treatment Period 1, after an overnight fast of at least 8 h, each participant 
will take a single 6 mg oral dose of daprodustat. After approximately 1 h, participants 
will receive 50 µg of [14C]-GSK1278863 (approximately 4.63 kBq; 125 nCi) by IV 
infusion over 1 h. Blood samples will be collected for 144 h after oral dosing (until Day 
7), while duodenal bile will be collected by Entero-Test as described below. Participants 
will be discharged on study Day 7 after completion of the 144 h sample collection.
The Entero-Test to collect duodenal bile will be used only in Treatment Period 1. The 
Entero-Test will be swallowed about 3.5 h before the oral dose, a duration recommended 
to allow transit of the Entero-Test to the duodenum, while participants are in a fasted 
state. It will be removed about 3 h after the oral dose (about 1 h after the end of the IV 
infusion), a time when the oral dose is expected to have transitioned from the stomach to 
the duodenum [Guiney, 2011]. At about 0.5 h after the start of IV infusion (i.e., 1.5 h 
before string withdrawal) a food cue will be used to stimulate gall bladder emptying.
Treatment Period 2 (oral solution)
On Day 1 of Treatment Period 2, after an overnight fast of at least 8 h, each participant
will receive 25 mg [14C]-GSK1278863 (approximately 2.31 MBq; 62.5 µCi) as an oral 
solution; participants will continue to fast for 4 h after dosing.  Blood, urine and faecal 
samples will be collected for a minimum of 144 h (up to Day 7) after dosing, depending 
on the amount of radioactivity excreted by each participant. Radioactivity quantification 
using liquid scintillation counting (LSC) will be performed daily on the 24-h urine 
collections and 24-h faecal homogenates on Day 6 (96–120 h) and Day 7 (120–144 h).
Based on the radioquantitification results on Days 6 and 7, participants will be asked to 
do the following:

If  ≥ 90% of the administered radioactivity has been recovered and less than 1% 
of the dose is excreted on both Day 6 (96–120 h) and Day 7 (120–144 h) for a 
given participant, he may be discharged on Day 8 (after the LSC results are 
available), and no further samples will be collected.  Drug Metabolism and 
Pharmacokinetics (DMPK) at GSK should be consulted to agree with release of a 
participant.

If excretion is higher than 1% in the 96-144 h (Day 6-7) collection period, or if 
the results are inconclusive, the participant will remain at the unit, and urine and 
faecal collections will continue at 24-h intervals for up to 7 additional days (until 
the morning of Day 14). Once less than 1% of the dose is excreted in 
2 consecutive 24-h periods where samples are provided, or ≥ 90% of the 
radioactivity has been recovered, the participant will be discharged. All 
remaining participants will be discharged from the unit no later than Day 15.

In the unlikely event that excretion is still higher than 1% in the 24-h collection 
period prior to discharge on Day 15, the participant will continue to collect faecal 
samples only, at home, at 24-h intervals. Samples will be returned to the unit 
every 2 to 3 days for analysis.


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Follow-up
Follow-up procedures will be done 7-14 days after the participant’s last assessment in 
Treatment Period 2. The follow-up period may be extended if:
(i)
radioactivity excretion is still higher than 1%;
(ii)
a participant has an unresolved AE at the follow-up visit, which, in the 
opinion of the investigator, merits further follow-up; or
(iii)
new information becomes available that supports an extended follow-up 
period.
The investigator will decide on the nature of the extended follow-up. For example,
participants may have a telephone follow-up at which they are asked about AEs, or 
participants may be asked to attend extra outpatient visits for additional monitoring of 
blood levels and/or for extra safety tests. The extra safety tests might include tests that 
are not described in this protocol. The investigator reserves the right, during or after the 
study, to repeat safety tests or to do any extra safety tests that are in the best interest of 
the participants. Those extra tests may or may not be described in this protocol.
5.2.
Number of Participants
6 healthy male participants will be enrolled.
If one or more participants prematurely discontinue the study, replacement participants 
may be enrolled at the discretion of the sponsor and in consultation with the investigator.
Replacement subjects may be required to complete one or both treatment periods, at the 
discretion of the sponsor.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he has completed all phases of 
the study including the last follow-up visit.
The end of the study is defined as the date of the last contact with the last participant in 
the study.
5.4.
Scientific Rationale for Study Design
In the first treatment period of this study, an IV microtracer dose of [14C]-GSK1278863
will be infused over 1 h. The infusion will be administered after an oral dose of non-
radiolabelled daprodustat. The non-radiolabelled dose of daprodustat is to ensure that the 
PK of the microdose represents a therapeutically-relevant dose. In the second treatment 
period, an oral solution of [14C]-GSK1278863 will be used for comparison.
Metabolic elimination pathways will be characterised after the IV dose by the planned 
inclusion of duodenal bile collection. Complexities in human faecal sample analysis such 
as extraction, stability in the gastrointestinal tract, and endogenous contamination are 
minimised through assessment of the metabolic profile in duodenal bile.


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5.5.
Dose Justification
Daprodustat (GSK1278863) Dose
The dose of [14C]-GSK1278863 to be administered intravenously is a microdose of
50 μg, which will be infused over 1 h. A microdose was selected because daprodustat 
has not previously been administered by IV infusion to humans.  That dose level meets 
the criterion for a microdose, for the following reasons:

It is ≤ 100 µg

It is ≤ 1/100th of the lowest pharmacologically-active oral dose in healthy 
participants with normal renal function (i.e., 15 mg single, oral dose) based on an 
increase in plasma erythropoietin (GSK study PHX111427)

It is ≤ 1/100th the no observed adverse effect level (NOAEL) of 3 mg/kg/day in 
the 39-week monkey where gastric erosions were observed at doses of 
≥10 mg/kg/day
In an in vitro hemolysis assay using human erythrocytes, daprodustat formulations at 
concentrations ≤181.8 µg/mL (containing ethanol/tromethamine buffer) did not produce 
hemolysis when added to human blood.  Additionally, a 50 µg total dose of
[14C]-GSK1278863 will be formulated as a 5 μg/mL solution in 0.9% phosphate-buffered 
saline (pH adjusted between 7 and 8, with a target of 7.5; 10 mL total volume).
To ensure clinically-relevant systemic exposure during the microdose, the IV infusion of 
[14C]-GSK1278863 will be administered concomitant to an oral non-radiolabelled dose. 
Following oral administration, daprodustat is rapidly absorbed (tmax: 1.5 to 2 h) and 
exhibits a dose-proportional increase in exposure over the range 2 mg to 300 mg. The 
terminal half-life of daprodustat is 2.4 to 4 h, and it did not accumulate upon repeated-
dose administration of doses up to 100 mg, once daily, in healthy participants.
The oral non-radiolabelled daprodustat dose is within the therapeutic range for the 
treatment of anaemia of CKD. The 6 mg dose was identified as the dose most likely to 
be administered to haemodialysis-dependent CKD patients based on a longitudinal dose
Hgb-response model [GSK Document Number 2015N248947_00]. The 6 mg dose is 
lower than the highest once-daily dose currently under investigation in the ongoing Phase 
3 studies (24 mg), and is substantially lower than current single, oral dose clinical 
experience (500 mg; GSK study PHI113635).
The planned dose of the oral solution of [14C]-GSK1278863 is 25 mg. That dose is 
similar to the maximum once-daily dose currently under investigation in the ongoing 
Phase 3 studies (24 mg; GSK studies 200807 &200808); it is approximately one-half the 
potentially highest three-times weekly dose (48 mg; GSK study 204837). Therefore, a 
single dose of 25 mg [14C]-GSK1278863 oral solution bridges both the once-daily and 
three-times weekly dosing paradigms.
In summary, the doses selected are suitable to meet the objectives of the study whilst 
minimising exposure of participants to daprodustat.


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Radiolabel Dose
The effective dose of radiolabelled drug administered in human mass balance studies is
calculated from data on the distribution and elimination of the radioactive drug from
laboratory animals, taking into account the nature of the isotope, the concentration of
radioactivity in individual tissues/organs and the residence or elimination half-life of the
radioactivity from those tissues/organs.
In this study, each participant will receive the following doses of radioactivity:

approximately 4.63 kBq (125 nCi) in Treatment Period 1.

approximately 2.31 MBq (62.5 µCi) in Treatment Period 2.
It is estimated that the combined total effective dose for the two treatment periods will be 
<1mSv. On this basis, the maximum administered activity would comply with the ICRP 
1992 recommendation of a 1 mSv maximum for Category IIa projects (further details are 
in Appendix 3).
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Specific information regarding warnings, precautions, contraindications, adverse events,
and other pertinent information on the GSK investigational product is provided in the IB
and IB supplements, if applicable.
Deviations from inclusion and exclusion criteria are not allowed because they can
potentially jeopardize the scientific integrity of the study, regulatory acceptability or
participant safety. Therefore, adherence to the criteria as specified in the protocol is 
essential.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Aged 30 to 55 years, inclusive, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2.
Healthy, as determined by the investigator or medically qualified designee, based on 
a medical evaluation including medical history, physical examination, vital signs, 
laboratory tests, and ECG. A participant with a clinical abnormality or laboratory 
parameter (i.e., outside the reference range for the population being studied), which 
is not specifically listed in the eligibility criteria, may be included only if the 


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investigator agrees and documents that the finding is unlikely to introduce additional 
risk factors and will not interfere with the study procedures.
3.
Haemoglobin value at screening greater than the lower limit of the laboratory 
reference range and less than or equal to 16.0 g/dL.
4.
History of regular bowel movements (averaging one or more bowel movements per 
day).
5.
Non-smoker, or ex-smoker who hasn’t regularly smoked for the 6 months before 
screening.
Weight
6.
Body weight of 50 kg and above, and body mass index (BMI) within the range 19.0–
31 kg/m2 (inclusive).
Sex
7.
Male only.
Participants must agree to use contraception as follows: participants with female 
partners of childbearing potential must agree to use a condom from the time of first 
dose of study treatment until 1 month after their last dose. Further details are given 
in Appendix 7.
Informed Consent
8.
Capable of giving signed informed consent as described in Appendix 5 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
9.
Willingness to give written consent to have data entered into The Overvolunteering 
Prevention System.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). Participants 
with a history of cholecystectomy must be excluded.
2.
Any clinically relevant abnormality identified at the screening medical assessment 
(physical examination/medical history), clinical laboratory tests, or 12-lead ECG.
3.
Miocardial infarction or acute coronary syndrome ≤ 12 weeks prior to screening 
through to enrollment (Day 1, Treatment Period 1).
4.
History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, haematological, or neurological disorders capable of significantly altering 
the absorption, metabolism, or elimination of drugs, or which could constitute a risk 
when taking the study treatment, or interfere with the interpretation of data.


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5.
Evidence of actively bleeding gastric, duodenal or esophageal ulcer disease OR 
clinically significant GI bleeding ≤ 12 weeks prior to screening through to 
enrollment (Day 1, Treatment Period 1).
6.
History of malignancy within the two years before dosing, with the exception of 
localized squamous cell or basal cell carcinoma of the skin that has been definitively 
treated prior to screening; currently receiving treatment for cancer; has a strong 
family history of cancer (e.g., familial cancer disorders).
7.
Mentally or legally incapacitated.
8.
Heart Failure: Class II, III or IV heart failure, as defined by the New York Heart 
Association (NYHA) functional classification system.
9.
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.
Prior/Concomitant Therapy
10. Daprodustat is a substrate of CYP2C8.  Co-administration of drugs that are inhibitors 
of this enzyme are prohibited (see Section 7.7).
11. Past or intended use of over-the-counter or prescription medication including herbal 
medications prior to dosing except occasional use of paracetamol (acetaminophen), 
within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives 
(whichever is longer) prior to the first dose of study treatment until completion of the 
follow-up visit, unless in the opinion of the investigator and GSK Medical Monitor 
the medication will not interfere with the study.
Prior/Concurrent Clinical Study Experience
12. Current enrolment in a clinical trial; recent participation in a clinical trial and has 
received an investigational product within 3 months before their first dose in the 
current study.
13. Exposure to more than 4 new chemical entities within 12 months before their first 
dose in the current study.
14. Participation in a clinical trial involving administration of 14C-labelled compound(s) 
within the last 12 months.  A participant’s previous effective dose will be reviewed 
by the medical investigator to ensure there is no risk of contamination/carryover into 
the current study.
15. Received a total body radiation dose of greater than 10.0 mSv (upper limit of WHO 
category II) or exposure to significant radiation (e.g., serial x-ray or computed 
tomography [CT] scans, barium meal, etc.) in the 3 years before this study.  Further 
details in Appendix 2.


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Diagnostic assessments
16. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).
17. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
18. QTc >500 msec
NOTES:

The QTc must be the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB).

The specific formula that will be used to determine eligibility for an individual 
participant should be determined prior to initiation of the study. In other words, 
several different formulae cannot be used to calculate the QTc for an individual 
participant and then the lowest QTc value used to include the participant from the 
trial.

For purposes of data analysis, QTcB will be used as specified in the Reporting 
and Analysis Plan (RAP).
19. Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C 
antibody test result at screening or within 3 months before the first dose of study 
treatment.
20. Positive pre-study drug/alcohol screen.
21. Positive human immunodeficiency virus (HIV) antibody test.
22. Regular use of known drugs of abuse.
23. Regular alcohol consumption within 6 months prior to the study defined as an 
average weekly intake of >21 units. One unit is equivalent to 8 g of alcohol: a glass
(~240 mL) of beer, 1 small glass (~100 mL) of wine or 1 (~25 mL) measure of 
spirits.
24. At screening, a supine blood pressure BP that is persistently higher than 
140/90 millimeters of mercury (mmHg) taken in triplicate, unless deemed not 
clinically significant by the investigator.
25. At screening, a supine mean heart rate (HR) outside the range of 40–100 beats per 
minute, unless deemed not clinically significant by the investigator.
Other Exclusions
26. Has had an occupation which requires monitoring for radiation exposure, nuclear 
medicine procedures, or excessive x-rays within the past 12 months.
27. Unable to refrain from consumption of prohibited food and drinks (Section 6.3.1)
from 7 days before the first dose of study medication until the follow up visit.
28. Participation in the study would result in donation of blood or blood products in 
excess of 550 mL within a 90 day period.


