Clinical trial NCT04292912
Conditions: Macular Edema
Keywords: Diabetic macular edema GSK2798745 Refraction Visual acuity.
Sponsor: GlaxoSmithKline
Start date: 2020-09-07; Completion date: 2022-04-11
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study will be composed of 3 periods for all participants: Screening, 28-day Treatment period, and Follow-up visit (approximately 28 days after the final dose).

Detailed description:

Arms: arm 1: Eligible participants received single dose of GSK2798745 for 28 days. Participants were instructed to have GSK2798745 about the same time each day.
Interventions: intervention 1: GSK2798745
Intervention descriptions: intervention 1: GSK2798745 will be administered.

Protocol documents:
Prot_000.pdf: 
TMF-14377129 
CONFIDENTIAL 
GlaxoSmithKline group of companies 
212669 
1 
TITLE PAGE 
Protocol Title: Phase I, Open-Label, Multi-Center Study to Evaluate Safety, 
Pharmacokinetics and Pharmacodynamics of GSK2798745 after 28 Day Repeat Oral 
Administration to Adults with Diabetic Macular Edema 
Protocol Number: 212669/Amendment 05 
Compound Number: GSK2798745 
Study Phase: Phase 1  
Short Title: Study 212669: A Phase I Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of GSK2798745 in Participants with Diabetic 
Macular Edema 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Medical Monitor Name and Contact Information: In the Study Reference Manual 
(SRM) 
Regulatory Agency Identifying Number(s): 
Registry  
ID  
United States 
154168 
 
Approval Date: 02-Feb-2022 
 
 
 
Copyright 2022 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 


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SPONSOR SIGNATORY: 
Protocol Title: Phase I, Open-Label, Multi-Center Study to Evaluate Safety, 
Pharmacokinetics and Pharmacodynamics of GSK2798745 after 28 Day Repeat Oral 
Administration to Adults with Diabetic Macular Edema 
Protocol Number: 212669/Amendment 05 
Compound Number: GSK2798745 
 
 
 
 
 
 
 
Richard A Brigandi, MD, PhD 
Group Leader 
Discovery Medicine, CPEM 
 
Date 
 
The signed page is a separate document. 
 
 
 
 
 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
List dates of original protocol and all amendments in reverse chronological order. 
Document 
Date 
DNG Number 
Amendment 05 
02-Feb-2022 
TMF-14377129 
Amendment 04 
11-NOV-2021 
TMF- 14073254 
Amendment 03 
24-MAR-2021 
TMF-11874499 
Amendment 02 
28-OCT-2020 
2019N404030_02 
Amendment 01 
11-MAY-2020 
2019N404030_01 
Original Protocol 
19 SEP 2019 
2019N404030_00 
 
Amendment 05 02-Feb-2022 
Overall Rationale for the Amendment:  Protocol Amendment 05 is implementing 
modifications to the Inclusion and Exclusion criteria and study assessments, including 
removal study visit Day 7. The majority of changes focus on relaxing criteria to ease the 
study burden on the participant during the ongoing COVID-19 pandemic. The other 
changes clarify or correct the wording in the risk:benefit table and have Inclusion / 
Exclusion changes based on new modelling and for clarification.  
Where the Amendment Applies: 
This protocol Amendment 5 applies to all countries and sites participating in the study. 


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Table of Specific Changes: 
NOTE: for PREVIOUS TEXT, the content is exactly as in the original; for REVISED 
TEXT, text deleted from the original has a dotted underline and text added has a solid 
underline. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3.1:  28 Day – 4 
Week Treatment 
Period SoA 
Previous Text: 
Current SoA 
Revised Text: 
Addition of the following footnote 
to Screening column: 
 
Any laboratory or ECG assessments 
completed within the 28 days prior 
to the start of screening may be used 
to determine eligibility.  These 
assessments must not have been 
collected for the purposes of this 
study, but for the routine care of the 
participant.  Any assessments with 
abnormal values may be re-tested 
within the screening window and 
post-consent collection would be 
considered the first assessment of 
that lab/ECG.  Additional guidance 
is contained within the SRM. 
Feedback from Investigators is 
that through routine diabetic 
care, participants may have had 
recent lab or ECG assessments. 
To help decrease the need to go 
out in public for clinical 
assessments, during continued 
COVID pandemic we are 
looking to use incidentally 
collected labs or ECG within 
the 28 days prior to screening 
in lieu of collecting at 
screening.  This is only if the 
assessments were collected as 
part of routine care and 
independent of study 
considerations.  Note that the 
allowed assessments are also 
being collected within the 
study itself for Baseline. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
1.3.1:  28 Day – 4 
Week Treatment 
Period SoA 
 
 
 
 
 
 
 
 
5.3.2: Caffeine, 
Alcohol and 
Tobacco 
Changing Visit 3, Day 7 from all 
participants to only the intensive PK 
Subset 
Previous Text: 
Current SoA 
Revised Text: 
Addition of the following footnote 
to Visit 3, Day 7: 
*Day 7 for Participants in the PK 
Subset only. 
Removed the “X” for PK – Trough 
Sampling and greying out the box 
for Visit 3, Day 7 Column. 
 
