A Two-part, Randomized, Double-blind, Single-dose, Crossover Study to Compare Formulations Produced by Two Methods of Manufacture for Bioequivalence and Dissolution in Healthy Adult Volunteers
Phase: PHASE1
Conditions: Anaemia
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
213022
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TITLE PAGE
Protocol Title: A two-part, randomized, double-blind, single-dose, crossover study to 
compare formulations produced by two methods of manufacture for bioequivalence and 
dissolution in healthy adult volunteers
Protocol Number: 213022
Compound Number 
or Name:
GSK1278863 
Study Phase: Phase 1 
Short Title: BE and Dissolution PK Study
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Regulatory Agency Identifying Number(s):
IND: 101,291
Approval Date: 21-AUG-2020
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

1
From:
Sent:
Monday, August 24, 2020 7:35 PM
To:
Subject:
FW: Prot-213022-sponsign
 
 
From: Alex Cobitz 
  
Sent: Friday, August 21, 2020 1:59 PM 
To:
Cc: 
Subject: RE: Prot-213022-sponsign 
 
, 
 
                I approve. 
 
                                Alex 
 
From: 
  
Sent: Friday, August 21, 2020 12:36 PM 
To: Alex Cobitz 
Subject: Prot-213022-sponsign 
 
Dear Sponsor, 
 
To approve the clinical protocol indicated below, reply to this email and state your approval. 
 
PROTOCOL NUMBER: 213022 
 
DOCUMENT IDENTIFIER:  2020N427368_00 
 
PROTOCOL TITLE:  A two-part, randomized, double-blind, single-dose, crossover study to compare formulations 
produced by two methods of manufacture for bioequivalence and dissolution in healthy adult volunteers 
 
I have read this report and confirm that to the best of my knowledge it accurately describes the conduct and results of 
the study. 
Name of Sponsor Signatory: 
Alexander R. Cobitz, M.D., Ph.D 
Title of Sponsor Signatory: 
Executive Director, Clinical Development 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................6
1.1.
Synopsis.......................................................................................................6
1.2.
Schema ........................................................................................................9
1.3.
Schedule of Activities (SoA)........................................................................10
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Background ................................................................................................13
2.3.
Benefit/Risk Assessment ............................................................................13
2.3.1.
Benefit Assessment.....................................................................15
2.3.2.
Overall Benefit: Risk Conclusion..................................................15
3.
OBJECTIVES AND ENDPOINTS...........................................................................16
4.
STUDY DESIGN ....................................................................................................17
4.1.
Overall Design ............................................................................................17
4.2.
Scientific Rationale for Study Design ..........................................................18
4.2.1.
Participant Input into Design ........................................................18
4.3.
Justification for Dose ..................................................................................18
4.4.
End of Study Definition ...............................................................................18
5.
STUDY POPULATION...........................................................................................18
5.1.
Inclusion Criteria.........................................................................................19
5.2.
Exclusion Criteria........................................................................................20
5.3.
Lifestyle Considerations..............................................................................21
5.3.1.
Meals and Dietary Restrictions ....................................................21
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................21
5.3.3.
Activity .........................................................................................21
5.4.
Screen Failures...........................................................................................21
5.5.
Self-isolation...............................................................................................22
6.
STUDY INTERVENTION........................................................................................22
6.1.
Study Intervention(s) Administered .............................................................22
6.2.
Preparation/Handling/Storage/Accountability..............................................24
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................25
6.4.
Study Intervention Compliance ...................................................................26
6.5.
Concomitant Therapy..................................................................................26
6.6.
Dose Modification .......................................................................................26
6.7.
Intervention after the End of the Study........................................................26
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL.....................................................................27
7.1.
Discontinuation of Study Intervention..........................................................27
7.1.1.
Liver Chemistry Stopping Criteria ................................................27
7.1.2.
Other Stopping Criteria ................................................................28
7.1.3.
Temporary Discontinuation ..........................................................28
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................28
7.3.
Lost to Follow Up........................................................................................29

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8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................29
8.1.
Safety Assessments ...................................................................................30
8.1.1.
Physical Examinations.................................................................30
8.1.2.
Vital Signs....................................................................................30
8.1.3.
Electrocardiograms......................................................................30
8.1.4.
Clinical Safety Laboratory Assessments ......................................31
8.2.
Adverse Events and Serious Adverse Events.............................................31
8.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................31
8.2.2.
Method of Detecting AEs and SAEs.............................................32
8.2.3.
Follow-up of AEs and SAEs.........................................................32
8.2.4.
Regulatory Reporting Requirements for SAEs .............................32
8.2.5.
Pregnancy ...................................................................................33
8.2.6.
Adverse Events of Special Interest ..............................................33
8.3.
Treatment of Overdose...............................................................................33
8.4.
Pharmacokinetics .......................................................................................34
8.5.
Pharmacodynamics ....................................................................................34
8.6.
Genetics .....................................................................................................34
8.7.
Biomarkers .................................................................................................34
9.
STATISTICAL CONSIDERATIONS........................................................................35
9.1.
Statistical Hypotheses.................................................................................35
9.2.
Sample Size Determination ........................................................................35
9.3.
Populations for Analyses ............................................................................36
9.4.
Statistical Analyses.....................................................................................37
9.4.1.
General Considerations ...............................................................37
9.4.2.
Primary Endpoint(s).....................................................................38
9.4.3.
Secondary Endpoint(s) ................................................................39
9.4.4.
Safety Analyse(s).........................................................................39
9.5.
Interim Analyses .........................................................................................40
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................41
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight
Considerations............................................................................................41
10.1.1.
Regulatory and Ethical Considerations ........................................41
10.1.2.
Financial Disclosure.....................................................................41
10.1.3.
Informed Consent Process ..........................................................42
10.1.4.
Data Protection............................................................................42
10.1.5.
Dissemination of Clinical Study Data ...........................................42
10.1.6.
Data Quality Assurance ...............................................................43
10.1.7.
Source Documents ......................................................................44
10.1.8.
Study and Site Start and Closure.................................................44
10.1.9.
Publication Policy.........................................................................45
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................46
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................48
10.3.1.
Definition of AE............................................................................48
10.3.2.
Definition of SAE..........................................................................49
10.3.3.
Recording and Follow-Up of AE and SAE....................................50
10.3.4.
Reporting of SAE to GSK.............................................................52

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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................53
10.4.1.
Definitions:...................................................................................53
10.4.2.
Contraception Guidance: .............................................................53
10.4.3.
Collection of Pregnancy Information: ...........................................55
10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................56
10.6.
Appendix 6: Abbreviations and Trademarks................................................58
10.7.
Appendix 7: Handling of Clinical Testing Samples for Pivotal 
Bioequivalence Studies...............................................................................61
10.8.
Appendix 8: COVID-19 Considerations.......................................................63
11. REFERENCES.......................................................................................................65

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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A two-part, randomized, double-blind, single-dose, crossover study to 
compare formulations produced by two methods of manufacture for bioequivalence and 
dissolution in healthy adult volunteers
Short Title: BE and Dissolution PK study
Rationale: Daprodustat tablets manufactured via Process 1 (twin screw granulation) have 
been administered in the daprodustat Phase III program and with the intent to be 
commercialized.  Daprodustat tablets produced by a second process (Process 2, using 
high shear wet granulation) are being developed to enable manufacturing flexibility and 
add supply capacity.  
To support the development of daprodustat tablets via process 2, the proposed study, 
Study 213022, will be conducted and will consist of two parts, Part A and Part B. Part A 
and Part B will be conducted independently. Results from Part A will not be required 
prior to the start of Part B.
Part A will be a three-treatment period, period balanced crossover design to characterize 
the pharmacokinetic (PK) profile of 4 mg reference tablet made by Process 1 compared to 
two sets of 4 mg tablets made by Process 2 each with successively differentiated 
dissolution profiles. PK results from Part A will be used to justify how much variation in 
dissolution profiles may be acceptable and to establish the clinical relevance of 
dissolution profiles in order to obtain regulatory flexibility in the dissolution 
specification.    
Part B will be a two-treatment period, period balanced crossover design to assess the PK 
bioequivalence (BE) of tablets produced by Process 1 and Process 2 following 
administration of a single dose of 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg of daprodustat in 5 
groups of healthy participants. The purpose of Part B is to demonstrate BE for each of the 
dose strengths. The results from Part B will be used to support the global file and 
supplying Japan with daprodustat manufactured by the new process for commercial use.