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29. Unwillingness or inability to follow the procedures outlines in the protocol, 
including the use of the Entero-Test capsule.
30. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products in the 6 months prior to screening.
31. History of drug abuse or dependence within 6 months of the study.
32. History of sensitivity to daprodustat, or their components thereof, or a history of drug 
or other allergy that, in the opinion of the investigator or GSK Medical Monitor, 
contraindicates their participation.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Participants will be required to fast for at least 5 h before laboratory safety tests, 
and for at least 8 h before dosing in both treatment periods.  In both treatment 
periods, participants will also be required to fast for 4 h after dosing.

Meal times are specified in both treatment periods for Day 1 (please refer to the 
SoA, Section 2); on all other days, meals will be served at the standard times of 
the clinical site.

Participants will refrain from consumption of red wine, Seville oranges, grapefruit 
or grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, nuts, seeds or 
fruit juices from 7 days before the start of study treatment until the follow-up 
visit.

Adequate hydration should be encouraged to help facilitate stool sample 
production. If needed, participants may consume prunes or prune juice to 
facilitate stool samples.

No water is allowed until 1.5 h after oral dosing (apart from rinsing the oral 
solution dose of [14C]-GSK1278863); water is allowed ad libitum at all other 
times.
6.3.2.
Caffeine, Alcohol, and Tobacco

During each treatment period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) from 
24 h before admission until discharge from the unit.

Participants will abstain from alcohol for 24 h before the screening visit until the 
follow-up visit.

Use of tobacco- or nicotine-containing products will not be allowed from 
screening until after the final follow-up visit; only non-smokers will be enrolled in 
the study.


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6.3.3.
Activity
Participants will abstain from strenuous exercise from 3 days before screening and until 
their final follow-up visit. Participants may participate in light recreational activities 
during studies (e.g., watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled in the study. 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 serious adverse 
events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.
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.


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7.1.
Treatments Administered
Table 3
Treatments administered during the study
Study Treatment 
Name:
[14C]-GSK1278863 
solution for IV 
infusion
[14C]-GSK1278863 
oral solution
Daprodustat
Dosage formulation:
IV solution
Oral solution
Oral tablet
Unit dose strengths:
Strength: 5 µg/mL
Dosage Level: 50 µg
Strength: 200 µg/mL
Dosage Level: 25 mg
Strength: 6 mg tablet
Dosage Level: 6 mg
Route of 
Administration:
IV
Oral
Oral
Dosing instructions:
Administer 10 mL 
intravenously over 
1 h approximately 1 h
post oral dose
Administer 125 mL in 
the fasted state in the 
morning. Follow with 
125 mL of room 
temperature water 
while rinsing dosing 
container.
One tablet taken in 
the fasted state in the 
morning with 240 mL 
of room temperature 
water
Manufacturer:
Drug product: HMR
Drug product:  HMR
GSK
Physical Description:
A clear, colourless 
solution free from 
visible particulate 
matter
A clear, colorless 
solution
9.0 mm round, white 
film coated tablet
For more information on the preparation of the oral and IV dosing solutions, please refer
to the Study Reference Manual (SRM) and/or Technical Agreement (TA).
7.2.
Dose Modification
There will be no deviation from the treatments listed in Section 7.1 in this study.
7.3.
Method of Treatment Assignment
This is an open-label study; each participant will be assigned to each of the following
treatments in a non-randomised manner:

Treatment Period 1 (IV infusion concomitant with a solid oral dose of 
daprodustat), first;

Treatment Period 2 (oral solution), second.
7.4.
Blinding
This is an open-label study.


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7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorised site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorised site staff.

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).

A description of the methods and materials required for preparation of 
[14C]-GSK1278863 solution for IV infusion and oral administration is provided in 
the SRM and/or TA and will be accompanied by a Quality Agreement.

Further guidance and information for the final disposition of unused study 
treatment are provided in the SRM.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions 
to avoid direct eye or skin contact and the generation of aerosols or mists. In the 
case of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

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.

Dose administrators must follow site-specific procedures for handling 
radiolabelled GSK1278863.
7.6.
Treatment Compliance

Any individual dose for a participant prepared from a bulk supply will be 
confirmed by a second member of the study site staff.

All participants will receive their doses at the site; they will receive study 
treatment directly from the investigator or designee, under medical supervision. 
The date and time of each dose administered in the clinic will be recorded in the 
source documents. The dose of study treatment and study participant
identification will be confirmed at the time of dosing by a member of the study 
site staff other than the person administering the study treatment. For oral doses, 
study site personnel will examine each participant’s mouth to ensure that the 
study treatment was ingested.


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7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and GSK Medical Monitor, the medication will not interfere with the study.
Paracetamol (acetaminophen) at doses of 2 grams/day is permitted for use any time 
during the study. Other concomitant medication may be considered on a case-by-case 
basis by the investigator in consultation with the GSK Medical Monitor.
Special warnings and precautions for use of daprodustat are given in the IB, Section 6 
(Development Core Safety Information (DCSI)).
7.8.
Treatment of Study Treatment Overdose
For this study, any dose of daprodustat greater than those listed in this protocol given 
within a 24-hour time period will be considered an overdose.
There is no specific antidote for overdose with daprodustat. The expected manifestations 
of daprodustat overdosage include signs and symptoms associated with an excessive 
and/or rapid increase in Hgb concentration.
In the event of a suspected overdose, it is recommended that the appropriate supportive 
clinical care be instituted, as dictated by the participant’s clinical status. Additionally, 
subjects should be monitored closely for CV events, increased heart rate and hematologic 
abnormalities.
7.9.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the
study because only healthy volunteers are eligible for study participation.


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8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
A participant may permanently discontinue study treatment at any time at his own 
request, or at the discretion of the investigator for safety or compliance reasons.  A 
participant must permanently discontinue study treatment for the pre-specified reasons 
below.

Haemoglobin value greater than or equal to 16.0 g/dL.

Severe pain, redness, bleeding or swelling at the infusion site.

Liver chemistry abnormalities exceeding the threshold criteria (Section 8.1.1).

Diagnosis of cancer (new or recurrent), with the exception of localized squamous
cell or basal cell carcinoma of the skin.
In all cases, the reason for study treatment discontinuation and the date of the last dose 
will be recorded in the participant’s case report form (CRF) and the participant will be 
withdrawn from the study as described in Section 8.2.
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 the algorithm
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.
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met:


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Figure 2
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 8.
8.2.
Withdrawal from the Study
A participant may withdraw from the study at any time at his own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance or administrative reasons.
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 may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.
Refer to the SoA (see Section 2) for data to be collected at the time of study 
discontinuation. The investigator will record in the source documents the results of 
follow-up examination of withdrawn participants, if the participant gives their consent.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:


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
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). Those contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, only then will he be considered 
to have withdrawn from the study with a primary reason of “lost to follow-up”.
8.4.
Study Stopping Criteria
The trial will be stopped if either of the following occurs:

one or more serious adverse event that is considered to be at least possibly related 
to study treatment.

2 or more severe, clinically significant adverse events that are considered to be at 
least possibly related to study treatment.
If, after an internal safety review, it is appropriate to restart the trial, a substantial 
amendment will be submitted to the Medicines and Healthcare Products Regulatory 
Agency (MHRA) and Independent Ethics Committee (IEC). The trial will not restart 
until the amendment has been approved by the MHRA and IEC.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA (see Section 2).

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the GSK Medical Monitor
immediately upon occurrence or awareness to determine if the participant should 
continue or discontinue study treatment.

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., blood count) and obtained before signing 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).


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
The timing and number of planned study assessments, including safety, and 
pharmacokinetic 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.

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File which is approved by the relevant GSK 
study team member and then archived in the study sponsor and site study files, 
but this will not constitute a protocol amendment.

The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the ICF.

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 550 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Screening and Critical Baseline Assessments
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 6.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 6.
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 (see Section 8).
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (see Section 2).  However, any SAEs 
assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study.

All AEs will be collected from start of treatment until the follow-up visit at the 
time points specified in the SoA (see Section 2).


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
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 case report form (CRF), not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 h, as indicated in Appendix 6. 
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 notify the sponsor within 24 hours following 
knowledge of the SAE.

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 6.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.
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 (as defined in Section 9.2.4) 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 6.
9.2.4.
Adverse Events of Special Interest (AESI)
Adverse Events of Special Interest (AESI) 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 AESI for daprodustat are as follows:

Thrombosis and tissue ischemia secondary to excessive erythropoiesis

Risk of death, MI, stroke, venous thromboembolism, thrombosis of vascular 
access

Cardiomyopathy

Pulmonary artery hypertension

Increased cancer-related mortality and tumor progression and recurrence


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
Manifestations of gastric erosions (e.g., upper GI bleeding, severe abdominal 
pain, upper GI perforations)

Proliferative retinopathy, macular edema, choroidal neovascularization

Exacerbation of rheumatoid arthritis
9.2.5.
Regulatory Reporting Requirements for SAEs

Notification by the investigator to the sponsor within 24 hours following 
knowledge of an SAE is essential so that legal obligations and ethical 
responsibilities towards the safety of participants and the safety of the 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, IRB/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 SAE) from the 
sponsor will review and then file it along with the IB and will notify the IRB/IEC, 
if appropriate according to local requirements.
9.2.6.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until the participant’s final visit.

If a pregnancy is reported, the investigator should inform GSK within 24 h of
learning of the pregnancy and should follow the procedures outlined in Appendix 
6.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (see Section 2).
9.3.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
eyes, skin, joints, and the cardiovascular, respiratory, gastrointestinal and 
neurological systems. Height and weight will also be measured and recorded, and 
BMI calculated.


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
A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.3.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, and pulse and 
respiratory rate.

For time points where vital signs are collected in triplicate, there should be about 
a 2 minute interval between readings.

Baseline will be defined as the mean of the 3 pre-dose measurements taken on 
Day 1 in each treatment period.
9.3.3.
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 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, single ECG measurments are 
appropriate; however, two additional ECGs are required if the initial ECG 
measurement indicates prolonged QTc (i.e., QTcB ≥ 500 msec) using the 
automated or manually calculated QTcB value.  The average QTcB value of all 
three ECGs will be used to determine eligibility.
9.3.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 4 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 CRF. The laboratory reports must be filed with the source 
documents.

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 aetiology should be identified and the sponsor 
notified.


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
All protocol-required laboratory assessments, as defined in Appendix 4, must be 
conducted in accordance with the laboratory manual and the SoA (see Section 2).
9.4.
Pharmacokinetics

Separate whole blood samples will be collected for measurement of each of the 
following as specified in the SoA (see Section 2): blood and plasma total 
radioactivity, [14C]-GSK1278863, plasma concentrations of daprodustat and 
predominant circulating metabolites and metabolite profiling. A maximum of 5 
samples may be collected at additional time points during the study if warranted 
and agreed upon between the investigator and the sponsor. The actual date and 
time (24-h clock time) of each sample will be recorded. The timing of PK 
samples may be altered and/or PK samples may be obtained at additional time 
points to ensure thorough PK monitoring.

Details of PK blood sample collection (including the volumes to be collected), 
processing, storage and shipping procedures are provided in the SRM.

Plasma samples for metabolite profiling will be analysed under a separate GSK 
protocol. The results of these analyses will be reported separately.

For samples used to evaluate the PK of daprodustat and predominant circulating 
metabolites, each plasma sample will be divided into 2 aliquots (1 each for PK, 
and a back-up). Samples collected for analyses of daprodustat plasma
concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study.

Samples will be stored for no longer than 15 years after the end of the trial.
9.5.
Urine Sample collection
Urine samples to measure total radioactivity excreted in urine and for metabolite profiling
(to be conducted in a separate study) will be collected over the time periods specified in 
the SoA (Treatment Period 2 only; see Section 2). All participants will be asked to void 
their bladders before study treatment administration. A blank urine sample will be 
collected pre-dose (up to 3 h before oral dosing) in Treatment Periods 1 and 2. Details of 
urine sample collection, processing, storage and shipping procedures are provided in the 
SRM.
9.6.
Faecal Sample Collection
Faecal samples to measure total radioactivity excreted in faeces and for metabolite 
profiling (to be conducted in a separate study) will be collected over the time periods 
specified in the SoA (Treatment Period 2 only; see Section 2). A faecal sample will be 
collected from each participant before dosing in Treatment Periods 1 and 2 (the pre-dose 
sample can be collected up to 48 h before oral dosing). Details of faecal sample 
collection, processing, storage and shipping procedures are provided in the SRM.


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9.7.
Bile Sample Collection
Bile samples for analysis of metabolites (to be conducted in a separate GSK study) will 
be collected via the Entero-Test in Treatment Period 1 only, as specified in the SoA (see 
Section 2). The Entero-Test comprises a gelatine capsule which contains 90 cm or 
140 cm of nylon string attached to a 1 g steel weight. One end of the string is attached to 
the outside of the mouth before swallowing the capsule, so that it can still be retrieved. 
The gelatine capsule dissolves in the stomach whilst the string and weight continue to the 
duodenum via peristalsis. Following a food cue to stimulate gall bladder emptying the 
string is withdrawn. On withdrawal of the string through the mouth the steel weight 
separates from the string at the pyloric sphincter and is excreted in the faeces. Once the 
string has been removed from the participant it will be frozen and shipped for metabolite 
profiling (to be conducted in a separate study). Full details of the Entero-Test sample 
collection, processing, storage and shipping procedures are provided in the SRM.
9.8.
Sample Analysis
Total radioactivity measurements in urine samples and faecal homogenates will be
determined by LSC and by accelerator mass spectrometry (AMS). Total radioactivity 
measurements from blood and plasma derived from blood will be analysed, as 
appropriate, by LSC and if required AMS, for Treatment Period 1 and Treatment Period 
2, as detailed in the SRM.
[14C]-GSK1278863 and daprodustat plasma concentrations and predominant circulating 
metabolites will be analysed, as appropriate, as detailed in the SRM.
Plasma and aliquots of urine and faecal homogenates will be analysed in a separate GSK 
study for metabolite profiling investigations. Duodenal bile samples collected via the 
Entero-Test will similarly be analysed in a separate GSK study. The results of these 
analyses will be reported separately.
Analysis of all samples (blood, plasma, urine, faeces, and duodenal bile) will be 
performed under the control of Platform Technology and Science (PTS) - BIB
(Bioanalysis, Immunogenicity and Biomarkers) and Mechanistic Safety and Disposition 
(MSD), GlaxoSmithKline, the details of which will be included in the SRM. Raw data 
will be archived at the bioanalytical site (detailed in the SRM).
9.9.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.10.
Genetics
Genetics are not evaluated in this study.
9.11.
Biomarkers
Biomarkers are not evaluated in this study.


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10.
DATA MANAGEMENT

For this study data will be double-entered into a clinical database management
system (ClinPlus Version 3.3).