 
Previous Text: 
Participants participating in the PK 
subset and for all participants on 
Day 7 and Day 28 will abstain from 
ingesting caffeine- or xanthine-
containing products (e.g., coffee, 
tea, cola drinks, and chocolate) for 8 
hours before the start of dosing until 
after collection of the final 
pharmacokinetic sample 
Revised Text: 
Participants participating in the PK 
subset on Day 7 and Day 28 and for 
all participants on Day 28 will 
abstain from ingesting caffeine- or 
xanthine-containing products (e.g., 
coffee, tea, cola drinks, and 
chocolate) for 8 hours before the 
start of dosing until after collection 
of the final pharmacokinetic sample 
Based on the continued 
COVID pandemic and 
subsequent restrictions and 
lockdowns, removal of this 
visit for most study participants 
will decrease the need to go out 
in public to get to the clinic for 
assessments.  Prior dosing in 
completed clinical studies have 
been through 7 days in Heart 
Failure and Chronic Cough 
patients and through 14 days in 
healthy subjects.  No clinical 
safety findings of concern have 
been noted. 
 
For general participants, 
deferring 12-Lead ECG, 
CSSRS, VS, Clinical 
Chemistry, Hematology & UA 
(including Cardiac Troponin, 
CPK), Compliance Check for 
Study Medication, AE-SAE 
Assessments, and Concomitant 
Medical Assessment should 
not increase the risk to the 
patient relative to the risk of 
going out in public during the 
continued pandemic.  
Evaluation of 
pharmacokinetics (Trough 
Sampling) is being done on 
Day 28.  Removal of Day 7 
pharmacokinetic sampling will 
not have significant impact on 
data evaluation. 
Visit 3, Day 7 will remain for 
participants in the Intensive PK 
Subset as detailed in Section 
1.3.2 PK Subset - Intensive PK 
Sampling Day 7 and Day 28 
SoA 


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Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Inclusion 
Criteria 
Previous Text: 
7. 
Body weight ≥50 kg and 
body mass index (BMI) within the 
range 18 to 40 kg/m2 (inclusive) at 
screening. 
 
Revised Text: 
7. 
Body weight ≥50 kg and 
body mass index (BMI) within the 
range 18 to 43 kg/m2 (inclusive) at 
screening. 
Preliminary physiologically-
based pharmacokinetic 
modelling and simulations 
indicate minimal impact on 
systemic exposure to 
GSK2798745 for BMI up to 43 
kg/m2.  The expansion of the 
BMI limit is being changed to 
reflect this new information. 
5.2 Exclusion 
Criteria 
Previous Text: 
13. 
Uncontrolled diabetes as 
indicated by HbA1c >10% at 
screening. 
 
Revised Text: 
13. 
Uncontrolled diabetes as 
indicated by HbA1c >12% at 
screening. 
Feedback from investigators 
and recent publications 
(Fragala, 2021) indicate that 
HbA1c has increased even 
amongst otherwise controlled 
patients due to the COVID 
pandemic and subsequent 
restrictions and lockdowns.  
The increase is attributed to the 
inability to continue close 
monitoring of HbA1c and the 
inability to intensify diabetes 
therapy (Fragala, 2021).  This 
can lead to an increase of up to 
11% from diminished 
monitoring and up to 18.6% 
from failure to intensify 
actionable diabetes treatment 
(Samuels, 2008).  These 
increases, if applied to the prior 
HbA1c cut-off of 10%, would 
result in HbA1c of 11.1% and 
11.9%, respectively.  The 
change in the criterion reflects 
this. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
5.2 Exclusion 
Criteria 
 
 
 
 
 
Previous Text: 
14. 
Active ulcer disease or 
gastrointestinal bleeding at the time 
of screening (positive FOBT at 
screening). 
 
Revised Text: 
14. 
Active ulcer disease or 
gastrointestinal bleeding by history 
within 6 months of screening or by 
exam at the time of screening. 
By expanding the history of 
ulcer/gastrointestinal disease, 
confirmation by positive FOBT 
is no longer required to 
determine subject eligibility. 
 
 
Section 1.3.1  
28 Day – 4 Week 
Treatment Period 
Previous Text: 
Fecal Occult Blood Test (FOBT) 
assessment schedule 
Revised Text: 
Removal of Fecal Occult Blood Test 
(FOBT) assessment schedule 
By expanding the history of 
ulcer/gastrointestinal disease, 
confirmation by positive FOBT 
is no longer required to 
determine subject eligibility. 
 