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Objectives and Endpoints:
Part A
Objectives
Endpoints
Primary

To characterize single dose  PK 
profile of  4 mg daprodustat tablets 
with two different dissolution 
profiles made by Process 2 relative 
to the reference 4 mg daprodustat 
tablet made by Process 1
Area under the concentration-time curve
[AUC (0-t)] and Maximum observed 
concentration (Cmax) of daprodustat
Secondary

To assess remaining daprodustat 
pharmacokinetic parameters
AUC (0-inf), Time of occurrence of Cmax
(Tmax), half life (t1/2), clearance/fraction 
(CL/F) and volume/fraction (V/F) of 
daprodustat
Safety

To evaluate the safety and 
tolerability of single doses of 
daprodustat made by Process 2 
relative to daprodustat made by 
process 1
Safety and tolerability will be assessed by 
clinical data from adverse event (AE) 
reporting, vital signs, and clinical 
laboratory tests
Part B
Objectives
Endpoints
Primary

To establish BE between
daprodustat tablets made by two 
different manufacturing 
processes, Process 1 and Process 
2, for the following dose 
strengths administered as a 
single dose:

1 mg
AUC (0-t) and Cmax of
daprodustat

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Objectives
Endpoints

2 mg

4 mg

6 mg

8 mg
Secondary

To assess remaining daprodustat 
PK parameters
AUC (0-inf), Tmax, t1/2, CL/F and V/F of 
daprodustat
Safety

To evaluate the safety and 
tolerability of single doses of 
daprodustat made by Process 2 
relative to daprodustat made by 
Process 1
Safety and tolerability will be assessed 
by clinical data from adverse event (AE) 
reporting, vital signs, and clinical 
laboratory tests
Overall Design: Part A of this randomized, double-blind, single-dose, 3-period crossover
study in healthy volunteers will compare the PK parameters and safety of 4 mg of 
daprodustat tablets with two different dissolution profiles made by Process 2 relative to 
the reference 4 mg daprodustat tablet made by Process 1.
Part B of this randomized, double-blind, single-dose, 2-period crossover study in healthy 
volunteers will establish the BE and compare the safety of daprodustat tablets produced 
by two different manufacturing processes (Process 1 and Process 2) for each of the 
following dose strengths: 1 mg, 2 mg, 4 mg, 6 mg, and 8mg. Participants will be 
randomized to only one dose strength.
Disclosure Statement: This is comprised of two discrete Parts. Part A is a 3-period cross 
over evaluating relative bioavailability. Part B is a 2-period cross over evaluating 
bioequivalence. Participants will participate in Part A or Part B, but not both. 
Number of Participants:
The expected number of participants who will complete Part A is 30. 
The expected number of participants who will complete Part B is 190. 
The expected number of participants who will complete the study is 220. 

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Intervention Groups and Duration: Part A participants can expect a study duration of 
approximately 56 days from screening through the follow up visit; Part B participants can 
expect a study duration of approximately 49 days from screening through the follow up 
visit. 
For both Part A and Part B, the screening period is up to 30 days, each single-dose 
treatment period is up to 48h, each washout period between treatments (and between the 
last dose and follow up) is at least 7 days. 
Data Monitoring or Other Committee: No
1.2.
Schema
Part A study schematic
Part B study schematic:

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1.3.
Schedule of Activities (SoA)
Part A -OR- Part B
Procedure
Screen1
Intervention (Part A Periods 1, 2, & 3 OR Part B Periods 1 & 2)10
Follow-
up9
Day -1
Day 1
Day 2
Pre-dose
0h
0.5h
1h
2h
2.5h
3h
4h
6h
8h
12h
24h
Informed Consent
X
Inclusion / Exclusion2
X
X
Demography
X
Physical Examination3
X
X
12-Lead electrocardiogram (ECG)
X
Vital Signs4
X
X
X
X
Clinical Laboratory Test5
X
X
X
Pregnancy Test6
X
X
X
Urine Drug Screen and Alcohol 
Screen7
X
Randomization
X
Study Intervention Dose8
X
PK Blood Sampling
X
X
X
X
X
X
X
X
X
X
X
AE/Serious AE
----------------------------------------------------------------------------------------------------------------------------------------
Concomitant Medication Review
----------------------------------------------------------------------------------------------------------------------------------------
Admission to Unit
X
Discharge from Unit
X
Outpatient Visit
X
X
COVID-19 testing (PCR or antigen)
X
X12
<--------------------------------Ad hoc based on continuous review------------------------------>
1 Within 30 days of Day 1, Period 1
2 Re-check eligibility at Day -1 (admission to Unit)
3 Brief Physical Examination on Day -1
4 Body temperature, pulse, systolic & diastolic blood pressure (semi-supine)

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5 Hematology, clinical chemistry (including liver), and urinalysis
6 Urine or serum per site standard; females only
7 Alcohol screening can be performed via urine or breathalyser per site standard
8 Time 0 is the time of study interventional drug dosing, and all subsequent timed assessments are calculated from Time 0. 
97 (1) days from dose day Period 3, Part A -OR- 7 (1) days from dose day Period 2, Part B. Same assessments will be performed for early withdraw visit.
10A minimum of 7 days is required between each treatment-period’s dosing, i.e., at least 7 days between Period 1 and Period 2, and between Period 2 and Period 3 
dosing in Part A, and 7 days between Period 1 and Period 2 dosing in Part B
12 COVID-19 PCR or antigen testing may be done prior to Day -1 (admission to the study unit) such that the results are timed to arrive just prior to admission, 
ideally within 72h of admission to the study unit.

2 0 2 0 N 4 2 7 3 6 8 _ 0 0
C O N FI D E N TI A L
2 1 3 0 2 2
1 2
2.
IN T R O D U C TI O N
H y p o xia -i n d uci ble fact or ( HI F) pr olyl  h ydr o x yl ase i n hi bit ors ( P HIs) are a n e mer gi n g ne w 
class of a ge nts u n der i n vesti gati o n f or t he treat me nt of a ne mia ass ociate d wit h c hr o nic 
ki d ne y  disease (C K D ). T hese m olec ules sti m ulate er yt hr o p oiesis t hr o u g h i n hi biti on of 
HI F- pr ol y l h ydr o x y lase d o mai n e nz ymes ( P H D 1, P H D 2, P H D 3). T his acti vit y  res ults i n 
t he acc u m ulati o n of HI F α tra nscri pti o n fact ors w hic h lea ds t o i ncrease d tra nscri pti o n of 
HI F-res p o nsi ve ge nes, sti m ulati n g c o m p o ne nts of t he nat ural res p o nse t o h y p o xia . D uri n g 
h y p o xia, P H D e nz y mes are i n hi bite d, res ulti n g i n t he acc u m ulati o n of u n h y dr o x y late d 
HI F α s u b u nits, w hic h di merize wit h HI F β s u b u nits t o affect t he tra nscri pti o n of HI F -
res p o nsi ve ge nes, i ncl u di n g er yt hr o p oieti n (E P O ) a n d ot hers i n v ol ve d i n i ncreas i n g 
o x y ge n a vaila bilit y a n d utilizati o n. Ot her f u ncti o ns re g ulate d b y  HIFs i ncl u de ir o n 
meta b olis m a n d utilizati o n, a n gi o ge nesis, e xtracell ular matri x meta b olis m, a p o pt osis, 
e ner g y a n d gl uc ose meta b olis m, vasc ular t o ne, cell a d hesi o n, a n d m otilit y [Haase , 2 0 1 3].
Da pr o d ustat ( G S K 1 2 7 8 8 6 3) is a s mall m olec ule, oral i n hi biter of t he HI F -P H D e nz y mes 
w hic h ma y  prese nt se veral i m p orta nt a d va nta ges o ver ot her er yt hr o p oieti n sti m ulati n g 
a ge nts (E S As ). It is a n oral me dicati o n a n d d oes n ot re q uire c ol d-c hai n st ora ge as d o 
s o me E S As, t h us i ncreasi n g ease of use f or patie nts. M ore o ver, data i n dicate t hat 
da pr o d ustat ca n effecti vel y  raise he m o gl o bi n ( H g b ) c o nce ntrati o ns wit h l o wer E P O le vels 
t ha n t h ose o bser ve d after a d mi nistrati o n of E S As [Pr o ve nza n o , 2 0 1 1]. 
 