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) and an internal validated 
medication dictionary, GSKDrug by GSK.

Original CRFs will be retained by GSK, while the investigator will retain a copy.  
Subject initials will not be collected or transmitted to GSK according to GSK 
policy.
11.
STATISTICAL CONSIDERATIONS
11.1.
Sample Size Assumptions
No formal sample size calculation has been performed for this study. The primary
objective of the study is to gain a better understanding of the compound’s excretory and
metabolic profile and 4 to 6 participants are deemed sufficient for this purpose. 
6 participants will be enrolled into the study. In order to minimise the number of 
participants exposed to radiation, those participants that discontinue early will not be 
replaced unless the total number of participants who complete dosing and all critical 
assessments drops below 4.
11.1.1.
Sample Size Sensitivity
Not applicable.
11.1.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
11.2.
Data Analysis Considerations
11.2.1.
Analysis Populations
11.2.1.1.
Screened Population
All participants who sign the ICF. This will be the population for reporting screened 
population data.


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11.2.1.2.
All Subjects Population
All participants who take at least 1 dose of study treatment. Participants will be analysed 
according to the treatment they actually received. This will be the population for 
reporting safety and study population data.
11.2.1.3.
Pharmacokinetic Population
All participants in the ‘Safety’ population for whom sufficient data are available to 
calculate the derived pharmacokinetic parameters on an as-treated basis.  This will be the 
population used for all the pharmacokinetic displays.
11.2.2.
Interim Analysis
No interim analyses will be performed.
11.3.
Key Elements of Analysis Plan
Final analyses will be performed after the completion of the study and final dataset 
authorization.
11.3.1.
Pharmacokinetic Analyses
Plasma daprodustat and metabolite concentration-time data will be listed for each 
participant and summarised by treatment and planned sampling time. [14C]-GSK1278863 
and radioactivity concentrations in plasma will be reported similarly. Individual 
participant, mean and median plasma daprodustat, [14C]-GSK1278863 and total 
radioactivity concentration–time profiles will be plotted for each treatment on both a 
linear and semi-log scale.
Pharmacokinetic analysis will be performed by or under the direct auspices of Clinical 
Pharmacology Modelling & Simulation, GSK. Plasma daprodustat, [14C]-GSK1278863 
and total radioactivity concentration–time data will be analysed by non-compartmental 
methods with WinNonlin Version 6.3 or above. Calculations will be based on the actual 
sampling times recorded during the study. From the plasma concentration-time data the 
following pharmacokinetic parameters will be determined, for daprodustat, 
[14C]-GSK1278863 and total radioactivity, as data permits: maximum observed plasma 
concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve 
[AUC(0–t) and AUC(0-inf)], terminal phase rate constant (λz), and apparent terminal 
phase half-life (t1/2) following oral and IV dosing. Additionally, volume of distribution at 
steady state (Vss) and total systemic clearance (CL) will be derived following IV dosing. 
These parameters will be summarised descriptively.
Absolute bioavailability will be estimated from the oral and IV doses administered in 
Period 1 with Equation 1.


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Equation 1
Further details will be provided in the Reporting and Analysis Plan (RAP).
Derivation of the urine and faecal radioactivity parameters will be the responsibility, or 
under the direct auspices, of the BIB department within GSK. The following parameters 
will be determined from the urine and faecal radiolabelled drug-related material (total 
radioactivity) data, and will be listed and summarised by treatment:

Absolute amount excreted and percentage excreted in urine (Ae[urine] and 
Fe%[urine]) within each collection period and cumulative urinary recovery and 
fraction excreted over the total collection period.

Absolute amount excreted and percentage excreted in faeces (Ae[faecal] and 
Fe%[faecal]) with each collection period and cumulative faecal recovery and 
fraction excreted over the total collection period and cumulatively over the 
collection period.

Total excretion (sum of urine and faecal excretion), Ae [total] and Fe% [total] will 
be calculated by collection interval for each participant. 
The urine, faecal and total radioactivity parameters will be listed, summarised and 
plotted.
All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline 
Pharmaceuticals, R&D. Production of the summaries, listings and figures of the plasma, 
urine and faeces data will be performed under the direct auspices of Clinical Statistics, 
GSK.
Further details regarding the tables, figures and listings to be produced for the study 
report will be given in the RAP.
11.3.2.
Metabolite profiling
The metabolic profiling/structural characterisation aspect of this work will be performed 
by GSK in a separate GSK study and reported separately.
11.3.3.
Safety Analyses
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards. Further details will be given 
in the RAP.


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12.
REFERENCES
FDA Drug Safety Communication: Modified dosing recommendations to improve the 
safe use of Erythropoiesis-Stimulating Agents (ESAs) in chronic kidney disease. 
(Available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm; Posted June 
24, 2011).
Guiney, W.J; Beaumont, C; Thomas, S.R; Robertson, D.C; McHugh, S.M; Koch, A; 
Richards, D; Use of Entero-Test, a simple approach for non-invasive clinical evaluation 
of the biliary disposition of drugs.  Br J Clin Pharmacol. 2011; 72:133-142.
Szczech, L. A.; Barnhart, H. X.; Inrig, J. K.; Reddan, D. N.; Sapp, S.; Califf, R. M.; Patel, 
U. D.; Singh, A. K. Secondary analysis of the CHOIR trial epoetin-alpha dose and 
achieved hemoglobin outcomes. Kidney Int 2008, 74, 791-8.


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13.
APPENDICES
13.1.
Appendix 1: Abbreviations and Trademarks
Table 4
Abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase 
AMS
Accelerator Mass Spectrometry
AUC
Area under concentration-time curve
AUC(0–inf)
Area under the concentration-time curve from time zero (pre-dose)
extrapolated to infinite time
AUC(0–t)
Area under the concentration-time curve from time zero (pre-dose) to
last time of quantifiable concentration within a participant across all
treatments
BCRP
Breast cancer resistant protein
BIB
Bioanalysis, Immunogenicity and Biomarkers
BID
Bis In Die (Twice A Day)
BMI
Body mass index
BP
Blood Pressure
Bq
Becquerel
CKD
Chronic Kidney Disease
Cmax
Maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CV
Cardiovascular 
CYP
Cytochrome P450
DCSI
Development Core Safety Information
DMPK
Drug Metabolism and Pharmacokinetics
ECHO
Echocardiogram
ECG
Electrocardiogram
EPO
Erythropoietin
ESA
Erythropoiesis Stimulating Agent
F
Absolute bioavailability
FDA
Food and Drug Administration
FU
Follow-up
GCP
Good Clinical Practice
GI
Gastrointestinal
GSK
GlaxoSmithKline
h
Hour(s)
HBsAg, Hep B, 
Hep C
Hepatitis Surface Antigen, Hepatitis B and C
HIF
Hypoxia inducible factor
Hgb
Haemoglobin


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HIV
Human Immunodeficiency Virus
HMR
Hammersmith Medicines Research
HO-1
Heme Oxygenase-1
IB
Investigator’s Brochure
ICF
Information Consent Form
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
Intravenous
LC
Liquid Chromatography
LC/MS
Liquid Chromatography–Mass Spectrometry
LSC
Liquid Scintillation Counting
LFTs
Liver Function Tests
LVEF
Left Ventricular Ejection Fraction
μCi
Micro Curie
μg
Microgram
μSv
Microsievert
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
MHRA
Medicines and Healthcare Regulatory Agency
mL
Millilitre
MSDS
Material Safety Data Sheet
mSv
Millisievert
nCi
Nano Curie
NOAEL
No Observed Adverse Effect Level
NYHA
New York Heart Association
PAH
Pulmonary Arterial Hypertension
OATP
Organic Anion-Transporting Polypeptide
PHDs
Prolyl-4-hydroxylase
PK
Pharmacokinetic(s)
PRVP
Peak Right Ventricular Pressure
PTS
Platform Technology Services
QD
Quaque Die (Once A Day)
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SoA
Schedule of Activities
sPAP
Systolic Pulmonary Artery Pressure
SRM
Study Reference Manual
tmax
Time of occurrence of Cmax
UK
United Kingdom


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ULN
Upper Limit of Normal
VEGF
Vascular Endothelial Growth Factor
WHO
World Health Organisation
z
Lambda-z (Terminal Phase Rate Constant)
Table 5
Trademark Information
Trademarks of the GlaxoSmithKline group of 
companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Entero-Test
SAS
WinNonlin


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13.2.
Appendix 2: Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Excessive erythropoiesis (polycythemia) leading 
to thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis attributed to 
daprodustat was associated with vascular congestion, 
microthrombi, and tissue ischemia in a number of organs.
Following review of clinical data received to date, this has 
not been identified as a safety concern for daprodustat.
Phase 2 dose-ranging studies, and associated statistical 
and dose response modelling has informed Phase 3 dose 
rationale, starting doses, dose steps, and dose adjustment 
scheme to optimize Hgb management.

Specific eligibility criteria related to requirements 
for entry Hgb are detailed in Section 6

Specific guidance for discontinuation of 
daprodustat based on Hgb is provided in Section 
8.1

Monitoring of emerging safety data by an internal 
GSK Safety Review Team.
Death, MI, stroke, heart failure, thromboembolic 
events, thrombosis of vascular access at Hgb 
levels which are within the normal range (i.e. not 
polycythemic conditions)
Marketed rhEPO/ESAs have been associated with an 
increased risk for death and serious cardiovascular events 
when used in patients with anaemia of CKD.
Following review of clinical data received to date, this has 
not been identified as a safety concern for daprodustat.

Specific eligibility criteria related to CV risk are 
outlined in Section 6.

Monitoring of emerging safety data by an internal 
GSK Safety Review Team.
Oesophageal and gastric erosions
In animal studies, undesirable gastrointestinal effects 
including emesis, abnormal faeces and/or decreased food 
consumption/body weight loss and stomach 
erosions/ulcers with haemorrhage were observed with 
daprodustat.
In rodents stomach erosions observed with intravenous 
and oral administration of daprodustat.
Gender-averaged systemic exposure (AUC) at the no 
observed adverse effect levels (NOAEL) are 3.3 -fold 
(monkeys) and 737 -fold (rats) above human exposure (25 
mg daprodustat).
In clinical trials to date with daprodustat, mild-moderate 
gastrointestinal signs and symptoms represent the most 
frequently reported adverse event, however causal 
association has not been established.

Suspected GI bleeding or significant symptoms 
consistent with erosion or ulcers should be 
investigated diagnostically (i.e. endoscopic 
examination) as clinically warranted.

Monitoring of emerging safety data by an internal 
GSK Safety Review Team.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Following review of clinical data received to date, 
gastrointestinal erosions have not been identified as a 
safety concern for daprodustat.
Cancer-related mortality and tumour 
progression and recurrence
Marketed rhEPOs have been associated with increased 
risk of cancer related morbidity and mortality when used in 
patients with cancer.
Administration of 60 mg/kg daprodustat to mice caused 
minimal increases in circulating VEGF while significant 
EPO increases were observed.
In clinical studies conducted to date, administration of
daprodustat has been associated with:

In studies up to 4 weeks duration, a dose-ordered 
increase in VEGF plasma concentrations, an 
angiogenic factor that has been implicated in tumour 
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.

Systemic EPO concentrations within the physiologic 
range.
Following review of clinical data received to date, this has 
not been identified as a safety concern for daprodustat. 

Specific eligibility criteria related to personal 
history of malignancy or participants with 
complex kidney cyst are outlined in Section 6. 

Stopping criteria for participants with treatment 
emergent malignancy are outlined in Section 8.1.

Monitoring of emerging safety data by an internal 
GSK Safety Review Team.
Pulmonary artery hypertension (PAH)
A role for HIF-regulated pathways in the pathophysiology 
of PAH has been 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 

Monitoring of emerging safety data by an internal 
GSK Safety Review Team.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
13 weeks duration in mice and dog, up to 26 weeks in rat, 
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. These hypoxia-induced PRVP changes fall 
within the range of PRVP differences noted among non-
treated rats.
Results from a clinical study of acute hypoxic challenge in 
healthy volunteers demonstrated that short-term (5 days) 
therapy with daprodustat 5 mg or 100 mg has no clinically 
significant effect on echocardiographically-estimated 
systolic pulmonary artery pressure (sPAP) under either 
normoxic or hypoxic conditions.
ECHO assessments performed in Phase 2b studies (24 
weeks treatment duration) did not identify any clinically-
meaningful changes in sPAP in participants not on dialysis 
for daprodustat. In haemodialysis participants, mean 
absolute change from baseline in sPAP was similar for 
both treatment groups; however, there was a numeric 
imbalance (Daprodustat: 8 [7%]; Control 0) in participants 
reaching the sPAP PCI (>20 mmHg increase from 
baseline). Regarding this imbalance, there were a number 
of confounding factors in the study, most notably a 4.5:1 
randomization scheme and inconsistency in timing of 
ECHOs relative to dialysis day. Additionally, 2 of 3 
participants with resolution of sPAP on safety follow-up 
ECHOs had confounding conditions that could contribute 
to resolution other than discontinuation of study treatment; 
and there was no dose relationship for participants meeting 
the sPAP PCI criterion. Overall, there is insufficient 
evidence to conclude a relationship to treatment with 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
daprodustat.
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.
Cardiomyopathy has not been associated with naturally 
occurring mutation in man which results in increased HIF 
stabilization.
ECHO assessments performed in phase 2b studies (24 
weeks treatment duration) did not identify any clinically 
meaningful changes in LVEF for daprodustat.
Following review of clinical data received to date, this has 
not been identified as a safety concern for daprodustat.

Monitoring of emerging safety data by an internal 
GSK Safety Review Team
Proliferative retinopathy, macular oedema, 
choroidal neovascularization
Increases in local (ocular) VEGF production with retinal 
neovascularization and macular oedema observed in 
diabetic retinopathy and to choroidal leakage, oedema and 
neovascularization seen in age-related macular 
degeneration [Campochiaro, 2006].
Administration of 60 mg/kg daprodustat to mice caused 
minimal increases in circulating VEGF while significant 
EPO increases were observed.
No ocular abnormalities with daprodustat were seen in 
non-clinical studies of up to 13 weeks duration in mice and 

Suspected proliferative retinopathy, macular 
oedema, choroidal neovascularization or 
symptoms consistent with these events should 
be investigated by ophthalmologic consultation 
as clinically warranted.