 
2. 1.
St u d y R ati o n al e
Da pr o d ustat ta blets ma n ufact ure d via Pr ocess 1 ha ve bee n a d mi nistere d i n t he 
da pr o d ustat P hase III pr o gra m a n d wit h t he i nte nt t o be c o m mercialize d.  Da pr o d ustat 
ta blets pr o d uced b y  a sec o n d pr ocess ( Pr ocess 2) are bei n g de vel o pe d t o e na ble 
ma n ufact uri n g fle xi bilit y  a n d a d d s u p ply ca pacit y.   
T o s u p p ort t he de vel o p me nt of da pr o d ustat ta blets via Pr ocess 2, t he pr o p ose d st u d y , 
St u d y  2 1 3 0 2 2, will be c o n d ucte d a n d will c o nsist of t wo parts, Part A a n d Part B. Part A 
a n d Part B will be c o n d ucte d i n de pe n de ntl y . Res ults fr o m Part A will n ot be re q uire d 
pri or t o t he start of Part B. 
Part A will be a t hree- treat me nt peri o d, peri o d bala nce d cr oss o ver desi g n t o c haracterize 
t he p har mac o ki netic ( P K ) pr ofile of 4 m g refere nce ta blet ma de b y Pr ocess 1 c o m pare d t o 
t w o sets of 4 m g ta blets ma de by Pr ocess 2 eac h wit h s uccessi vel y differe ntiate d 
diss ol uti o n pr ofiles. P K res ults fr o m Part A will be use d t o j ustif y  h o w m uc h variati o n i n 
diss ol uti o n pr ofiles ma y  be acce pta ble a n d t o esta blis h t he cli nical rele va nce of 
diss ol uti o n pr ofiles i n or der t o o btai n re g ulat or y  fle xi bilit y i n t he diss ol uti o n 
s pecificati o n.    
Part B will be a t w o -treat me nt peri o d, peri o d bala nce d cr oss o ver desi g n t o assess t he P K 
bi oe q ui vale nce ( B E) of ta blets pr o d uce d b y Pr ocess 1 a n d Pr ocess 2 f oll o wi n g 
C CI

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administration of a single dose of 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg of daprodustat in 5 
groups of healthy participants. The purpose of Part B is to demonstrate BE for each of the 
dose strengths. The results from Part B will be used to support global file and supplying 
Japan with daprodustat manufactured by the new process. 
2.2.
Background
Daprodustat is a HIF-PHI currently being investigated as a treatment for anemia 
associated with CKD in both dialysis dependent (DD) and non-dialysis dependent (ND) 
participants, with adequate safety and efficacy demonstrated in clinical trials of up to 24 
weeks’ duration. Both pre-clinical and clinical data show that daprodustat stimulates EPO 
production resulting in increased erythropoiesis and elevation in Hgb concentrations. 
These increases in Hgb are achieved with peak EPO levels substantially lower than those 
observed with ESAs [Hofherr, 2018] [Holdstock, 2016]. Daprodustat is approved in 
Japan. 
Data from completed clinical and pre-clinical studies are provided in the Daprodustat 
Investigator Brochure (IB) [GlaxoSmithKline Document Number RM2008/00267/11, 
2020].
Considering the global COVID-19 pandemic, all participants will be screened for 
COVID-19 prior to, during and at the end of the study period. Please see further details 
for risk assessment and mitigation strategy below.
2.3.
Benefit/Risk Assessment
Pre-clinical and clinical data to date have not identified prohibitive risks associated with 
daprodustat at the exposures planned for this study in healthy subjects.  Overall, the 
compound has been generally well tolerated with no clinically significant safety-related 
findings observed to date following administration in completed studies of up to 500 mg 
single dose and up to 100 mg once daily for 2 weeks in healthy subjects and up to 24 mg 
once daily for 12 months in CKD patients.
Based on the non-clinical studies, the primary areas of interest for daprodustat are related 
to gastrointestinal (GI) tolerability (e.g., stomach erosions with bleeding) and potential 
for thrombosis with ischemia secondary to erythrocytosis (excessive erythropoiesis).
In addition, several events of special interest have been identified based on clinical 
experience with ESAs including increased risk of cancer related morbidity and mortality; 
increased risk of major cardiovascular events (e.g., stroke, myocardial infarction, 
congestive heart failure); and worsening hypertension.
Lastly based on what is currently known of the possible roles for HIF-regulated pathways 
in mediating hypoxia-associated pathophysiology, pulmonary artery hypertension and 
tissue neo-vascularization (e.g., retinal, joint synovium) have also been identified as areas 
of special interest.
Where appropriate, specific eligibility criteria or monitoring instructions relevant to these 
theoretical concerns are included in the study protocol.  

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More detailed information about the known and expected benefits and risks and 
reasonably expected adverse drug reactions of daprodustat may be found in the 
Investigator’s Brochure [GlaxoSmithKline Document Number RM2008/00267/11, 2020].

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2.3.1.
Benefit Assessment
Study participants will not derive any benefit from taking the investigational product 
during the study. 
Study participants will receive study evaluations and assessments and be made aware of 
any findings that may affect decisions about their individual health.
By participating, study participants will be contributing to the process of developing this 
clinically-valuable oral alternative to rhEPO for the treatment of anemia in CKD. 
Study participants may receive a stipend for the inconveniences of study participation, 
participant to local policies and ethical (institutional review board) approval. 
2.3.2.
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, these can 
be addressed with proper participant selection, close safety monitoring, and specific risk 
characterization and mitigation.

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3.
OBJECTIVES AND ENDPOINTS
Part A
Objectives
Endpoints
Primary

To characterize single dose  PK 
profile of  4 mg daprodustat tablets 
with two different dissolution 
profiles made by Process 2 relative 
to the reference 4 mg daprodustat 
tablet made by Process 1
Area under the concentration-time 
curve [AUC (0-t)] and Maximum 
observed concentration (Cmax) of
daprodustat
Secondary

To assess remaining daprodustat 
pharmacokinetic parameters
AUC (0-inf), Time of occurrence of Cmax
(Tmax), half life (t1/2), clearance/fraction 
(CL/F) and volume/fraction (V/F) of 
daprodustat
Safety

To evaluate the safety and 
tolerability of single doses of 
daprodustat made by Process 2 
relative to daprodustat made by 
process 1
Safety and tolerability will be assessed by 
clinical data from adverse event (AE) 
reporting, vital signs, and clinical 
laboratory tests
Part B
Objectives
Endpoints
Primary

To establish BE between
daprodustat tablets made by two 
different manufacturing processes, 
Process 1 and Process 2, for the 
following dose strengths 
administered as a single dose:

1 mg
AUC (0-t) and Cmax of daprodustat

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Objectives
Endpoints

2 mg

4 mg

6 mg

8 mg
Secondary

To assess remaining daprodustat 
PK parameters
AUC (0-inf), Tmax, t1/2, CL/F and V/F of 
daprodustat
Safety

To evaluate the safety and 
tolerability of single doses of 
daprodustat made by Process 2 
relative to daprodustat made by 
Process 1
Safety and tolerability will be assessed by 
clinical data from adverse event (AE) 
reporting, vital signs, and clinical 
laboratory tests
4.
STUDY DESIGN
Part A of this clinical trial is a bioavailability study. 
Part B of this clinical trial is a bioequivalence study. As such, reserve samples from this 
study must be retained (Appendix 7). 
4.1.
Overall Design
Part A of this randomized, double-blind, single-dose, 3-period crossover study in healthy 
volunteers will compare the PK parameters and safety of 4 mg of daprodustat tablets with 
two different dissolution profiles made by Process 2 (high shear wet granulation) relative 
to the reference 4 mg daprodustat tablet made by Process 1 (twin screw granulation).
Part B of this randomized, double-blind, single-dose, 2-period crossover study in healthy 
volunteers will establish the BE and compare the safety of daprodustat tablets produced 
by two different manufacturing processes (Process 1 and Process 2) for each of the 
following dose strengths: 1 mg, 2 mg, 4 mg, 6 mg, and 8mg.

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Part A and B will be conducted independently, i.e., Part B starting will not await Part A
finishing.
4.2.
Scientific Rationale for Study Design
Part A will be utilizing a randomized, three-period, single dose crossover design which is 
well-recognized for assessing PK properties of tablets with two different dissolution 
profiles.
Part B will be utilizing a randomized, two-period, single dose crossover design which is
well established for the demonstration of BE between two drug products according to BE 
guidance from Japan (MHLW, 2012) and the United States (FDA, 2014).  
The double-blind design will allow for the appropriate assessments of the 
safety/tolerability of the two products with as little bias as possible.
4.2.1.
Participant Input into Design
Direct participant input into the study design has not been solicited. Measures to reduce 
participant inconvenience have been incorporated, balanced with study output 
requirements, such as flexible scheduling at the research unit, provision of in-dwelling 
catheter for blood sampling, and stipend for participant time / inconvenience. 
4.3.
Justification for Dose
The doses 1 mg, 2 mg, 4 mg 6 mg, and 8 mg are selected for the study based on the 
dosing of daprodustat in the clinical program and specifically to support the bridging 
strategy for Process 1 and Process 2 globally.
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the follow-up visit.
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities for the last participant in the trial.
This applies to both part A and B separately.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Approximately 48 healthy volunteer participants may be screened to obtain 36
participants eligible for randomization for Part A. The expected number of participants 
who will complete Part A is 30. 

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Approximately 275 healthy volunteer participants may be screened to obtain 210 
participants eligible for randomization for Part B. The expected number of participants 
who will complete Part B is 190 (38 per dose cohort). 
Approximately 323 healthy volunteer participants may be screened to obtain 246
participants eligible for randomization. The expected number of participants who will 
complete the study is 220. 
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1.
Participant must be 18 to 50 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants must be overtly healthy as determined by medical evaluation including 
medical history, physical examination, and laboratory tests. A participant with a 
clinical abnormality or laboratory parameter(s) which is/are not specifically listed in 
the inclusion or exclusion criteria, outside the reference range for the population 
being studied may be included only if the investigator and/or the Medical Monitor 
agree and document that the finding is unlikely to introduce additional risk factors 
and will not interfere with the study procedures
Weight
3.
Body weight 45 kg and body mass index (BMI) within the range 19-31 kg/m2
(inclusive).
Sex
4.
Male or female 
Female participants: A female participant is eligible to participate if she is not 
breastfeeding, and at least one of the following applies (see Appendix 4):
(i)
Not pregnant as confirmed by pregnancy testing 
(ii)
Not a woman of childbearing potential (WOCBP)
(iii)
For WOCBP that are currently utilizing a highly-effective contraceptive 
method prior to enrolment, agrees to follow the contraceptive guidance 
during the treatment period to the follow-up visit.  
Informed Consent
5.
Capable of giving signed informed consent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.

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5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions Any medical condition in a prospective study participant not 
meeting the definition above, Type of Participant and Disease Characteristics.
a.
History of malignancy within the prior 2 years OR currently receiving treatment for 
cancer. Note: the ONLY exception is localized squamous- or basal-cell carcinoma of 
the skin definitively treated 12 weeks or more prior to enrolment. 
b.
Prior/Concomitant Therapy Unable to refrain from the use of prescription or non-
prescription drugs, including vitamins, herbal and dietary supplements (including St 
John’s Wort) 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 medication, unless in 
the opinion of the Investigator and Medical Monitor the medication will not interfere 
with the study procedures or compromise participant safety
Prior/Concurrent Clinical Study Experience
c.
Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 30 days prior to Day 1 in this study
o
Exposure to more than 4 new chemical entities within 12 months prior to 
the first dosing day
d.
Current enrolment or past participation (i.e., administration of last dose of 
investigational study treatment) within the last 30 days (or 5 half-lives, whichever is 
longer) before Day 1 in this study in any other clinical study involving an 
investigational study intervention or any other type of medical research
e.
Part A participants may not participate in Part B, and Part B participants may not 
participate in Part A if enrolment is concurrent or overlaps.
Diagnostic assessments
f.
Positive pre-study drug/alcohol screen
g.
Regular use of known drugs of abuse
h.
A positive laboratory confirmation of COVID-19 infection, or high clinical index of 
suspicion for COVID-19
Other Exclusions
i.
Regular alcohol consumption within 6 months prior to the study defined as: 

average weekly intake of >[14] units.  One unit is equivalent to 8 g of alcohol: a 
half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of 
spirits. 
j.
Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products (e.g. nicotine patches or vaporizing devices) within 6 
months prior to screening 

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k.
Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

Both Part A and Part B will be conducted under fasting conditions (after an overnight 
fast)

Participants will refrain from any food and drink (except water) at least 10 h before 
dosing and 4 h after dosing of the investigational product. Water is allowed ad libitum 
at all times.

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 24 hours 
before the start of study intervention until after the final dose.
5.3.2.
Caffeine, Alcohol, and Tobacco

Participants will be instructed to limit ingesting caffeine- or xanthine-containing 
products (e.g., coffee, tea, cola drinks, chocolate) for 24 hours prior to the start of 
dosing until collection of the final pharmacokinetic blood sample.

Participants will abstain from alcohol for 24 hours prior to the start of dosing until 
collection of the final pharmacokinetic blood sample.
5.3.3.
Activity

Participants will abstain from strenuous exercise for 24 hours before each blood 
collection for clinical laboratory tests, for 24 hours prior to admission to the clinical 
research unit, and while in the clinical research unit. Participants may participate in 
light recreational activities during studies (e.g., watching television, reading).
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations and any 
serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened participant to consultation with the GSK Medical Monitor. In the case 
of a re-screen, the participant should be assigned a new participant number.

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5.5.
Self-isolation
Where it is site policy to do so, participants will be asked to attend the Unit a few days 
prior to admittance to receive a COVID-19 test (Polymerase chain reaction [PCR] or 
antigen). Once tested, participants will be asked to self-isolate at home until their 
admittance to the Unit for their next dosing period.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
6.1.
Study Intervention(s) Administered
Part A
Part A will include a screening visit and 3 treatment periods. These treatment periods, 
Periods 1, 2 and 3, will be conducted in the same manner; and there will be a minimum of 
a 7-day washout period between treatment periods. A single dose of investigational 
product will be administered for each treatment. The screening visit will be conducted 
within 30 days prior to the first dose in Period 1. 
A follow up visit will occur 7 days after administration of the last dose of study 
medication in Period 3.  

Eligible participants will be enrolled and randomized in a 1:1 ratio to a treatment 
sequence of either Regimen A, B, or C:
Regimen
Period 1
Period 2
Period 3
A
Daprodustat 4 mg 
Dissolution profile #1 
from Process 2
Daprodustat 4 mg 
Dissolution profile #2 
from Process 2
Daprodustat 4 mg 
Reference Process 1
B
Daprodustat 4 mg 
Dissolution profile #2 
from Process 2
Daprodustat 4 mg 
Reference Process 1
Daprodustat 4 mg 
dissolution profile #1 
from Process 2
C
Daprodustat 4 mg  
Reference Process 1
Daprodustat 4 mg 
Dissolution profile #1 
from Process 2
Daprodustat 4 mg
Dissolution profile #2 
from Process 2
The total study duration for each participant will be approximately 8 weeks (minimum) 
for Part A.  All participants will receive study treatment according to the randomization 
schedule.
Part B
For each of the dose strengths being evaluated, the study will be setup and conducted in 
the same manner, but a different set of healthy volunteers will be recruited. A total of 5 
groups of healthy volunteers will be recruited for the respective dose strengths being 
evaluated. A single dose will be administered for all dose strengths. 

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Evaluation of each dose strength will include a screening visit and 2 treatment periods; 
there will be a minimum of a 7-day washout period between study treatment 
administration in Period 1 and Period 2. The screening visit will be conducted within 30 
days prior to the first dose in Period 1 for each dose strength.
There will be a post-treatment follow-up visit 7 days after participants receive last dose of 
study medication in the second treatment period. 