Monitoring of emerging safety data by an internal 
GSK Safety Review Team.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
dogs, 26 weeks in rats, and 39 weeks in monkeys.
In clinical studies up to 4 weeks duration, a dose-ordered 
increase in VEGF plasma concentrations was observed at 
doses ranging from 10 to 150 mg. In studies up to 24 
weeks duration at doses up to 25 mg, changes in VEGF 
plasma concentrations were variable but similar relative to 
control.
Ophthalmologic assessments performed in phase 2b 
studies (24 weeks treatment duration) did not identify any 
clinically meaningful changes in proliferative retinopathy, 
macular oedema, or choroidal neovascularization with 
daprodustat.
Following review of clinical data with daprodustat 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 seen in non-clinical studies conducted to 
date for daprodustat.
Following review of clinical data received to date, this has 
not been identified as a safety concern for daprodustat.

Monitoring of emerging safety data by an internal 
GSK Safety Review Team.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Drug-drug interactions
Co-administration of daprodustat with the strong CYP2C8 
inhibitor, gemfibrozil increased the Cmax and AUC of 
daprodustat, 4- and 19-fold, respectively, while co-
administration of the weak inhibitor, trimethoprim increased 
the Cmax and AUC of daprodustat by 1.3- and 1.5-fold, 
respectively. 
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 
approximately 10-14 days of dosing with rifampin [Brodie, 
2013 and 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.
Population PK analysis from completed Phase 2 studies 
suggests that co-administration of daprodustat with a 
moderate CYP2C8 inhibitor (clopidogrel) leads to a ~2-fold 
increase in AUC, with no clinically-significant increase in 
the measured Hgb response.
Daprodustat is an inhibitor of CYP2C8 in vitro, with an 
IC50 value of 21 µM.
Co-administration of daprodustat with moderate CYP2C8 
inhibitors (i.e., clopidogrel, teriflunomide, deferasirox) 
should be performed with caution.
Co-administration of daprodustat with potent BCRP 
inhibitors has the potential to increase exposure of 
daprodustat. Use of BCRP inhibitors (mostly weak) was 

Chronic co-administration of daprodustat with the 
strong CYP2C8 inhibitor, gemfibrozil and 
inducers, rifampin/rifampicin is not permitted as 
outlined in Section 7.7. Short duration (i.e., less 
than or equal to 14 days) is permitted.

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 dose is changed, Hgb 
should be monitored every 4 weeks for 12 weeks 
as outlined in Section 7.7 and the IB.

Specific guidance on the management of 
potential drug-drug interactions and concomitant 
medications is provided in Section 7.7 and the 
IB.

Monitoring of emerging safety data by an internal 
GSK Safety Review Team.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
found to result in a small change in metabolite exposure 
(20% increase in AUC).
Daprodustat is an inhibitor of OATP1B1/1B3 in vitro, with 
IC50 values of 6 µM and 11 µM, respectively. A clinical 
drug interaction study between 100 mg daprodustat with 
either a CYP2C8 substrate or an OATP1B1/1B3 substrate 
showed that there is no PK interaction at this dose of 
daprodustat.
Radioactivity exposure risk
The total effective dose associated with IV and oral
administrations of [14C]-GSK1278863 is <1 mSv.  That 
effective dose is within WHO recommendation of a <5 mSv 
maximum for Category 2 projects, which is considered to 
be within dose limits for members of the public with a minor
risk. The total effective dose is also below the 
GlaxoSmithKline Global Safety Board level of radiation 
which would require specific additional justification and 
exemption (10 mSv).

Participants will be monitored for recovery of 
radioactivity throughout the study

To avoid recruitment of radiation worker or serial 
study volunteers, participants who have been 
exposed to ionising radiation in excess of 10mSv 
above background over the previous 3 year 
period as a result of occupational exposure to 
radiation or as a result of research studies are 
excluded. Clinically justified (therapeutic or 
diagnostic) exposures are not included in the 
exposure calculation. Participants are asked 
about any occupational exposure or previous 
participation in research studies at screening so 
that dose estimates can be obtained where 
necessary.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Intravenous dosing of daprodustat 
(GSK1278863)
This is the first time daprodustat will be administered IV to 
humans. The total systemic exposure of daprodustat from 
the combined IV microtracer (50 μg) and oral dose (6 mg), 
as well as the single oral dose of 25 mg is well below 
exposures observed in previous trials in healthy 
participants.
IV administration can be associated with pain at the 
injection site. Non-clinical IV irritancy studies have been 
performed in a number of species (refer to the IB); those 
studies did not show significant dermal irritation.

In addition to taking samples for pharmacokinetic 
analysis of daprodustat, routine safety tests, 
including vital signs, 12-lead ECG, and a panel 
of laboratory safety tests, will be done whilst 
participants are resident at the unit.

Participants will be monitored for signs of pain at 
the injection site. Paracetamol (acetaminophen), 
at doses of ≤ 2 g/day can be taken if required.

Stopping criteria for participants with severe 
pain, redness, bleeding or swelling at the 
infusion site are outlined in Section 8.1.
Study Procedures
Entero-Test for bile collection risk
The use of the Entero-Test has been approved by the
European regulatory authorities (ISO 9001 and CE Mark 
Certification; European Union Medical Devices Directive 
(MDD)).

Streaks of blood on the string due to local irritation 
have been infrequently noted.

Rarely, a participant will be unable to swallow the 
capsule because of gagging or will vomit after doing 
so.

Gagging upon retrieval of the string can occur.

On a few occasions, an entire string has been 
swallowed without ill effects and passes out from the 
body in the faeces.

The string will be securely taped in place (to the 
cheek of each individual) during the collection 
time to minimise risk of swallowing the entire 
string.


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References
Campochiaro PA and the first ARVO/Pfizer Institute Working Group et al. Ocular versus 
extraocular neovascularization: Mirror images or vague resemblances. Invest Ophthalmol 
& Vis Sci. 2006; 47:462-474.
Formenti F, Beer PA, Croft QPP, Dorrington KL, Gale DP, Lappin TRJ, Lucas GS, 
Maher ER, Maxwell PH, McMullin MF, O’Connor DF, Percy MJ, Pugh CW, Ratcliffe 
PJ, Smith TG, Talbot NP, Robbins PA. Cardiopulmonary function in two human 
disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and 
HIF-2α gain-of-function mutation. FASEB J. 2011; 25:2001-2011.
Muz B, Khan MN, Kiriakidis S, Paleolog EM. The role of hypoxia and HIF-dependent 
signalling events in rheumatoid arthritis. Arthritis Research & Therapy 2009; 11:201-
209.
Smith TG, Brooks JT, Balanos GM, Lappin TR, Layton DM, Leedham DL, Liu C, 
Maxwell PH, Treacy M, Robbins PA. Mutations of von Hippel-Lindau tumour 
suppressor and heman cardiopulmonary physiology. PLos Med. 2006; 3:3290.
Westra J, Molema G, Kallenberg CG. Hypoxia-inducible factor-1 as regulator of 
angiogenesis in rheumatoid arthritis - therapeutic implications. Curr Med Chem. 2010; 
17:254-63.


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13.3.
Appendix 3: An assessment of the radiation dose to male 
volunteers from the oral and IV administration of the study 
treatment


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PPD


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PPD


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13.4.
Appendix 4:  Clinical Laboratory Tests

The tests detailed in Table 6 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.


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Table 6
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
MCV
MCH
Absolute and %
Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Haematocrit
Clinical Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and 
direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total 
Protein
Fasting glucose
Calcium
Alkaline 
phosphatase
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick

Microscopic examination (if leukocyte esterase, nitrites, blood or 
protein is abnormal)
Other Screening Tests

Alcohol breath test, urine cotinine test

Carbon Monoxide (CO) breath test

Drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody)
NOTES :
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1.1 and Section 13.8. All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding studies 
of hepatic impairment or cirrhosis).


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13.5.
Appendix 5: 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, IB, 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 AE/SAE/protocol deviations 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 legally authorised representative and answer all questions 
regarding the study.

Participants must be informed that their participation is voluntary. Participants or 
their legally authorised representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 


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ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study centre.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorised 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 authorised 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 authorised 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 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 hi medical records may be examined by 
Clinical Quality Assurance auditors or other authorised 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 multicentre studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be designated 
by mutual agreement.


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
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
Where required by applicable regulatory requirements, an investigator signatory will be
identified for the approval of the clinical study report. 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.
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.
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 (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/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 authorised 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 
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)/equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written 
notification to the sponsor.


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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 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 SPM.
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


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13.6.
Appendix 6: 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, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (ie, 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.
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 (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 


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Events NOT Meeting the AE Definition 
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 (eg, 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 fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 
and accidental trauma (eg, 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 


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A SAE is defined as any untoward medical occurrence that, at any dose:
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.
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
participants receiving anticoagulants. If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Section 13.8 (Appendix 8) for the required liver chemistry follow-up 
instructions.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all 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.


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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.

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.


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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 GSK within 24 h of receipt of 
the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Paper CRF

Facsimile transmission or email of the SAE paper CRF are the preferred methods to 
transmit this information to the Sponsor/medical monitor/SAE coordinator.  Fax 
number and email address can be found in the SRM.

In rare circumstances and in the absence of facsimile equipment or email, 
notification by telephone is acceptable with a copy of the SAE data collection tool 
sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.


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13.7.
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information
Contraception Guidance

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined time 
frame in Section 6.1:

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to 
remain abstinent

Agree to use a male condom when having penile-vaginal intercourse with 
a woman of childbearing potential

Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the protocol-defined time frame.

In addition, male participants must refrain from donating sperm for during the 
protocol-defined time frame.
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male 
participant’s female partner of a male study participant who becomes pregnant 
while participating in this study. This applies only to participants who receive 
study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 h of learning of the partner’s 
pregnancy.

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of 
foetal status (presence or absence of anomalies) or indication for procedure.


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13.8.
Appendix 8: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event aetiology.
These protocol guidelines are in alignment with FDA premarketing clinical liver safety 
guidance.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Table 7
Phase I liver chemistry stopping criteria and required follow up 
assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 h

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 participant until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
h

Monitor participants twice weekly until liver 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.


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Liver Chemistry Stopping Criteria 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 h

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants 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 participant 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 
participants receiving anticoagulants
3 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 
4 PK sample may not be required for participants 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 PK 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’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.


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References
Brodie MJ, et.al. Enzyme induction with antiepileptic drugs: Cause for concern?. 
Epilepsia. 2013;54(1):11-27. 
GlaxoSmithKline Document Number 2015N248947_00. Phase 2 Population 
Pharmacodynamic Analyses of GSK1278863 in Anemic Subjects with Chronic Kidney 
Disease. Report Date 22-APR-2016. 
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. 
Ohnhaus EE, Breckenridge AM, Park BK. Urinary Excretion of 6-Beta-Hydroxycortisol 
and the Time Course Measurement of Enzyme Induction in Man. Eur J Clin Pharmacol. 
1989;36:39-48. 


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13.9.
Appendix 9: Protocol Amendment 01
Where the Amendment Applies
This amendment applies to all sites participating in this clinical trial. 
Summary of Amendment Changes 
In the List of Specific Changes below, except minor format changes, the previous 
protocol version text is shown with strikethrough revision marks denoting removed text; 
bold text denotes text that has been added.
Rational for Changes:
The changes noted in the List of Specific Changes Protocol Section 9.2.5.: Regulatory 
Reporting Requirements for SAEs, Bullet 1, are made by requirement of the Regulatory 
Authority: Medicines and Healthcare Products Regulatory Agency (United Kingdom). 
The changes noted in the List of Specific Changes Protocol Section 9.2.1.: Time Period 
and Frequency for Collecting AE and SAE Information, Bullet 5, are made because the 
time requirement for reporting is the same, therefore, “promptly” has also been clarified 
in this section. 
List of Specific Changes
Section 9.2.1. Time Period and Frequency for Collecting AE and SAE 
Information, Bullet 5:
PREVIOUS TEXT
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 within 24 hours following knowledge of the SAE.
REVISED TEXT
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 
notify the sponsor within 24 hours following knowledge of the SAE.
Section 9.2.5. Regulatory Reporting Requirements for SAEs, Bullet 1:
PREVIOUS TEXT
Prompt notification Notification by the investigator to the sponsor within 24 hours 
following knowledge of an SAE is essential so that legal obligations and ethical 


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responsibilities towards the safety of participants and the safety of the a study treatment 
under clinical investigation are met.
REVISED TEXT
Notification by the investigator to the sponsor within 24 hours following knowledge of an
SAE is essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of the a study treatment under clinical investigation are met.