For the 1 mg dose strength, eligible participants will be enrolled in the study and 
randomized in a 1:1 ratio to a treatment sequence of either Regimen D or E:
Regimen
Period 1
Period 2
D
Daprodustat 1 mg Process 
2
Daprodustat 1 mg Process 
1
E
Daprodustat 1 mg Process 
1
Daprodustat 1 mg Process 
2

For the 2 mg dose strength, eligible participants will be enrolled in the study and 
randomized in a 1:1 ratio to a treatment sequence of either Regimen F or G:
Regimen
Period 1
Period 2
F
Daprodustat 2 mg Process 
2
Daprodustat 2 mg Process 
1
G
Daprodustat 2 mg Process 
1
Daprodustat 2 mg Process 
2

For the 4 mg dose strength, eligible participants will be enrolled in the study and 
randomized in a 1:1 ratio to a treatment sequence of either Regimen H or I:
Regimen
Period 1
Period 2
H
Daprodustat 4 mg Process 
2
Daprodustat 4 mg Process 
1
I
Daprodustat 4 mg Process 
1
Daprodustat 4 mg Process 
2

For the 6 mg dose strength, eligible participants will be enrolled in the study and 
randomized in a 1:1 ratio to a treatment sequence of either Regimen J or K:
Regimen
Period 1
Period 2
J
Daprodustat 6 mg Process 
2
Daprodustat 6 mg Process 
1
K
Daprodustat 6 mg Process 
1
Daprodustat 6 mg Process 
2

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
For the 8 mg dose strength, eligible participants will be enrolled in the study and 
randomized in a 1:1 ratio to a treatment sequence of either Regimen L or M:
Regimen
Period 1
Period 2
L
Daprodustat 8 mg Process 
2
Daprodustat 8 mg Process 
1
M
Daprodustat 8 mg Process 
1
Daprodustat 8 mg Process 
2
The total study duration for each participant will be approximately 7 weeks (minimum) 
for Part B.  All participants will receive study treatment according to the randomization 
schedule.  
Daprodustat will be supplied as film coated tablets for oral administration containing 1, 2, 
4, 6, or 8 mg of daprodustat.  The doses, tablet size, and description are provided in Table 
1. Participants are to take the daprodustat tablet(s) daily with water, and these tablets can 
be taken without regard to food.
Table 1
Description of Daprodustat and Placebo Tablets
Tablet 
size
Dose
Description
7 mm
Daprodustat 1 mg, 2 mg, 4 mg
7.0 mm round, compound radius, white film 
coated tablets
9 mm
Daprodustat 6 mg and 8 mg
9.0 mm round, compound radius, white film 
coated tablets
6.2.
Preparation/Handling/Storage/Accountability
The Investigator will be supplied with investigational products in amounts that exceed the 
quantity needed to perform the clinical trial. Please see the Study Reference Manual for 
further information.  
i.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.

Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).

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
Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual. 

Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Study using 
Pre-Coded 
Randomization 
provided to site
On Day (-1), participants will be assigned a unique number 
(randomization number) in ascending numerical order at each study 
site(s). The randomization number encodes the participant’s 
assignment to one of the 3 regimen sequences of Part A, or one of 
the 2 regimen sequences for a given dose strength of Part B in the 
study, according to the randomization schedule generated prior to 
the study by the Statistics Department at GSK, or designee. 
Participants randomized to Part B will only be randomized to one 
dose strength. Each participant will be dispensed blinded study 
intervention, labeled with his/her unique randomization number, 
throughout the study. A central randomization approach will be 
used.
Blinded study 
with unblinded 
site pharmacist 
who is dispensing 
drug
Participants will be randomized in a [1:1] ratio to receive study 
intervention. Investigators will remain blinded to each 
participant’s assigned study intervention throughout the course of 
the study. In order to maintain this blind, an otherwise uninvolved 
3rd party will be responsible for the dispensation of the study 
intervention and will endeavor to ensure that there are no 
differences in time taken to dispense following randomization.
Unblinded monitors and in the event of a Quality Assurance 
audit, the auditor(s) will be allowed access to un-blinded study 
intervention records at the site(s) to verify that 
randomization/dispensing has been done accurately.
.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy.

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6.4.
Study Intervention Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

When participants are dosed at the site, they will receive study intervention 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 intervention 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 intervention.  Study site personnel will examine each 
participant’s mouth to ensure that the study intervention was ingested.
6.5.
Concomitant Therapy
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, i.e., rifampin/rifampicin, a strong inducer of CYP2C8) or 5 
half-lives (whichever is longer) before the start of study intervention until completion of 
the follow-up visit, unless, in the opinion of the investigator and sponsor, the medication 
will not interfere with the study.
Because daprodustat is a CYP2C8 substrate, examples of prescription drugs listed below 
will be prohibited as indicated above (also refer to exclusion criteria Section 5.2): 
•           Strong inhibitors of CYP2C8 (e.g., gemfibrozil)
•           Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)
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 Medical Monitor.
6.6.
Dose Modification
No dose modifications will be made during this bioequivalence study. 
6.7.
Intervention after the End of the Study
Since the study is a pharmacokinetic study in healthy participants, there are no 
arrangements for post-study treatment of a medical condition. 

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7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue 
(definitive discontinuation) study intervention. If study intervention is definitively 
discontinued, the participant will not remain in the study after his or her 
discontinuation/early withdrawal assessments. See the SOA for data to be collected at the 
time of discontinuation of study intervention and follow-up and for any further 
evaluations that need to be completed.
7.1.1.
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 intervention for abnormal liver tests is required when:
1. a participant meets one of the conditions outlined in the algorithm
2. when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in the 
best interest of the participant. 
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met:
Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm

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Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal.
Refer to Appendix 5 for required Liver Safety Actions and Follow up Assessments 
7.1.2.
Other Stopping Criteria
A participant must permanently stop dosing for the pre-specified reasons below.
•
Hemoglobin actual value >1 g/dL over 2 weeks following dosing
•
Becomes pregnant
•
Diagnosis of cancer (new or recurrent), with the exception of localized squamous 
cell or basal cell carcinoma of the skin
•
Need for more than 14 days use of prohibited medication (Section 6.5.)
7.1.3.
Temporary Discontinuation
There is no provision in this relative and bioequivalence study for a temporary 
discontinuation per se. Withdrawal from study intervention (i.e., the decision of either the 
participant or the Principal Investigator to stop dosing or not complete all dosing 
occasions) will require the participant’s withdrawal from the study (see Section 7.2).
7.2.
Participant Discontinuation/Withdrawal from the Study

If a participant develops COVID-19 like symptoms during the course of the study 
the following actions should be taken:
o
Participants who develop a high clinical index of suspicion for COVID-19 
disease should be isolated and tested for COVID-19 in accordance with 
site procedures.
o
Assessments should be continued per the protocol during this period; 
withdrawal of participants from the study will be at the discretion of the 
Principal Investigator but should first be discussed and agreed with the 
GSK Medical Monitor.

A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons. This is expected to be 
uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. See SoA for data to be collected 
at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

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
If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study are handled as stated in Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 

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baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.1.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded.

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.
8.1.2.
Vital Signs

Oral temperature, pulse, and blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed in a semi-supine
position with a completely automated device. Vital signs measurements taken 
from the device can be repeated once if clinically significant changes or a 
machine error occurs. If the measurements continue to be out of range, these 
will be repeated at the investigator’s discretion. 

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones) and taken prior to blood collection for laboratory tests.

For all vital signs (to be taken before blood collection for laboratory tests), a 
single measurement of systolic and diastolic blood pressure and pulse will be 
performed as outlined in the SoA (see Section 1.3).
8.1.3.
Electrocardiograms

A single 12-lead ECG (to be taken before vital signs and blood collection for 
laboratory tests) will be obtained, in the semi-supine position after 5 minutes 
rest, as outlined in the SoA (see Section 1.3) using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and 
corrected QT (QTc) intervals.

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8.1.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study 
intervention 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 time period judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
8.2.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7). 
8.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of intervention until the follow-up visit
at the time points specified in the SoA (Section 1.3). However, any SAEs 
assessed as related to study participation (e.g., study intervention, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to 
a GSK product will be recorded from the time a participant consents to 
participate in the study.

All AEs will be collected from the start of intervention until the follow-up visit 
at the time points specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 

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Medical Conditions section of the CRF not the AE section unless they are 
assessed as related to study participation.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. 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 
intervention or study participation, the investigator must promptly notify the 
sponsor.
8.2.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.

Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
8.2.3.
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 8.2.6.), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3.
8.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

For all studies except those utilizing medical devices 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.

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
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
8.2.5.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study intervention and until 7 days after the last dose.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
8.2.6.
Adverse Events of Special Interest 
Adverse Events of Special Interest (AESI) have been identified based on non-clinical 
studies with daprodustat, clinical experience with recombinant, human erythropoietins 
(rhEPOs), and current information regarding HIF-regulated pathways in mediating 
hypoxia-associated pathophysiology.  The currently identified AESI for daprodustat are 
as follows:
•
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis
•
Death, myocardial infarction (MI), stroke, heart failure, thromboembolic events, 
thrombosis of vascular access
•
Cardiomyopathy
•
Pulmonary artery hypertension
•
Cancer-related mortality and tumor progression and recurrence
•
Esophageal and gastric erosions
•
Proliferative retinopathy, macular edema, choroidal neovascularization
•
Exacerbation of rheumatoid arthritis

Worsening of hypertension
8.3.
Treatment of Overdose
For this study, any dose of daprodustat greater than the dose indicated within the 
treatment arm within a 24-hour time period 1 hour will be considered an overdose.
GSK does not recommend specific treatment for an overdose.

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In the event of an overdose, the investigator should:

Contact the Medical Monitor immediately.
1.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
daprodustat can no longer be detected systemically (at least 2 days).
2.
Obtain a plasma sample for PK analysis within 2 days from the date of the last dose 
of study intervention if requested by the Medical Monitor (determined on a case-by-
case basis).
3.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
8.4.
Pharmacokinetics
Blood samples of approximately 5 mL will be collected for measurement of plasma 
concentrations of daprodustat as specified in the SoA.

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 
timing of sampling 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.

Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded.

Samples will be used to evaluate the PK of daprodustat. 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.

Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
8.5.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.6.
Genetics
Genetics are not evaluated in this study.
8.7.
Biomarkers
Biomarkers are not evaluated in this study.

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9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
Part A:
There will be no formal statistical hypotheses for part A.
The comparison of two 4 mg daprodustat tablets with different dissolution profiles 
relative to the reference 4 mg daprodustat tablet made by Process 1 will be performed
using descriptive statistics. The ratio of the geometric means (µ dissolution 1, 2/µ Process 
1) for AUC(0-t) and Cmax will be calculated and 90% confidence interval (CI) will be 
generated as part of the descriptive statistics.
Part B:
For each tablet strength of daprodustat (1 mg, 2 mg, 4 mg, 6 mg, and 8mg), the following 
statistical hypotheses will be used:
The bioequivalence between daprodustat manufacturing process 1 and process 2 will be 
assessed using a framework of statistical hypothesis testing. The ratio of the geometric 
means (µ Process 2 /µ Process 1) for AUC(0-t) and Cmax is the measure in the following 
statistical hypotheses:
H0 (null hypothesis) : µ Process 2 /µ Process 1 ≤ 0.80 or µ Process 2 /µ Process 1 ≥ 1.25,
H1 (alternative hypothesis) : 0.80 < µ Process 2 /µ Process 1 < 1.25
Bioequivalence will be determined if the 90% confidence interval (CI) of µ Process 2 /µ 
Process 1 falls within a range of 0.80 to 1.25. This is equivalent to carrying out two one-
sided tests of hypothesis at the 5% level of significance.
A demonstration of bioequivalence requires the null hypothesis for both AUC and Cmax
to be rejected. All doses must meet the criteria for bioequivalence to be concluded.
9.2.
Sample Size Determination
Part A:
A total sample size of 30 participants (10 participants per regimen) is recommended for 
the 3-way crossover design of Part A.
With a coefficient of variation within participant (%CVw) of 25% (based on Cmax 
having the highest CV), N=30 in a 3x3 crossover design, and assuming an observed ratio 
of 1.0, the estimated half-width of the 90% CI for the comparison of the ratio of the PK 
parameter  will be 11% of the point estimate. On the normal scale, this would result in a 
90% CI of (0.90, 1.11)
Additional participants may be recruited as replacement for withdrawn participants 
including those impacted by COVID-19.

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Part B:
A total sample size of 190 participants is required for Part B. A sample size of 38 
participants (19 participants per regimen) is required to complete each of the five 
bioequivalence 2-way crossover design comparison of doses 1 mg, 2 mg, 4 mg, 6 mg, 
and 8 mg of daprodustat.
Sample size calculation assumes a true ratio is 1.0, the coefficient of variation within 
participant (%CVw) of 25% (based on Cmax having the highest CV), power of 97%, and 
a regulatory definition of BE criteria; the 90% confidence interval (CI) of the ratio for 
Cmax between manufacturing processes should lie within the range of 0.80-1.25. 
Additional participants may be recruited as replacement for withdrawn participants 
including those impacted by COVID-19.
Total:
A total sample size of 220 participants are required to complete for both part A and part 
B combined. If a 15% dropout rate is assumed for the for the 3-way crossover design of 
part A, and a 10% dropout rate is assumed for the five 2-way crossover design of Part B, 
a total sample size of around 246 participants randomized is required. 
For AUC, assuming a true ratio of 1.0, the coefficient of variation within participant 
(%CVw) of 19%, a sample size of 38, and a regulatory definition of BE criteria; the 90% 
confidence interval (CI) of the ratio for AUC(0-t) between manufacturing processes 
should lie within the range of 0.80-1.25, results in >99% individual power per dose.
The %CVw has been assumed from the GSK daprodustat study 207727 and PHI115385. 
The largest %CVw seen in Part 1 of study 207727 (bioequivalence of 2x2mg and 4mg 
tablets of daprodustat) was 22.6%, from Cmax. The highest %CVw for AUC was 14.6%. 
The %CVw from study PHI115385, Part 1 was based on a power model using all dose 
groups. The power model used to estimate %CVw is as below. 
loge(PK parameter) = µ + Si + β*log(Dj) + εij 
where µ is the intercept, β is the slope, Si is the random effect for participant i, Dj is the 
dose, εij is the random error. The %CVw estimates based on the random error are 24.3% 
and 26.8% for AUC(0-inf) and Cmax, respectively. An average of the highest Cmax 
%CVw from these studies (22.6% and 26.8%) gives an estimated Cmax %CVw of 25%.
An average of the highest AUC %CVw from these studies (14.6% and 24.3%) gives an 
estimated AUC %CVw of 19%.
The global power for part B is 87%. This accounts for the 10 CIs needed to be generated 
to assess bioequivalence across the 5 doses, each with one CI for AUC and Cmax. The 
individual power per dose for Cmax is 97% and for AUC is >99% as noted above.
9.3.
Populations for Analyses
The following populations are defined for both Part A and B separately:

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Population
Description
Enrolled
All participants who signed the ICF
Safety
All randomized participants who take at least 1 dose of study 
intervention. Participants will be analyzed according to the 
intervention they actually received.
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).
9.4.
Statistical Analyses
The statistical analysis plan will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints.
Part A and Part B will be conducted independently. Upon completion of Part A, Part A 
will be unblinded and the results of Part A will be analysed, and headline results will be 
generated. The results of Part A will not determine if Part B begins. Part B can begin 
regardless of the completion or outcome of the analysis of Part A.
9.4.1.
General Considerations
All PK analyses will be performed on the PK Population for each Part.
For both Part A and Part B, the plasma concentrations of daprodustat will be summarized 
by nominal time and individual plasma concentration-time profiles and median/mean 
profiles will be plotted. Each of the figures will contain one plot on the untransformed 
scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. a log-linear plot).
For both Part A and Part B, from the plasma concentration-time data, the following PK 
parameters will be determined by non-compartmental methods with Phoenix WinNonlin 
(version 6.3 or higher), as data permit: AUC(0-t), AUC(0-inf), Cmax, Tmax, t1/2, CL/F, 
Vz/F. The bioequivalence between the tablets will be confirmed with comparisons of the 
values of the logarithmic parameters [AUC(0-t) and Cmax]. 
Calculations will be based on the actual sampling times recorded during the study. PK 
data, will be presented in graphical and/or tabular form and will be summarized 
descriptively, using summary statistics (n, arithmetic mean with associated 95% CI, 
standard deviation (SD), minimum, median, and maximum). Except for Tmax, geometric 
mean with associated 95% CI, SD on loge scale and coefficient of variation between 
participants (%CVb) will also be provided. Listings will be generated for each derived 
plasma PK parameters.