SAP_001.pdf: 
CONFIDENTIAL
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Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for an open-label study in 
healthy male participants to determine the mass balance, 
absolute bioavailability and pharmacokinetics of daprodustat, 
administered as a single intravenous microtracer 
(concomitant with an oral dose of non-radiolabelled 
daprodustat) and a single, oral radiolabelled dose.
Compound Number 
:
GSK1278863 (daprodustat)
Effective Date 
:
30-JAN-2018
Description:

The purpose of this Reporting and Analysis plan (RAP) is to describe the planned 
analyses and output to be included in the Clinical Pharmacology Study Report for 
Protocol 200232

This RAP will be provided to the study team members to convey the content of 
the Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval 
Method
N/A
N/A
Junior Statistician ([Future Pipeline Discovery, QSI])
12-JAN-2018
e-signature
Manager ([Clinical Pharmacology, Clinical 
Pharmacology, QSCi, PCPS, R&D])
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
200232
2
RAP Team Approvals:
Approver
Date
Approval Method
Statistics Director (Future Pipeline Discovery, 
RD PCPS Qsci Clinical Statistics 5D)
12-JAN-2018
e-signature
02-JAN-2018
e-signature
Principal Data Manager ([Future Pipeline 
Discovery, CPSSO Data Management])
18-JAN-2018
e-signature
Clinical Development Manager ([Future Pipeline 
Discovery, RD PCPS CPSSO 1C])
 
Senior Director ([Future Pipeline Discovery,
Clinical Development, RD MPC HUP])
30-JAN-2018
e-mail
Programming Manager ([Future Pipeline 
Discovery, RD Qsci Clinical Programming 
Metabolic], Clinical Programming)
04-JAN-2018
e-signature
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
04-JAN-2018
e-signature
Associate Manager Statistics, ([Future Pipeline 
Discovery, Quantitative Sciences India], Clinical 
Statistics)
Programming Manager ([Future Pipeline 
Discovery, RD Qsci Clinical Programming 
Metabolic], Clinical Programming)
02-JAN-2018
e-signature
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
200232
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses / Statistical Analyses .................................................9
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Interim Analyses .........................................................................................10
3.2.
Final Analyses ............................................................................................10
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................12
5.1.
Study Treatment & Sub-group Display Descriptors.....................................12
5.2.
Baseline Definitions ....................................................................................12
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................14
6.1.
Overview of Planned Study Population Analyses........................................14
7.
SAFETY ANALYSES .............................................................................................15
7.1.
Adverse Events Analyses ...........................................................................15
7.2.
Clinical Laboratory Analyses.......................................................................15
7.3.
Other Safety Analyses ................................................................................15
8.
PHARMACOKINETIC ANALYSES.........................................................................16
8.1.
Primary and Secondary Pharmacokinetic Analyses ....................................16
8.1.1.
Endpoint / Variables.....................................................................16
8.1.1.1.
Drug Concentration Measures....................................16
8.1.1.2.
Derived Pharmacokinetic Parameters.........................16
8.1.1.2.1.
Deriving Blood and Plasma 
Pharmacokinetic Parameters..................16
8.1.1.2.2.
Derived Urine and Faecal 
Pharmacokinetic Parameters..................18
8.1.2.
Summary Measure ......................................................................19
8.1.3.
Population of Interest...................................................................19
8.1.4.
Statistical Analyses / Methods .....................................................19
8.1.4.1.
Statistical Methodology Specification..........................19
9.
REFERENCES.......................................................................................................22
10. APPENDICES........................................................................................................23
10.1.
Appendix 1: Protocol Deviation Management .............................................23


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200232
4
10.2.
Appendix 2: Schedule of Activities ..............................................................24
10.2.1.
Protocol Defined Schedule of Events...........................................24
10.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................28
10.3.1.
Study Phases for Concomitant Medication...................................28
10.3.1.1.
Treatment States for AE Data.....................................28
10.3.2.
Treatment Emergent Flag for Adverse Events .............................29
10.4.
Appendix 4: Data Display Standards & Handling Conventions....................30
10.4.1.
Reporting Process .......................................................................30
10.4.2.
Reporting Standards....................................................................30
10.4.3.
Reporting Standards for Pharmacokinetic....................................31
10.5.
Appendix 5: Derived and Transformed Data ...............................................32
10.5.1.
General........................................................................................32
10.5.2.
Study Population..........................................................................32
10.5.3.
Safety ..........................................................................................32
10.5.4.
Pharmacokinetic ..........................................................................33
10.6.
Appendix 6: Reporting Standards for Missing Data.....................................35
10.6.1.
Premature Withdrawals................................................................35
10.6.2.
Handling of Missing Data.............................................................35
10.6.2.1.
Handling of Missing and Partial Dates ........................35
10.7.
Appendix 7: Values of Potential Clinical Importance ...................................37
10.7.1.
Laboratory Values........................................................................37
10.7.2.
ECG.............................................................................................38
10.7.3.
Vital Signs....................................................................................38
10.8.
Appendix 8: Abbreviations & Trade Marks ..................................................39
10.8.1.
Abbreviations...............................................................................39
10.8.2.
Trademarks .................................................................................40
10.9.
Appendix 9: List of Data Displays ...............................................................41
10.9.1.
Data Display Numbering..............................................................41
10.9.2.
Mock Example Shell Referencing ................................................41
10.9.3.
Deliverables.................................................................................41
10.9.4.
Study Population Tables..............................................................42
10.9.5.
Pharmacokinetic Tables...............................................................43
10.9.6.
Pharmacokinetic Figures .............................................................46
10.9.7.
Safety Tables...............................................................................47
10.9.8.
ICH Listings .................................................................................49
10.9.9.
Non-ICH Listings..........................................................................52
10.10. Appendix 10: Example Mock Shells for Data Displays ................................53


CONFIDENTIAL
200232
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
Document Number
Date
Reason for revision
2017N310967_00
30-MAY--2017
Original
2017N310967_01
1-SEP-2017
“Promptly” has been changed to “within 24 hours following
knowledge of the SAE.”


CONFIDENTIAL
200232
6
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were slight deviations to the “Analysis population” and PK collection Time point 
in Period 2 which is outlined in Table 1. However, no changes to originally planned 
statistical analysis specified in the protocol amendment 1 [(Dated: 01/SEP/2017)].
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

All Subjects: All 
participants who take at 
least 1 dose of study 
treatment. Participants will 
be analysed according to 
the treatment they actually
received. 

Safety: All participants who take at 
least 1 dose of study treatment.  
Participants will be analysed    
according to the treatment they 
actually received.

To be consistent with 
current standards for 
naming population

Not Defined 

Enrolled: All participants who 
passed screening and entered the 
study. Included are: Run-in 
Failures; And participants who 
were assigned a treatment in a 
non-randomised study.

Note screening failures (who never 
passed screening even if 
rescreened) and participants 
screened but never enrolled into 
the study (Reserve, Not Used) are 
excluded from the Enrolled 
population as they did not enter the 
study.

This population Required 
for data disclosure 
displays.

Pharmacokinetic:
All participants in the ‘Safety’
population for whom sufficient 
data are available to calculate 
the derived pharmacokinetic 
parameters on an as-treated 
basis. 

Pharmacokinetic: All
participants in the Safety 
population who had at least 1 non-
missing PK assessment (Non-
quantifiable [NQ] values will be 
considered as non-missing values).

Definition mentioned in 
the Protocol is 
ambiguous from a 
programming perspective 
hence standard definition 
is used after confirming 
with Study Team.
Blood sample is collected in time 
point mentioned in Table 1

Blood sample is collected in two 
additional time points following 
infusion termination than 
mentioned in Table 4 (i.e. 2.25 and 
2.5hr) to capture the immediate 
decline of drug

To capture the 
immediate decline of 
drug blood sample is 
collected in two extra 
time points.


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2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints1
Primary Objectives
Primary Endpoints

To determine total radioactivity (drug 
related material) in blood and plasma
following a single IV microtracer dose of 
[14C] -GSK12788631 (concomitant with 
an oral dose of non-radiolabelled 
daprodustat1) and a single, oral dose of 
[14C]-GSK1278863.

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2 of total 
drug-related material (radioactivity) in blood and
plasma.

Volume (Vss) and clearance (CL) of total drug-
related material (radioactivity) after IV dose only 
(Treatment Period 1).

To determine the rate and extent of 
excretion of total radioactivity in urine 
and faeces and the total recovery of 
radioactivity following a single, oral dose 
of [14C]-GSK1278863.

Urinary and faecal cumulative excretion as a 
percentage of the total radioactive dose 
administered over time (Treatment Period 2 only).
Secondary Objectives
Secondary Endpoints

To determine parent daprodustat and 
metabolite concentrations in plasma 
following a single IV microtracer dose of 
[14C]-GSK1278863 and both oral doses
of daprodustat.

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2 of
daprodustat parent and metabolite in plasma from 
the IV dose and both oral doses.

Volume (Vss) and clearance (CL) of daprodustat 
parent and metabolite (if possible) after IV dose 
only (Treatment Period 1).

To estimate the absolute bioavailability 
of daprodustat following oral 
administration.

F (absolute bioavailability) after oral dosing.

To generate samples that will be used 
to characterise the metabolite profile of
daprodustat following a single IV 
microtracer dose of [14C]-GSK1278863 
concomitant with an oral dose of non-
radiolabelled daprodustat (plasma and 
duodenal bile) and a single, oral dose of 
[14C]-GSK1278863 (plasma, urine and
faeces).

Characterisation and quantification of metabolites 
in plasma, urine, faeces, and duodenal bile 
(These analytical investigations will be conducted and 
the results reported under a separate GSK protocol).

To evaluate the safety and tolerability of 
daprodustat after single IV and oral 
doses in healthy participants.

Incidence and severity of adverse events.

Laboratory safety, 12-lead ECG, and vital sign
parameters.
1 For measured concentrations of daprodustat in blood and plasma, the nomenclature [14C]-GSK1278863 describes 
the parent daprodustat concentration derived via analysis by liquid chromatography (LC) + Accelerator Mass 
Spectrometry(AMS), whereas daprodustat describes the parent daprodustat concentration derived via liquid 
chromatography tandem mass spectrometry (LC/MS).


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200232
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2.3.
Study Design
Overview of Study Design and Key Features
Design 
Features

This is an open-label, single-centre, non-randomised, 2-period, single-
sequence, crossover, mass balance study in 6 healthy male participants.  

Each participant will be involved in the study for up to 10 weeks.  He will have 
a screening visit, two treatment periods (Treatment Periods 1 and 2), 
separated by 14 days, and a follow up visit 1-2 weeks after the last 
assessment in Treatment Period 2.  During both treatment periods, participants 
will reside in the unit from the afternoon before Day 1 (Day -1) until all 
procedures are completed on Day 7.  Participants may be asked to stay for up 
to 1 week longer in Treatment Period 2, if excretion of drug-related material 
takes longer than anticipated.

Screening Period
Participants must be screened within 30 days before the first dose of 
daprodustat, and must meet all eligibility criteria.

Treatment Period 1 (oral tablet and intravenous infusion)
On Day 1 of Treatment Period 1, after an overnight fast of at least 8 h, each 
participant will take a single 6 mg oral dose of daprodustat. After approximately 
1 h, participants will receive 50 μg of [14C]-GSK1278863 by IV infusion over 1 
h. Blood samples will be collected for 144 h after oral dosing (until Day 7), 
while duodenal bile will be collected by Entero-Test.

Treatment Period 2 (oral solution)
On Day 1 of Treatment Period 2, after an overnight fast of at least 8 h, each 
participant will receive 25 mg [14C]-GSK1278863 as an oral solution; 
participants will continue to fast for 4 h after dosing. Blood, urine and faecal 
samples will be collected for a minimum of 144 h (up to Day 7) after dosing, 
depending on the amount of radioactivity excreted by each participant. 


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9
Overview of Study Design and Key Features
Based on the radio quantification results on Days 6 and 7 a decision will be 
taken regarding continuation in Treatment Period 2, i.e.
o
If ≥90% of the administered radioactivity has been recovered and 
excretion rate is <1% then Participants may be discharged on day7 itself.
o
If excretion rate is >1% or if the results are inconclusive, the participant will 
remain at the unit, and urine and faecal collections will continue at 24-h 
intervals for up to 7 additional days.
o
Once less than 1% of the dose is excreted in 2 consecutive 24-h periods 
where samples are provided, or ≥ 90% of the radioactivity has been 
recovered, the participant will be discharged.
All remaining participants will be discharged from the unit no later than Day 15.

Follow-up
Follow-up procedures will be done 7-14 days after the participant’s last 
assessment in Treatment Period 2.
Dosing

The investigational drug is GSK1278863 (daprodustat).
In Treatment Period1, each participant will receive 50 μg of radiolabelled 
GSK1278863 ([14C]-GSK1278863) microtracer by IV infusion, concomitant with 
a 6 mg oral dose of daprodustat.

In Treatment Period 2, A single 25 mg dose of [14C]-GSK1278863 will be 
administered as an oral solution.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

This is an open-label study and all 6 participants will be assigned to the same 
treatment regimen in a non-randomised manner. All participants will receive IV 
infusion [concomitant with an oral non-radiolabelled dose] at Treatment Period 
1 followed by oral solution dose at Treatment Period 2.
Interim 
Analysis

No interim analysis will be performed in this study.
2.4.
Statistical Hypotheses / Statistical Analyses

This is an investigative study to determine the excretion mass balance of daprodustat 
(GSK1278863) using [14C]-radiolabelled drug substance, administered in Treatment 
Period 1 as a single intravenous microtracer dose (concomitant with a single oral non-
radiolabelled dose) and a single oral solution radiolabelled dose in Treatment Period 
2.

Due to its descriptive nature, there will be no formal statistical hypothesis tested; an 
estimation approach will be adopted to assess the study objectives.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses

No Interim Analysis is planned for this study.
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.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened 

All participants who sign the ICF. This will be the 
population for reporting screened population data.

Study Population
Enrolled

Enrolled: All participants who passed screening and 
entered the study. Included are: Run-in Failures; And 
participants who were assigned a treatment in a non-
randomised study.

Note screening failures (who never passed screening 
even if rescreened) and participants screened but 
never enrolled into the study (Reserve, Not Used) are 
excluded from the Enrolled population as they did not 
enter the study.

Study Population
Safety

All participants who take at least 1 dose of study 
treatment.  

Participants will be analysed according to the 
treatment they actually received.

Safety and Study 
population
Pharmacokinetic
(PK)

All participants in the Safety population who had at
least 1 non-missing PK assessment (Non-quantifiable 
[NQ] values will be considered as non-missing values).

PK
Refer to Appendix 9: List of Data Displays which details the population used for each display.
Note: Reason for Deviation in “Analysis Population” from Protocol to RAP is mentioned in the Table 1
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan [6OCT2017and 
versionV1].
Data will be reviewed prior to DBR to ensure all important deviations are captured 
and categorised on the protocol deviations dataset. 

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. 


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
Treatment Description
Data Displays for Reporting 
Code
Description
Description
(Safety)
Description
(PK Analysis)
Order [1]
A
GSK1278863 6mg Oral + 
[14C]-GSK1278863 50 mcg IV
A
A1
A2
1
2
B
[14C]-GSK1278863 25 mg Oral 
Solution
B
B
3
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
Study population displays will be summarized by total column.
Please add footnote in all the displays as follows for the treatment group

Note: For Safety Displays
A: GSK1278863 6mg Oral + [14C]-GSK1278863 50 mcg IV
B: [14C]-GSK1278863 25 mg Oral Solution

Note: For PK displays:
A1: GSK1278863 6mg Oral 
A2: [14C]-GSK1278863 50 mcg IV
B: [14C]-GSK1278863 25 mg Oral Solution
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 in the associated treatment period. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline.
Parameter
Study Assessments Considered as 
Baseline
Baseline Used in Data 
Display
Screening
Day -1
Day 1 (Pre-
Dose)
Safety
Vital Signs
X
X [1]
Day 1 (mean pre-dose) 
[2]
Laboratory 
(Haematology+ Clinical 
chemistry)
X
X
Day -1


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13
NOTES:
        [1] Taken in triplicate
[2] Mean of the triplicate pre-dose assessments.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
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: Study Phases and Treatment Emergent Adverse Events
10.4
Appendix 4: Data Display Standards & Handling Conventions
10.5
Appendix 5: Derived and Transformed Data
10.6
Appendix 6: Reporting Standards for Missing Data
10.7
Appendix 7: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Screened/Enrolled/Safety population, 
unless otherwise specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 9: List of Data Displays.