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9.4.2.
Primary Endpoint(s)
The primary objective of Part A is to characterize the PK profile of two 4 mg daprodustat 
tablets with different dissolution profiles relative to the reference 4 mg daprodustat tablet 
made by Process 1.
The primary objective of Part B is to assess the bioequivalence between manufacturing 
Process 1 and Process 2 for the following tablet strengths: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg.
Part A:
For Part A the following statistical analysis method will be used:
The exposure [AUC(0-t) and Cmax] of daprodustat will be assessed by using a mixed 
effect model as described below: 
loge (PK parameter) = β0 +γi + τj + πk + εijkl 
where β0 is the intercept, γi is the random participant effect for ith participant, τj is the 
tablet manufacturing effect (j = dissolution 1, dissolution 2, Process 1), πk is the period 
effect (k = period 1, period 2, period 3), and εijkl is the random error. The Kenward-
Roger degree of freedom approach will be used.
Point estimates (logeµ, model-based means of PK parameters on loge scale) for the 
model-based means of PK parameters on loge scale will be provided for dissolution 1, 
dissolution 2, and Process 1 and a point estimate of the mean difference between 
comparisons (logeµ dissolution 1, 2  - logeµ Process 1) will be constructed along with the 
associated 90% CIs using the residual variances. The point estimates, the point estimate 
of the mean difference, and the associated 90% CIs on loge scale will be exponentially 
back-transformed to obtain the model-based geometric means (µ), and the ratio for 
AUC(0-t) and Cmax (µ dissolution 1, 2  /µ Process 1) and the associated 90% CIs, 
respectively.

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Part B:
For each tablet strength of daprodustat (1 mg, 2 mg, 4 mg, 6 mg, and 8 mg), the 
following statistical analysis method will be used:
The exposure (AUC(0-t) and Cmax) of daprodustat will be assessed by using a mixed 
effect model as described below: 
loge (PK parameter) = β0 +γi + τj + πk + εijkl 
where β0 is the intercept, γi is the random participant effect for ith participant, τj is the 
tablet manufacturing effect (j = Process 1 or Process 2), πk is the period effect (k = period 
1 or period 2), and εijkl is the random error. The Kenward-Roger degree of freedom 
approach will be used.
Point estimates (logeµ, model-based means of PK parameters on loge scale) for the 
model-based means of PK parameters on loge scale will be provided for each tablet 
strength and a point estimate of the mean difference between processes (logeµ Process 2 -
logeµ Process 1) will be constructed along with the associated 90% CIs using the residual 
variances. The point estimates, the point estimate of the mean difference, and the 
associated 90% CIs on loge scale will be exponentially back-transformed to obtain the 
model-based geometric means (µ), and the ratio for AUC(0-t) and Cmax (µ Process 2 /µ 
Process 1) and the associated 90% CIs, respectively.
Bioequivalence will be evaluated using the FDA BE guidelines, Criterion 1. It is noted 
that if Criterion 1 fails, the next step per Japan BE guidance is Criterion 2. However, the 
study design is based on Criterion 1 given its more stringent criteria 
• Criterion 1:
The 90% CIs of the ratios of the geometric means for AUC(0-t) and Cmax (µ Process 2 
/µ Process 1) are within the range of 0.80 - 1.25. 
• Criterion 2 
The ratio of the geometric means for AUC(0-t) and Cmax (µ Process 2 / µ Process 1) is 
within the range of 0.90 - 1.11. 
A sensitivity analysis to jointly assess BE across all doses may be performed on Part B 
using a statistical model incorporating all doses used in Part B. See report and analysis 
plan (RAP) for further details.
9.4.3.
Secondary Endpoint(s)
Summary statistics will be provided for AUC(0-inf), Tmax, t1/2, CL/F and V/F 
separately for both Part A and Part B.
9.4.4.
Safety Analyse(s)
All safety analyses will be performed on the Safety Population for each Part. 

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Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards. 
AEs, changes from baseline in clinical laboratory tests, and vital signs will be 
summarized for each Part A and Part B. No statistical comparison will be made for the 
safety summaries.
9.5.
Interim Analyses
There is no interim analysis planned for the study. Part A is not considered an interim for 
Part B as it is analyzed separately, and Part B will be conducted regardless of the 
outcome of Part A.

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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with enough, 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 
study and for 1 year after completion of the study.

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10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 
A participant who is rescreened is not required to sign another ICF if the rescreening 
occurs within 30 days from the previous ICF signature date.
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about daprodustat or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have the daprodustat approved for 
medical use or approved for payment coverage. 
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.1.5.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator

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will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding
10.1.6.
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. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of 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. 

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
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. 
10.1.7.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the electronic case report form (eCRF)
that are transcribed from source documents must be consistent with the source 
documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.
10.1.8.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first site open and will be the study start date.
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 enough 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 intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up

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10.1.9.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.

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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 2 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing 

Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at screening, Day (-1), and at the follow up visit during study. 

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure. 

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant's participation in the 
study.
Table 2
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean corpuscular 
volume (MCV)
Mean corpuscular Hgb
(MCH)
%Reticulocytes
White blood cells 
(WBC) count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cells (RBC)
Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood Urea 
Nitrogen (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

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Laboratory 
Assessments
Parameters
Glucose fasting
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)2

•
COVID-19 testing (PCR or antigen performed at additional time noted 
in the SoA tables and as required)
The results of each test must be entered in the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1 and Appendix 7 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).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC.

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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (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 (i.e., not 
related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the 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.

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
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
o
Results in death
o
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.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
Results in persistent or significant 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, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect

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Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the 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, except for the participant 
number, will be redacted on the copies of the medical records before submission to 
GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will assess the 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 enough 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.

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An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the 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 assess causality for every event before 
the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality considering follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any post-
mortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.

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10.3.4.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence 
within the eCRF (e.g., check review box, signature, etc.) of review and verification 
of the relationship of each SAE to IP/study participation (causality) within 72 
hours of SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the study reference manual (SRM).
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor if the electronic data collection tool 
described above is not available.

In rare circumstances and in the absence of facsimile equipment, 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 in SRM.

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10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
10.4.1.
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required. 

Females whose menopausal status is in doubt will be required to use one of 
the non- hormonal highly effective contraception methods.
10.4.2.
Contraception Guidance:
Female participants of childbearing potential that are not currently utilizing a highly-
effective contraceptive method (non-hormonal) are eligible to participate if a pregnancy 
test conducted during screening and again pre-dose (Day -1) is negative.  It is not 

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necessary to require participants to start a new contraceptive method if they are not 
already established on one.
Female participants of childbearing potential that are currently utilizing a highly-effective 
contraceptive method are eligible to participate if they agree to continue to use this 
method consistently and correctly as described below.  In this instance a negative 
pregnancy test during screening and again pre-dose (Day -1) would not be required.
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year 
when used consistently and correctly.
Intrauterine device (IUD)
Bilateral tubal occlusion
Vasectomized partner
Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.
Sexual abstinence
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
ACCEPTABLE METHODSc
Male or female condom with or without spermicided
Cervical cap, diaphragm, or sponge with spermicide
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide 
(double-barrier methods)c
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly.
c.
Considered effective, but not highly effective - failure rate of ≥1% per year.  Periodic abstinence (calendar, 
sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method (LAM) are not acceptable methods of contraception. 
d.
Male condom and female condom should not be used together (due to risk of failure with friction).

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10.4.3.
Collection of Pregnancy Information:
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

The initial information will be recorded on the appropriate form and submitted to 
GSK within 24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) is always considered to be an SAE and will 
be reported as such. 

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK as described in Appendix 3. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting. 
Any female participant who becomes pregnant while participating  

will be withdrawn from the study

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10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase 1 Liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event etiology 
Phase 1 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 
international normalized ratio (INR) >1.5, Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF, and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAE2

Perform liver 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, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24 hours

Monitor participant twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained 48h of last dose4 

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form

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Liver Chemistry Stopping Criteria 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) 
and perform liver event follow up 
assessments within 24-72 hours

Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
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]. NOTE: not 
required in China.

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 intervention 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, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving anticoagulants
3.
Includes: Hepatitis A immunoglobulin (gM) antibody; Hepatitis B antigen (HBsAg) and HBcAb; Hepatitis C 
ribonucleic acid (RNA); Cytomegalovirus Immunoglobulin M (IgM) antibody; Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain heterophile antibody or monospot testing) and Hepatitis E IgM antibody 
4.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
interventions.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention 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.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA,et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.