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7.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
7.1.
Adverse Events Analyses
Adverse events analyses including the summaries of adverse events (AEs), Serious 
(SAEs) and other significant AEs will be based on GSK Core Data Standards. The details 
of the planned displays are provided in Appendix 9: List of Data Displays.
7.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. The details of the planned displays are in Appendix 9: List of Data 
Displays.
7.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 9: List of Data Displays


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8.
PHARMACOKINETIC ANALYSES
8.1.
Primary and Secondary Pharmacokinetic Analyses
8.1.1.
Endpoint / Variables
Primary Endpoint:

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2 of radioactivity in blood and
plasma.

Volume (Vss) and clearance (CL) of radioactivity after IV dose only (Treatment 
Period 1).

Urinary and faecal cumulative excretion as a percentage of the total radioactive 
dose administered over time (Treatment Period 2 only).
Secondary Endpoint:

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2 of daprodustat parent and 
metabolite in plasma from the IV dose and both oral doses.

Volume (Vss) and clearance (CL) of daprodustat parent and metabolite (if 
possible) after IV dose only (Treatment Period 1).

F (absolute bioavailability) after oral dosing of the 6 mg tablet dose.
8.1.1.1.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions(Section 10.4.3
Reporting Standards for Pharmacokinetic )
Plasma daprodustat, [14C]-GSK1278863, blood and plasma total radioactivity, metabolite 
(GSK2391220, GSK2506104, GSK2487818, GSK2506102, GSK2531398, 
GSK2531401) and [14C]-metabolite concentration-time data will be listed for each 
participant and standard summary statistics will be calculated (i.e. arithmetic mean, 
standard deviation, median, minimum and maximum) by treatment and planned sampling 
time.
Individual participant, mean and median plasma daprodustat, [14C]-GSK1278863, blood 
and plasma total radioactivity metabolite and [14C]-metabolite concentration-time 
profiles will be plotted for each treatment on both a linear and semi-log scale.
8.1.1.2.
Derived Pharmacokinetic Parameters
8.1.1.2.1.
Deriving Blood and Plasma Pharmacokinetic Parameters

PK parameters will be calculated by standard non-compartmental analysis according 
to current working practices and using the currently supported version of WinNonlin 
Version 6.3 or above. All calculations of non-compartmental parameters will be 
based on actual sampling times. PK parameters listed will be determined from the 


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plasma daprodustat, [14C]-GSK1278863, blood and plasma total radioactivity,
metabolite and [14C]-metabolite concentration-time data, as data permits.
Table 2
Derived Pharmacokinetic Blood and Plasma Parameters
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (C(t)) will be calculated using the linear trapezoidal rule 
for each incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid.
λz
The first order rate constant associated with the terminal (log-linear) portion of the 
concentration-time curve.
AUC (0-inf)
Area under the concentration-time curve extrapolated to infinity will be calculated 
as: 
AUC = AUC(0-t) + C(t) / λz
%AUCex
The percentage of AUC (0-∞) obtained by extrapolation (%AUCex) will be 
calculated as:
[AUC(0-inf) – AUC(0-t)] / AUC(0-inf) x 100
Cmax
Maximum observed concentration, determined directly from the concentration-time 
data.
Tmax
Time to reach Cmax, determined directly from the concentration-time data.
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / λz
Vss
Volume of distribution of at steady-state will be calculated as:
CL*MRTiv
where the mean residence time (MRT) is calculated as AUMC(0-inf) (area under 
the first moment curve)/AUC(0-inf).
Treatment period 1, analyte [14C]- GSK1278863 only.
CL
Total clearance will be calculated as:
Dose(iv)/AUC(0-inf)
Treatment period 1, analyte [14C]- GSK1278863 only.
Oral F
Absolute bioavailability from the oral tablet and IV doses administered in Period1 
for AUC(0-inf) and AUC(0-t) PK parameter calculated as:
Oral and IV Dose will be converted into ng using below conversion values.
1mg=1000000ng
1mcg=1000ng
[14C]-
GSK1278863/Total
radioactivity ratio
for Cmax, AUC(0-
Cmax Ratio = [14C] GSK961081 [Cmax] /Total radioactivity [Cmax]
AUC(0-inf) Ratio = [14C] GSK961081 [AUC[0-inf] /Total radioactivity [AUC(0-inf)]
AUC(0-t) Ratio = [14C] GSK961081 [AUC[0-t] /Total radioactivity [AUC(0-t)]


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Parameter
Parameter Description
inf), AUC(0-t)
NOTES:
Additional parameters may be included as required.
8.1.1.2.2.
Derived Urine and Faecal Pharmacokinetic Parameters

Derivation of the urine and faecal radioactivity parameters will be the responsibility, 
or under the direct auspices, of the BIB(Bioanalysis, Immunogenicity and 
Biomarkers) department within GSK. 

The following parameters will be determined from the urine and faecal radiolabelled 
drug-related material (total radioactivity) data, and will be listed by subject for each 
collection interval both in absolute terms and also cumulatively. Cumulative urinary, 
faecal and total excretion (amount excreted and % of total dose excreted over the 
study) will be summarised (N, n, arithmetic mean, SD, median, minimum, maximum) 
for each collection interval.  
Table 3
Derived Pharmacokinetic Urine and Faecal Parameters
Parameter
Parameter Description
Ae[urine]
Total radioactivity recovered in the urine (Ae[urine]) calculated for each collection interval
as:
(concentration in urine sample x collected sample weight)
for each urine collection interval.
In converting urine sample weight to volume, we assume 1g=1mL.
Ae[faeces]
Total radioactivity recovered in the faeces (Ae[faeces]) calculated for each collection
interval as:
(concentration in faecal homogenate aliquot analysed x weight of homogenate
aliquot analysed) x (total homogenate weight / collected sample weight)
for each faecal collection interval.
Ae[total]
Total radioactivity excretion will be estimated in each collection interval as:
Sum of Ae[urine] and Ae[faeces]
Fe%[urine]
% of total dose excreted as total radioactivity for each collection interval will be estimated
as:
(Ae[urine]) for each collection interval)/Radiolabelled Dose*100
Where radiolabelled dose is either dose(iv) or dose(oral) and excludes the inhaled
element of the dose.
Fe%[faeces]
% of total dose excreted as total radioactivity for each collection interval will be estimated
as:
(Ae[faeces] for each collection interval)/ Radiolabelled Dose*100
Where radiolabelled dose is either dose(iv) or dose(oral) and excludes the inhaled
element of the dose.
Fe%[total]
% of total dose excreted as radioactivity will be estimated in each collection interval as:
Sum of Fe%[urine] and Fe%[faeces]


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When summarising urine and faecal parameters, ‘NS’ (i.e., no sample provided as subject 
not voided at particular collection period) or ‘NQ’ values for these parameters will be 
imputed with zero.
8.1.2.
Summary Measure

Derived PK parameter estimates (AUC(0-inf), AUC(0-t), Cmax, tmax, t1/2) of 
plasma daprodustat, plasma metabolite and total radioactivity in blood and plasma for 
IV and oral along with volume and clearance (Treatment Period 1 after IV dose only)
will be summarised/listed.

Urinary and faecal cumulative excretion as a percentage of the total radioactive
dose over time will be summarised and listed (Treatment Period 2 only).

Absolute bioavailability after oral and IV dosing (Treatment Period 1) will be 
analysed by using AUC(0-t), AUC (0-∞) parameters.
8.1.3.
Population of Interest 
The PK analyses will be based on the PK population, unless otherwise specified.
8.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: 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, graphically presented (where appropriate) and 
listed.
8.1.4.1.
Statistical Methodology Specification
Pharmacokinetic Statistical Analyses (Absolute Bioavailability assessment in Treatment 
Period1)
Secondary Endpoint / Variables

AUC(0-t), AUC (0-∞) PK parameters of Plasma GSK1278863 from IV and oral dose 
will be analyzed after loge transformation (PK parameters should be divided by 
corresponding dose)
Model Specification

Will be statistically analyzed using a mixed model (MM) for Period1.

Terms fitted in the mixed effect ANOVA model will include:
o
Fixed effect                  : Treatment (IV dose/Oral dose in Period1)
o
Random Effect              : Subject

The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used.

Point estimates for the adjusted means on the loge scale, the mean difference between 
treatments and associated 90% confidence interval for the contrast (test-reference) 


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will be constructed using the residual variance. 


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Model Checking & Diagnostics

Dose normalized PK parameters should be used for the analysis.

For the Mixed Model analysis, Model assumptions will be applied, but appropriate 
adjustments may be made based on the data.

Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions 
are reasonable. 

If there are any departures from the distributional assumptions, alternative 
transformations, such as data squared, or square root of data, will be explored.
Model Results Presentation

The point estimate and confidence interval obtained from MM analysis will be 
exponentially back-transformed to obtain Adjusted (least square) geometric means for 
each treatment. 

Point estimates (Absolute Bioavailability of GSK1278863) and associated 90% 
confidence interval for the ratio Oral dose/IV dose along with within-subject 
variability (%CVw) will be reported.
Where %CVw=100*(SQRT (EXP(σw2)-1)) and σw2 is the mean squares error 
(MSE) from the statistical Mixed model.


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9.
REFERENCES
GlaxoSmithKline Document Number 2017N310967_00. An open-label study in healthy 
male participants to determine the mass balance, absolute bioavailability and
pharmacokinetics of daprodustat, administered as a single intravenous microtracer 
(concomitant with an oral dose of non-radiolabelled daprodustat) and a single, oral 
radiolabelled dose 30-MAY-2017.
GlaxoSmithKline Document Number 2017N310967_01. An open-label study in healthy 
male participants to determine the mass balance, absolute bioavailability and 
pharmacokinetics of daprodustat, administered as a single intravenous microtracer 
(concomitant with an oral dose of non-radiolabelled daprodustat) and a single, oral 
radiolabelled dose; 01-SEP-2017.
GUI_137354: Information for Authors – Reporting and Analysis Plan, Global; GSK.
SOP_54838: Development, Review & Approval of Reporting & Analysis Plan, Global; 
GSK.


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10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management 
A Per Protocol Population is not being defined for this study. 
Please Refer to Section 4.1 for handling and Reporting of Protocol Deviations.


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10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
The Schedule of Activities for Treatment Period 1 and Treatment Period 2 is presented in Table 4 and Table 5, respectively.
Table 4
Treatment Period 1 (oral tablet and intravenous infusion)
Visit
Screening1
Treatment Period 1
Day
Procedure
-30 to -1
-1
1
2
3
4
5
6
7
hour
Pre-
dose
0
0.5
1
1.25
1.5
2
3
4
6
8
10
12
24
36
48
72
96
120
144
Informed consent
X
Medical history 
(including drug/alcohol 
use)
X
Demography
X
Admission to unit
X
Discharge from unit2
X
Full physical exam, 
including height, weight 
and BMI
X
Brief physical exam 
X
X
Drugs of abuse screen 
X
X
Alcohol and cotinine 
tests, CO breath tests 
X
X
HIV and hepatitis B and 
C screen
X
Laboratory safety tests 
(including LFTs)
X
X
X
12-lead ECG3
X
X


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Visit
Screening1
Treatment Period 1
Day
Procedure
-30 to -1
-1
1
2
3
4
5
6
7
hour
Pre-
dose
0
0.5
1
1.25
1.5
2
3
4
6
8
10
12
24
36
48
72
96
120
144
Vital signs3,4
X
X
X
X
[14C]-GSK1278863 IV 
infusion 
Oral daprodustat5
X
Blood samples for drug 
assay and radioactivity8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine collection6
X
Faecal collection7
X
Entero-Test (duodenal 
bile)8
Meals8,9
X
X
X
AE/SAE/concomitant 
medication review10
Abbreviations: AE: adverse event; ECG: electrocardiogram; HIV: human immunodeficiency virus; IV: intravenous; LFTs: liver function tests; SAE: serious adverse event.
Notes:
1 Screening will be within 30 days before Day 1.
2 Participants will be discharged for a washout period prior to dosing in Treatment Period 2; there will be at least 14 days between a participant’s oral doses. Participants who withdraw from the study early 
should be subject to those assessments that would be required at discharge in that treatment period, if participants agree to that.
3 Single ECG measurements will be taken at at all time points.  If any measurement is considered abnormal, triplicate measurements will be taken and the mean of the triplicate measurements used.  The 
pre-dose measurement on Day 1 will be used as baseline.
4 Triplicate measurements of systolic and diastolic blood pressure; single measurements of oral temperature and respiratory rate.
5 Participants will fast for at least 8 h before oral dosing.
6 Samples will be taken for background radiation at screening, Day –1 and pre-dose only, while total radioactivity, [14C]-GSK1278863 analysis, cold daprodustat analysis, and metabolite profiling will 
include predose and all post-dosing samples.  Sampling times are relative to the oral dose on Day 1, unless otherwise indicated. Additional blood samples will be collected at 2.25 and 2.5 hr following 
infusion termination to capture the immediate decline of drug.
7 Urine and faeces will be collected at pre-dose (up to 3 h pre-dose for the urine sample; up to 48 h pre-dose for the faecal sample).
8 The Entero-Test will be swallowed about 3.5 h before the oral dose, while participants are in a fasted state.  It will be removed 3 h after the oral dose (about 1 h after the end of the IV infusion).  At about 
0.5 h after the start of IV infusion (i.e., 1.5 h before string withdrawal) a food cue will be used to stimulate gall bladder emptying.
9 Meal times are specified for Day 1 only.  On all other days, meals will be served at the unit’s standard times.
10 AEs and SAEs will be collected from the start of oral dosing until the final follow-up visit.  However, any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product will be recorded from the time a subject consent to participate in the study.


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Table 5
Treatment Period 2 (oral solution)
Visit
Treatment Period 2
FU1
Day
Procedure
-1
1
2
3
4
5
6
72
8–
152,3
hour
Pre-
dose
0
0.5
1
1.5
2
3
4
6
8
10
12
24
36
48
72
96
120
144
Admission to unit
X
Discharge from unit4
X
X
Brief physical exam 
X
X
X
X
Drugs of abuse screen 
X
Alcohol and cotinine 
tests, CO breath tests
X
Laboratory safety tests 
(including LFTs)
X
X
X
X
12-lead ECG5
X
X
X
Vital signs5,6
X
X
X
X
X
[14C]-GSK1278863 oral 
solution7
X
Blood samples for drug 
assay and radioactivity8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine collection9
X
Faecal collection9
X
Meals10
X
X
AE/SAE/concomitant 
medication review11
Abbreviations: AE: adverse event; ECG: electrocardiogram; FU: follow-up; HIV: human immunodeficiency virus; LFTs: liver function tests; SAE: serious adverse event.
Notes:
1 Follow-up will be 7–14 days after the participant’s last assessment.


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2 Urine and faecal samples will be collected for a minimum of 144 h (up to Day 7) after dosing, depending on the amount of radioactivity excreted by each participant.  Liquid scintillation counting (LSC) will 
be performed daily on 24-h urine collections and 24-h faecal homogenates on Day 6 (96–120 h) and Day 7 (120–144 h).  If less than 1% of the dose is excreted in each of those 24-h periods for a given 
participant, he may be discharged on Day 8 (after the LSC results from Days 6 and 7 are available), and no further samples will be collected.  If excretion is higher than 1% in the 96–144 h (Day 6–7) 
collection period, or if the results are inconclusive, the participant will remain at the unit, and urine and faecal collections will continue at 24-h intervals, for up to 7 additional days (until the morning of Day 
14).  Once less than 1% of the dose is excreted in a 24-h period, or ≥ 90% of the radioactivity has been recovered, that participant will be discharged.  Any remaining participants will be discharged from 
the unit on Day 15.  In the unlikely event that excretion is still higher than 1% in the 24-h collection period prior to discharge on Day 15, the participant will continue to collect faecal samples only, at home, 
at 24-h intervals.  Samples will be returned to the unit every 2 to 3 days for analysis.
3 Brief physical exam, laboratory safety tests, 12-lead ECG and vital signs to be done only on the day of discharge.  Blood samples for drug assay and radioactivity to be taken each morning (at the time of 
dosing on Day 1) until Day 7.
4 Participants withdrawing from the study early should be subject to those assessments that would be required at discharge.
5 Single ECG measurements will be taken at all time points.  If any measurement is considered abnormal, triplicate measurements will be taken and the mean of the triplicate measurements used.  The 
pre-dose measurement on Day 1 will be used as baseline.
6 Triplicate measurements of systolic and diastolic blood pressure; single measurements of oral temperature and respiratory rate.
7 Participants will fast for at least 8 h before oral dosing.
8 Samples will be taken for background radiation pre-dose only, while total radioactivity, [14C]-GSK1278863 analysis, cold GSK1278863 analysis, and metabolite profiling will include predose and all post-
dosing samples.
9 Urine and faeces will be collected at pre-dose (up to 3 h pre-dose for the urine sample; up to 48 h pre-dose for the faecal sample), then over 24 h collection periods as follows: 0–24 h, 24‒48 h, 48–72 h, 
72–96 h, 96–120 h and 120–144 h.  If participants are required to stay after Day 7, collections will continue at 24-h intervals.  An aliquot from each collection period will be taken for metabolic profiling 
(separate study).
10 Meal times are specified for Day 1 only.  On all other days, meals will be served at the unit’s standard times.
11 AEs and SAEs will be collected until the final follow-up visit.
If assessments are scheduled for the same nominal time, the assessments should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws
4. other assessments
Note: The timing of the assessments should allow the blood draw to occur at the exact nominal time


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10.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
10.3.1.
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, and up to the last scheduled visit
NOTES: 

Please refer to Appendix 6: 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.
10.3.1.1.
Treatment States for AE Data
Treatment State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date
On-Treatment
If AE onset date is on or after treatment start date & on or before treatment stop 
date.
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 1 
day
Post-Treatment
If AE onset date is after the treatment stop date.
AE Start Date > Study Treatment Stop Date + 1 day
Onset Time 
Since 1st Dose 
(Days, hours,
mins)
Start/Stop Time is Collected: (AE Onset Date/time - Treatment Start Date/time) / 
60
Start or Stop Time is missing:
If Treatment Start Date ˃ AE Onset Date = AE Onset Date - Treatment Start 
Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date 
+1 day
Missing otherwise.
Duration (Days,
hours,
Mins)
Start/Stop Time is Collected: Onset Time = (AE Resolution Date/time – AE Onset 
Date/time) / 60
Start or Stop Time is missing:
AE Resolution Date – AE Onset Date + 1 day
Drug-related
If relationship is marked ‘YES’ on [Inform/CRF OR value is missing].
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.
.


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10.3.2.
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. (plus washout or protocol-specified time limit (e.g. half-life of drug, certain 
number of days, etc.).

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date+ 1 day

If AE onset is during one period and worsens during a later period it would be 
counted in both periods. For the initial period the logic would be as above. For the 
later period the logic would use the treatment dates associated with the later 
period:
  Treatment Period Start Date ≤ AE Worsening 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.


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10.4.
Appendix 4: Data Display Standards & Handling 
Conventions
10.4.1.
Reporting Process
Software

The SAS Version 9.4 or above and WinNonlin Version 6.3 or above will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Compound
: arenv/arprod/ GSK1278863/mid200232/final_01
Analysis Datasets 

Analysis datasets will be created according to CDISC standards SDTM IG Version 3.1.3 ADaM IG 
Version 1.0. 

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated for final SAC.
10.4.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.


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Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
10.4.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created as per GUI_51487, 
Noncompartmental Analysis of Pharmacokinetic Data.
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive summary 
statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
AUC/Dose, 
Ratio of plasma [14C] GSK1278863/total radioactivity for Cmax, AUC(0-inf), AUCzl(0-t)
Ae[urine], Ae[faeces], Ae[total]
Fe%[urine], Fe%[faeces], Fe%[total]
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to GUI_51487.
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.


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10.5.
Appendix 5: Derived and Transformed Data
10.5.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First 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    
10.5.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:

Since Year of Birth is recorded in pCRF, date and month will be imputed as ‘30th June’ of that 
year.

Birth date will be presented in listings as ‘YYYY’.
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:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

For Period1 consider oral start date and IV stop date for duration of exposure Subjects who 
were allocated to treatment but did not report a treatment start date will be categorised as 
having zero days of exposure.
10.5.3.
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 decimal places in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 


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Laboratory Parameters

Example 1: 2 Decimal Places = ‘< x’ becomes x – 0.01

Example 2: 1 Decimal Places = ‘> x’ becomes x + 0.1

Example 3: 0 Decimal Places = ‘< x’ becomes x – 1
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.

Machine read values of RR should not be replaced with derived values.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as : 
10.5.4.
Pharmacokinetic
PK Endpoints
AUC(0-t), AUC (0-∞)

PK endpoints used to assess the bioavailability i.e. AUC(0-t) and AUC (0-∞) will be divided by 
corresponding dose (converted into ng) before passing to MM model.

Metabolite of interest are GSK2391220, GSK2506104, GSK2487818, GSK2506102, GSK2531398, 
GSK2531401

The ratio of plasma [14C] GSK1278863/total radioactivity for Cmax,AUC(0-inf),AUC(0-t) will be 
calculated and summarized for radiolabelled dose in  each period.


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10.6.
Appendix 6: Reporting Standards for Missing Data
10.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as one who has 
completed all phases of the study including the last follow-up visit.

The end of the study is defined as the date of the last contact with the last participant in 
the study.

Withdrawn subjects will not be replaced unless the total number of participants who 
complete dosing and all critical assessments drops below 4.

All available data from subjects who were withdrawn from the study will be listed and all 
available planned data will be included in summary tables and figures, unless otherwise 
specified.
10.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is 
excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.6.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The pCRF 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:

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 3: Study Phases and Treatment 
Emergent Adverse Events.

Missing Start Month: January will be used as the Month unless this is
before the Month of start of the study treatment; in that case the Month of 
study treatment start will be used.

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.

Missing Month of Stop: December will be used as the Month unless this
is after the Month of stop of the study treatment; in that case the Month
of study treatment stop, will be used.


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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.

Start or end dates which are completely missing (i.e. no year specified) will remain 
missing, with no imputation applied.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the pCRF 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.


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10.7.
Appendix 7: Values of Potential Clinical Importance
10.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Calcium
mmol/L
2
2.75
Creatinine
µmol/L
∆from BL
>30% increase from Baseline 
Glucose
mmol/L
3
9
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT


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10.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450 
Absolute PR Interval
msec
< 110 
> 220 
Absolute QRS Interval
msec
< 75 
> 110 
Change from Baseline
Increase from Baseline QTc
msec
> 60 
10.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥ 20
≥ 40
≥ 20
≥ 40
Diastolic Blood Pressure
mmHg
≥ 10
≥ 20
≥ 10
≥ 20
Heart Rate
bpm
≥ 15
≥ 30
≥ 15
≥ 30


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10.8.
Appendix 8: Abbreviations & Trade Marks
10.8.1.
Abbreviations
Abbreviation
Description
A&R
Analysis and Reporting 
ADaM
Analysis Data Model
AE
Adverse Event
Ae
Amount excreted
Fe
Fecal excreted
ALT
Alanine aminotransferase
AMS
Accelerator Mass Spectrometry
AUC(0–inf)
Area under the concentration-time curve from time zero (pre-dose)
extrapolated to infinite time
AUC(0–t)
Area under the concentration-time curve from time zero (pre-dose) to
last time of quantifiable concentration within a participant across all
treatments
BIB
Bioanalysis, Immunogenicity and Biomarkers
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
Cmax
Maximum observed concentration
CPMS
Clinical Pharmacology Modelling & Simulation
CSR
Clinical Study Report
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
F
Absolute bioavailability
FDA
Food and Drug Administration
GSK
GlaxoSmithKline
GUI
Guidance
IA
Interim Analysis
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
IV
Intravenous
mg
Milligrams
MSE
Mean Square Error
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 


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Abbreviation
Description
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
QTcB
Bazett’s QT Interval Corrected for Heart Rate
QTcF
Frederica’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RR
Respiratory Rate
SAC
Statistical Analysis Complete
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TFL
Tables, Figures & Listings 
μg 
Microgram
10.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
HARP
Entero-Test
SAS
WinNonlin


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41
10.9.
Appendix 9: List of Data Displays
10.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.8
Pharmacokinetic
2.1 to 2.13
2.1 to 2.11
Safety
3.1 to 3.13
Section
Listings
ICH Listings
1 to 26
Other Listings
27 to 35
10.9.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 10: Example Mock Shells for Data Displays Example 
Mock Shells for Data Displays.
Section
Figure
Table
Listing
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
10.9.3.
Deliverables
Delivery 
Description
DR
Dry Run
SAC 
Final Statistical Analysis Complete


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10.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1A
Summary of Participant Disposition for the Participant
Conclusion Record
DR, SAC
1.2.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
DR, SAC
1.3.
Enrolled
NS1
Summary of Number of Participant by Country and Site ID
DR, SAC
Protocol Deviation
1.4.
Safety
DV1
Summary of Important Protocol Deviations
DR, SAC
Population Analysed
1.5.
Screened
SP1A
Summary of Study Populations 
DR, SAC
Demographic and Baseline Characteristics
1.6.
Safety
DM3
Summary of Demographic Characteristics
Include height, weight & BMI.
DR, SAC
1.7.
Enrolled
DM11
Summary of Age Ranges
DR, SAC
1.8.
Safety
DM5
Summary of Race and Racial Combinations
DR, SAC


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43
10.9.5.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Plasma GSK1278863 and Plasma [14C] GSK1278863
2.1.
PK
pkct1
Summary of Plasma GSK1278863 and [14C] GSK1278863 Concentration 
by treatment and time 
GSK1278863: Summarized for A1 
only
[14C] GSK1278863: Summarized 
for A2 and B treatment group only
Page by Regimen 
DR, SAC
2.2.
PK
pkpt1
Summary of Untransformed Plasma GSK1278863 and [14C] GSK1278863 
Pharmacokinetic Parameters
GSK1278863: Summarized for A1 
only
[14C] GSK1278863: Summarized 
for A2 and B treatment group only
Page by Regimen
DR, SAC
2.3.
PK
pkpt3
Summary of Loge-transformed Plasma GSK1278863 and [14C] 
GSK1278863 Pharmacokinetic Parameters 
GSK1278863: Summarized for A1 
only
[14C] GSK1278863: Summarized 
for A2 and B treatment group only
Page by Regimen
DR, SAC
Plasma Metabolite and [14C] Metabolite
2.4.
PK
pkct1
Summary of Plasma Metabolite and [14C] Metabolite concentration by time
Metabolite: Summarized for A1 
only
[14C] Metabolite: Summarized for
A2 and B treatment group only
Page by Regimen
DR, SAC


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44
Pharmacokinetic: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.5.
PK
pkpt1
Summary of Untransformed Plasma Metabolite and [14C] Metabolite
Pharmacokinetic Parameters 
Metabolite: Summarized for A1 
only
[14C] Metabolite: Summarized for 
A2 and B treatment group only
Page by Regimen
DR, SAC
2.6.
PK
pkpt3
Summary of Loge-transformed Plasma Metabolite and [14C] Metabolite
Concentration Pharmacokinetic Parameters 
Metabolite: Summarized for A1 
only
[14C] Metabolite: Summarized for 
A2 and B treatment group only
Page by Regimen
DR, SAC


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45
Urine and Faecal Pharmacokinetic
2.10.
PK
PK_T 1
Summary of Cumulative Urinary and Faecal Total 
Radioactivity Pharmacokinetic Parameters (Amount 
Excreted(unit)) by Time (Treatment Period-2)
Includes (urine), Ae (faeces), Ae (total) 
parameter.
DR, SAC
2.11.
PK
PK_T1
Summary of Cumulative Urinary and Faecal Total 
Radioactivity Radioactivity Pharmacokinetic Parameters (% 
Excreted) by Time
Fe% (urine), Fe %(faeces), Fe% (total).
DR, SAC
Pharmacokinetic: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Total Radioactivity
2.7.
PK
pkct1
Summary of Blood and Plasma Total Radioactivity 
Concentration by Treatment and time
Page by Specimen Type
Summarized only for [14C]-863 50 mcg 
IV and [14C]-GSK863 25 mg Oral 
Solution -Treatment groups
DR, SAC
2.8.
PK
pkpt1
Summary of Untransformed Plasma Total Radioactivity 
Pharmacokinetic Parameters
Page by Specimen Type
Summarized only for [14C]-863 50 mcg 
IV and [14C]-GSK863 25 mg Oral 
Solution -Treatment groups
DR, SAC
2.9.
PK
pkpt3
Summary of Loge-transformed Blood Total Radioactivity 
Pharmacokinetic Parameters
Pageby Specimen Type
Summarized only for [14C]-863 50 mcg 
IV and  [14C]-GSK863 25 mg Oral 
Solution -Treatment groups
DR, SAC


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46
10.9.6.
Pharmacokinetic Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Plasma GSK1278863 and [14C]- GSK1278863
2.1.
PK
pkcf6
Individual Subject Plasma GSK1278863 and [14C] GSK1278863 
Concentration-time Plot (Linear and Semi-log) by Treatment
Different plot symbols will be used for 
each subject
DR, SAC
2.2.
PK
pkcf2
Arithmetic Mean Plasma GSK1278863 and [14C] GSK1278863 
Concentration-time Plot (Linear and Semi-log) by Treatment
DR, SAC
2.3.
PK
pkcf3
Median Plasma GSK1278863 and [14C] GSK1278863 Concentration -
time Plot (Linear and Semi-log) by Treatment
DR, SAC
Total Radioactivity
2.4.
PK
pkcf6
Individual Subject Total Radioactivity Concentration-time Plot (Linear 
and Semi-log) by Treatment and Specimen
Summarized only for [14C]-863 50 
mcg IV and [14C]-GSK863 25 mg 
Oral Solution -Treatment groups
DR, SAC
2.5.
PK
pkcf2
Arithmetic Mean Total Radioactivity Concentration-time Plot (Linear and 
Semi-log) by Treatment and Specimen
Summarized only for [14C]-863 50 
mcg IV and [14C]-GSK863 25 mg 
Oral Solution -Treatment groups
DR, SAC
2.6.
PK
pkcf3
Median Total Radioactivity Concentration -time Plot (Linear and Semi-
log) by Treatment
Summarized only for [14C]-863 50 
mcg IV and [14C]-GSK863 25 mg 
Oral Solution -Treatment groups
DR, SAC
Other Output
2.12.
PK
pkpt3
Summary of Ratio of plasma [14C] GSK1278863: Total 
Radioactivity PK parameter ratios by treatment
only for Cmax, AUC(0-t) and AUC(0-inf)
parameters
DR, SAC
PK Statistical Analysis
2.13.
  