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10.6.
Appendix 6: Abbreviations and Trademarks
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the concentration-time curve
BE
Bioequivalence
BMI
Body mass index
BUN
Blood urea nitrogen
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CFR
Code of Federal Regulations
CKD
Chronic kidney disease
CL
Clearance
Cmax
Maximum observed concentration
COVID-19
Coronavirus disease 2019
CPK
Creatine phosphokinase
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CSR
Clinical study report
CV
Cardiovascular
CVb
Between participant coefficient of variability
CVw
Coefficient of variation within participant
CYP
Cytochrome P450 enzyme
DD
Dialysis dependent
dL
deciliter
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EPO
Erythropoietin
ESA
Erythropoietin stimulating agents
F
Fraction
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GI
Gastrointestinal
GSK
GlaxoSmithKline
h
Hour
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
Hgb
Hemoglobin
HIF
Hypoxia-inducible factor
HIPAA
Health Insurance Portability and Accountability Act

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HPLC
High performance liquid chromatography
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
ICF
Informed Consent Form
IDSL
Integrated Data Standards Library
IEC
Independent ethics committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International normalization ratio
IP
Investigational product
IRB
Institutional Review Board
IU
International units
IUD
Intrauterine device
kg
Kilogram
LDH
Lactate dehydrogenase
MCH
Mean corpuscular Hgb
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
mm
Millimeter
mmHg
Millimeters of mercury
MSDS
Material Safety Data Sheet
ND
Nondialysis dependent
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
%CV
Coefficient of variation of the mean
PHD
prolyl-4-hydroxylases
PHI
Prolyl-hydoxylase inhibitor
PK
Pharmacokinetic
QTc
Corrected QT interval
RAP
Report and Analysis Plan
RBC
Red blood cells
rh
Recombinant human
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SD
Standard deviation
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SoA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected unexpected serious adverse reaction
t½
Half life
Tmax
Time of occurrence of Cmax

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ULN
Upper limit of normal
UK
United Kingdom
V
Volume
µ
Mean
µM
Micromolar
WBC
White blood cells
WOCBP
Woman of childbearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
None
Chiron RIBA
SAS
WinNonlin

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10.7.
Appendix 7: Handling of Clinical Testing Samples for Pivotal 
Bioequivalence Studies
The follow are responsibilities of the Investigator of the Study Site:

Ensure that a quantity of the clinical testing samples (e.g., study drug product and 
study drugs to be retained as reserve samples), enough to conduct the study, is 
randomly (non-systematically) selected from the drug shipment. The remaining 
testing study drugs must be retained as reserve samples.

Ensure that an adequate record is maintained of the receipt and distribution of all 
testing samples on the Drug Accountability forms. Storage of the study drugs to 
be retained as reserve samples is the responsibility of the Investigator and under 
no conditions can the reserve samples be returned to the Sponsor for storage.

Ensure that the study drugs to be retained as reserve samples are stored in the 
original primary packaging and outer cartons. The carton must be closed using 
tamper evident tape, and an additional label affixed to the outer carton indicating 
“Reserve Sample for GlaxoSmithKline Study 213022.” The label should have an 
area for the Investigator or pharmacist to sign and date it and the label must not be 
placed over any existing label(s).

Store all study drugs to be retained as reserve samples under the appropriate 
environmental conditions. For products requiring refrigeration or freezing, and for 
sites located in areas with extreme climate, the temperature must be controlled 
and a weekly temperature log must be maintained. The storage area must be 
segregated from the area where the clinical study was conducted and should be 
limited to access by authorized personnel only.

Ensure that the reserve samples are retained for a period of at least 5 years 
following the date on which the application or supplemental application is 
approved. In the case of non-approval, the retention period is at least 5 years 
following the date of completion of the corresponding study.

Consult with the Sponsor if the storage of the study drugs to be retained as reserve 
samples presents problems.

Contract with an independent third party to provide storage for study drugs to be 
retained as reserve samples if storage at the study site is not possible. Before the 
transfer of the study drugs to be retained as reserve samples, the Sponsor must 
assess and approve the facilities of the third party.

The independent third party must store the study drugs to be retained as reserve 
samples under the appropriate environmental conditions. For products requiring 
refrigeration or freezing, and for sites located in areas with extreme climate, the 
temperature must be controlled and a weekly temperature log must be maintained.

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
Transfer the study drugs to be retained as reserve samples to an independent third 
party for storage if the Investigator or study site ceases business.

When an independent third-party stores reserve samples, provide the Sponsor 
with the name and address of the facility and a contact name and telephone 
number. Provide the independent third party with a contact name and number for 
the Sponsor.

Upon request from the United States Food and Drug Administration (FDA), 
release the study drugs retained as reserve samples to the FDA and provide the 
FDA with a written assurance that the reserve samples came from the same
supplies used to conduct the specific bioavailability or bioequivalence study.

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10.8.
Appendix 8: COVID-19 Considerations
OVERALL RATIONALE FOR THIS APPENDIX 
COVID-19 pandemic may impact the conduct of clinical studies. Challenges may arise 
from quarantines, site closures, travel limitations, interruptions to the supply chain for the 
investigational product or other considerations if site personnel or study participants 
become infected with COVID-19. These challenges may lead to difficulties in meeting 
protocol-specified procedures, including administering or using the investigational 
product or adhering to protocol-mandated visits and laboratory/diagnostic testing.
This protocol appendix outlines measures that may be applicable for any site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity.
These measures will remain in place until study completion.
STUDY PROCEDURES DURING COVID-19 PANDEMIC
During the special circumstances caused by the current COVID-19 pandemic, you should 
consider specific public health guidance, the impact of any travel restrictions 
implemented by local/regional health authorities and local institutions, and individual 
benefit /risk when making enrollment and treatment decisions for trial participants.
As outlined in Section 8, Protocol waivers or exemptions are not allowed and every effort 
should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up however when not possible, for the duration of these 
special circumstances, the following measures may be implemented for enrolled 
participants.
•
Clinical investigators should document in site files and in participant notes as 
appropriate how restrictions related to COVID-19 led to the changes in study conduct and 
duration of those changes and indicate which trial participants were impacted and how 
those trial participants were impacted (as per the current local COVID-19 related 
regulatory guidance).
•
Missing protocol required data/visits due to COVID-19 should be noted in 
participant notes and recorded as a COVID-19 protocol deviation.
Protocol Defined Procedures/Visits:
•
The protocol defined interval for the collection of samples during the follow-up 
visit (see Section 1.3 Schedule of Activities), may be extended up to a maximum length 
of 14 days. 

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Data Management/Monitoring:
•
If a situation arises where on-site monitoring is no longer permitted, GSK will 
consider remote Source Data Verification/Source Document Review (SDV/SDR) where 
permitted by the clinical site/institution. Remote SDV/SDR will be proposed to study 
sites to meet a participant and/or critical quality need, e.g., to assess participant safety or 
to ensure data integrity. In case of remote SDV/SDR, GSK will work with the site to 
ensure participant privacy.
•
eCRF/CRF Final or Interim Sign off Process: The Principal Investigator (PI) is 
responsible for ensuring that the data within the eCRF casebook and any other data 
sources utilized during the study for each study participant is complete and consistent 
with source documents throughout the study (ICH GCP 4.9.1 4.9.2). The PI may sign/re-
sign the eCRF from any computer/location by accessing InForm (or other eDC platform) 
using his/her unique eCRF log-in credentials. The PI may delegate this activity to another 
medically qualified and trained sub-investigator and this must be documented on the 
Delegation of Responsibilities (DoR) Log. It is recommended that the PI identifies a sub-
investigator as a back-up for eCRF signatures. The sub-investigator must be appropriately 
trained on the protocol and eCRF requirements (with training documented), and the DoR 
log updated accordingly.
•
Essential Document Sign Off Process: If an investigator is unable to print and 
sign essential documents such as Protocol /Amendment signature page then Email 
approval can be accepted by replying to the relevant email that is sent by GSK

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11.
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GlaxoSmithKline Document Number RM2008/00267/11. Daprodustat (GSK1278863) 
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Hofherr, A., et al, HIF-1α drives cyst growth in advanced stages of autosomal dominant 
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MHLW. Guideline for Bioequivalence Studies for Different Strengths of Oral Solid
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Provenzano R, Tumlin J, Zabaneh R, et al. Pharmacokinetics of oral FG-4592 to treat 
anemia in hemodialysis patients. National Kidney Foundation Conference, 2011 
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