PK
PK_T2
Summary of Statistical Analysis of Loge-transformed Plasma 
GSK1278863 PK Parameters
DR, SAC


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200232
47
Metabolite and [14C]-Metabolite
2.7.
PK
pkcf6
Individual Subject Plasma Metabolite and [14C]-Metabolite 
Concentration-time Plot (Linear and Semi-log) for GSK1278863 6mg 
oral dose
Page by metabolites
DR, SAC
2.8.
PK
pkcf2
Arithmetic Mean Plasma Metabolite and [14C]-Metabolite 
Concentration-time Plot (Linear and Semi-log) for GSK1278863 6mg 
oral dose
Page by metabolites
DR, SAC
10.9.7.
Safety Tables
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE1CP
Summary of All Adverse Events by System Organ Class and 
Preferred Term
DR, SAC
3.2.
Safety
AE1CP 
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term/by Overall Frequency
DR, SAC
2.9.
PK
pkcf3
Median Plasma Metabolite and [14C]-Metabolite Concentration 
Plot (Linear and Semi-log) for GSK1278863 6mg oral dose
Page by metabolites
DR, SAC
Urine and Faecal Pharmacokinetic
2.10.
PK
PK_F1
Individual Subject Cumulative Total Radioactivity Recovered 
(% of Dose) for Urine, Faeces and Total Excretion by Subject
DR, SAC
2.11.
PK
PK_F2
Arithmetic Mean Cumulative 14C -Radioactivity Recovered (% 
of Dose) for Urine, Faeces and Total Excretion 
DR, SAC


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48
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.3.
Safety
AE15
Summary of Common (>=33%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences)
DR, SAC
Serious and Other Significant Adverse Events
3.4.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
DR, SAC
Laboratory: Chemistry 
3.5.
Safety
LB1
Summary of Chemistry Changes from Baseline 
DR, SAC
3.6.
Safety
LB1
Summary of Laboratory Values
DR, SAC
3.7.
Safety
LB15
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline 
DR, SAC
Laboratory: Hematology
3.8.
Safety
LB1
Summary of Hematology Changes from Baseline
Includes baseline values.
DR, SAC
3.9.
Safety
LB1
Summary of Hematology values 
DR, SAC
3.10.
Safety
LB15/
Summary of Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline
DR, SAC
ECG
3.11.
Safety
EG1
Summary of ECG Findings 
DR, SAC
3.12.
Safety
EG2
Summary of ECG Values
DR, SAC
Vital Signs
3.13.
Safety
VS1
Summary of Change from Baseline in Vital Signs
DR, SAC


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10.9.8.
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
DR, SAC
2.
Safety
ES3
Listing of Reasons for Study Withdrawal
DR, SAC
Protocol Deviations
3.
Safety
DV2A
Listing of Important Protocol Deviations 
DR, SAC
4.
Safety
IE4
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
DR, SAC
Demographic and Baseline Characteristics
5.
Safety
DM4
Listing of Demographic Characteristics
DR, SAC
6.
Safety
DM10
Listing of Race
DR, SAC
Prior and Concomitant Medications
7.
Safety
CP_CM4
Listing of Concomitant Medications
DR, SAC
Exposure and Treatment Compliance
8.
Safety
EX4
Listing of Exposure Data
DR, SAC
Adverse Events
9.
Safety
AE9CP
Listing of All Adverse Events
DR, SAC
10.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
DR, SAC
11.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
DR, SAC
Serious and Other Significant Adverse Events
12.
Safety
AE9CPa
Listing of Serious Adverse Events
DR, SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
13.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study
DR, SAC
14.
Safety
AE9CP
Listing of Treatment emergent AEs
DR, SAC
Hepatobiliary (Liver)
15.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
DR, SAC
16.
Safety
MH3
MH3 Listing of Medical Conditions for Subjects with Liver 
Stopping
DR, SAC
17.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping
Events
DR, SAC
All Laboratory
18.
Safety
LB6
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance/Outside Normal Range
DR, SAC
19.
Safety
LB6
Listing of Laboratory Values of Potential Clinical Importance
DR, SAC
20.
Safety
UR2b
Listing of Urinalysis Data for Subjects with Positive Dipstick
Results 
DR, SAC
ECG
21.
Safety
EG4
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
DR, SAC
22.
Safety
EG4
Listing of ECG Values of Potential Clinical Importance
DR, SAC
23.
Safety
EG6
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding
DR, SAC


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51
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
24.
Safety
VS5
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance
IDSL
Required for ClinPharm studies 
only. Display ALL Vital Signs for a 
subject who experienced a value of 
potential clinical importance.
DR, SAC
25.
Safety
VS5
Listing of Vital Signs of Potential Clinical Importance
IDSL
Required for ClinPharm studies 
only.
DR, SAC


CONFIDENTIAL
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52
10.9.9.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK
26.
PK
PK_L1
Listing of Urinary and Faecal Total -Radioactivity Parameters
(Amount Excreted) by Time
Include absolute and cumulative 
for urine, faeces and total
Only for Treatment Period-2
DR, SAC
27.
PK
PK_L2
Listing of Urinary and Faecal Total-Radioactivity Parameters (% 
Excreted) by Time
Include absolute and cumulative 
for urine, faeces and total
Only for Treatment Period-2
DR, SAC
28.
PK
pkcl1x
Listing of Plasma GSK1278863 and [14C] - GSK1278863
Concentration-time Data
DR, SAC
29.
PK
pkpl1x
Listing of Plasma GSK1278863 and [14C] - GSK1278863
Pharmacokinetic Parameters
DR, SAC
30.
PK
pkcl1x
Listing of Blood and Plasma Total-Radioactivity Concentration -time 
Data
DR, SAC
31.
PK
pkpl1x
Listing of Blood and Plasma Total -Radioactivity Pharmacokinetic 
Parameters
DR, SAC
32.
PK
pkcl1x
Listing of Plasma Metabolite and [14C]-Metabolite Concentration -
time Data
DR, SAC
33.
PK
pkpl1x
Listing of Plasma Metabolite and [14C]-Metabolite Pharmacokinetic 
Parameters
DR, SAC
34.
PK
N/A
Supportive SAS Output from Statistical Analysis of Loge-
transformed Plasma GSK1278863 Pharmacokinetic Parameters
DR,SAC


CONFIDENTIAL
200232
53
10.10.
Appendix 10: Example Mock Shells for Data Displays
Example 
: PK_T1
                        
Page 1 of n
Protocol
: 200232
Population
: PK
Table 2.10
Summary of Cumulative Urinary and Faecal Total Radioactivity Parameters (Amount Excreted (unit)) by Time
                                          Planned
                                          Relative                                                    
   Treatment                          N   Time         n    Mean   SD      Median  Min.   Max. 
   -------------------------------------------------------------------------------------------
   14C]GSKXXXX
     Ae Faeces     X   PRE DOSE     X     X.XX  X.XXX    X.XX   X.X    X.X 
                                          X-XX H       X     X.XX  X.XXX    X.XX   X.X   XX.X 
                                          XX-XX H      X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XX-XX H      X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XX-XX H      X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XX-XXX H     X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XXX-XXX H    X    XX.XX  X.XXX   XX.XX   X.X   XX.X  
                        Ae Urine      X   PRE DOSE     X     X.XX  X.XXX    X.XX   X.X    X.X 
                                          X-XX H       X     X.XX  X.XXX    X.XX   X.X   XX.X 
                                          XX-XX H      X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XX-XX H      X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XX-XX H      X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XX-XXX H     X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XXX-XXX H    X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                        Ae Total      X   PRE DOSE     X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                        (Faeces+Urine)    X-XX H       X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XX-XX H      X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XX-XX H      X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XX-XX H      X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XX-XXX H     X    XX.XX  X.XXX   XX.XX   X.X   XX.X 
                                          XXX-XXX H    X    XX.XX  X.XXX   XX.XX   X.X   XX.X 


CONFIDENTIAL
200232
54
Example 
: PK_T2
                                        Page 1 of n
Protocol
: mid200232
Population
: PK
Table 2.4
Summary of Statistical Analysis of Loge-transformed Plasma GSK1278863 PK Parameters
Parameter
   Comparison
       Adjusted Geometric Mean
               Ratio
90% Confidence
%CVw
Test vs Reference
(Dose normalised)
(Test/Ref)
Interval for the Ratio
          n    Test        n    Ref
AUC(0-inf)(units)  
   A1 vs    A2
                      x   xx.xx          x  xx.xx
x.xxxx
(x.xxxx, x.xxxx)
xx.x
   
AUC(0-t)(units)     
A1 vs a2
            
       x   xx.xx          x  xx.xx
x.xxxx
(x.xxxx, x.xxxx)
xx.x
FOOTNOTE:
Note:
A1: GSK1278863 6mg Oral
A2: [14C]-GSK1278863 50 mcg IV


CONFIDENTIAL
200232
55
Example 
: PK_F1 
       Page 1 of n
Protocol           : 200232
Population
: PK
Figure 2.7
Individual Subject Cumulative Total Radioactivity Recovered (% of Dose) for Urine, Faeces and Total Excretion by Subject
Actual Mid-Point of Collection (hrs)


CONFIDENTIAL
200232
56
Example 
: PK_F2
       Page 1 of n
Protocol
: 200232
Population
: PK
Figure 2.8
Arithmetic Mean Cumulative total -Radioactivity Recovered (% of Dose) for Urine, Faeces and Total Excretion 


CONFIDENTIAL
200232
57
Example 
: PK_L1 
                       Page 1 of X
Protocol
: MID200232
Population
: PK
Listing XX
Listing of Urinary and Faecal Total radioactivity Parameters (Amount Excreted) by Time
Treatment: [14C]GSKXXXX
         
         Fe Faeces    Fe Urine
         Start Date/  Start Date/
         Time/        Time/        Planned
Inv./   End Date/    End Date/    Relative             Cumulative          Cumulative          Cumulative
Subj.   Time         Time         Time       Ae Faeces Ae Faeces  Ae Urine  Ae Urine  Ae Total  Ae Total
---------------------------------------------------------------------------------------------------------
XXXXXX/ XXJUNXXXX/   XXJUNXXXX/   PRE DOSE X    X.X        X.X      X.X        X.X       X.X       X.X
XXX     X:XX/        XX:XX/
         XXJUNXXXX/   XXJUNXXXX/
         X:XX         XX:XX
        XXJUNXXXX/   XXJUNXXXX/   X-XX H       XX.X       XX.X      XX.X      XX.X      XX.X      XX.X
         X:XX/        X:XX/
         XXJUNXXXX/   XXJUNXXXX/
         X:XX         X:XX
         XXJUNXXXX/   XXJUNXXXX/   XX-XX H      XX.X       XX.X      X.X       XX.X      XX.X      XX.X
         X:XX/        X:XX/
         XXJUNXXXX/   XXJUNXXXX/
         X:XX         X:XX
         XXJUNXXXX/   XXJUNXXXX/   XX-XX H       X.X       XX.X      X.X       XX.X       X.X      XX.X
Note: Ae = Amount excreted. NS = No Sample.


CONFIDENTIAL
200232
58
Example 
: PK_L2 
                       Page 1 of X
Protocol
: MID200232
Population
: PK
Listing XX
Listing of Urinary and Faecal Total Radioactivity Parameters (% Excreted) by Time
   
Treatment: [14C]GSKXXXX
         
         Fe Faeces    Fe Urine
         Start Date/  Start Date/
         Time/        Time/        Planned
Inv./   End Date/    End Date/    Relative             Cumulative          Cumulative          Cumulative
Subj.   Time         Time         Time       Fe Faeces Fe Faeces    Fe Urine  Fe Urine  Fe Total  Fe Total
---------------------------------------------------------------------------------------------------------
XXXXXX/ XXJUNXXXX/   XXJUNXXXX/   PRE DOSE X     X.X        X.X      X.X        X.X       X.X       X.X
XXX     X:XX/        XX:XX/
         XXJUNXXXX/   XXJUNXXXX/
         X:XX         XX:XX
         XXJUNXXXX/   XXJUNXXXX/   X-XX H        XX.X       XX.X      XX.X      XX.X      XX.X      XX.X
         X:XX/        X:XX/
         XXJUNXXXX/   XXJUNXXXX/
         X:XX         X:XX
         XXJUNXXXX/   XXJUNXXXX/   XX-XX H        XX.X       XX.X      X.X       XX.X      XX.X      XX.X
         X:XX/        X:XX/
         XXJUNXXXX/   XXJUNXXXX/
         X:XX         X:XX
         XXJUNXXXX/   XXJUNXXXX/   XX-XX H       X.X       XX.X      X.X       XX.X       X.X      XX.X
Note: Fe = Fraction excreted as a percentage of total radioactive dose. NS = No Sample.