8.1.5 Fecal Occult 
Blood Test 
Previous Text: 
8.1.5 Fecal Occult Blood Test 
Based on the preclinical finding of 
gastric erosions (Section 2.3.1), 
FOBT will be performed at 
screening to determine eligibility.  
Revised Text: 
Section Removed  
By expanding the history of 
ulcer/gastrointestinal disease, 
confirmation by positive FOBT 
is no longer required to 
determine subject eligibility. 
 
Section 10.2 
Appendix 2: 
Clinical 
Laboratory Tests 
Table 4 Protocol-
Required Safety 
Laboratory 
Assessments 
Previous Text: 
Remove Fecal Occult Blood Test 
(Screening only) 
Revised Text: 
Section removed 
Per above, the Fecal Occult 
Blood Test is no longer 
required 
 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 10.6 
Appendix 6: 
Abbreviations and 
Trademarks 
Previous Text: 
FOBT    Fecal Occult Blood Test 
Revised Text: 
Abbreviation removed 
The Fecal Occult Blood Test is 
no longer required and FOBT 
wording is being removed from 
the protocol, so the 
abbreviation definition is no 
longer necessary. 
Section 2.3.1 Risk 
Assessment 
See Risk Tables below for 
Previous and Revised text 
Clarifying that the mucosal 
findings in the oral 4-week dog 
and 13-week rat studies were 
not adverse effects and do not 
impact exposure considerations 
in the Gastrointestinal Section.  
The original wording did not 
clearly reflect the conclusions 
of these two animal studies.  
Also changed was the wording 
for Exclusion 14 in the 
Gastrointestinal and Mortality 
and General Health Sections to 
reflect the revision of that 
criterion being completed in 
this amendment. 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
2 1 2 6 6 9  
9  
Secti o n # a n d 
N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Secti o n 9. 5  
Ol d te xt:  
9. 5. I nteri m A n al yses  
N o i nteri m a nal yses are pla n ne d f or 
t his st u d y.  
Ne w te xt:  
9. 5. I nteri m A n al yses  
As t his is a n o pe n -la bel st u d y, data 
will be re vie we d o n a n o n g oi n g basis 
a n d ma y be s hare d e xter nall y t o 
s u p p ort disc ussi o n wit h re g ulat or y 
a ge ncies.  
After a p pr o xi matel y 8 partici pa nts 
c o m plete d t he Da y 2 8 visit, O C T a n d 
data will be a nal yse d o n a n 
o n g oi n g basis t o assess f utilit y a n d 
t he st u d y ma y be ter mi nate d earl y if 
t he f utilit y criteria are met. A d diti o nal 
e n d p oi nts ma y be re vie we d as well if 
necessar y. F ull details will be 
pr o vi de d i n t he i nteri m a nal ysis 
c harter.  
I nteri m a nal ysis was a d de d t o 
s u p p ort de vel o p me nt disc ussi o ns 
of G S K 2 7 9 8 7 4 5 a n d all o w earl y 
ter mi nati o n of c urre nt st u d y if 
t he interi m data is ne gati ve.       
 
C CI


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Previous Text: 
Potential Risk of Clinical 
Significance and Summary 
of Data/Rational for Risk 
Impact on Eligibility Criteria 
Mitigation Strategy 
Investigational Product (IP) [GSK2798745] 
Gastrointestinal:  
Oral 4-wk repeat dose dog study:  
Mucosal erosion/ulceration in the 
stomach and/or duodenum was 
observed at doses of 3 mg/kg/day 
and higher. 
Oral 4-wk repeat dose rat study:  
Mucosal erosion/ulceration in the 
stomach and/or duodenum was 
observed at 300 mg/kg/day. 
Oral 13-wk repeat dose rat study:  
Mucosal erosion in the stomach was 
observed at 60 mg/kg/day. 
 
Exclusion criterion #14: 
Active ulcer disease or 
gastrointestinal bleeding at the time 
of screening (positive fecal occult 
blood test [FOBT] at screening). 
 
Exclusion criterion #18: 
History or current evidence of any 
serious or clinically significant 
cardiac, gastrointestinal, renal, 
endocrine, neurologic, hematologic or 
other condition that is uncontrolled on 
permitted therapies or that would, in 
the opinion of the Investigator or the 
Medical Monitor, make the participant 
unsuitable for inclusion in this study. 
Scheduled assessments of safety 
labs, including hemoglobin and 
hematocrit. 
 
General safety and tolerability will be 
monitored, and the participant may 
be withdrawn at any time at the 
discretion of the Investigator for 
safety.   
Mortality and General Health: 
 
Oral 4-wk repeat dose dog study:  
One male dog at 30 mg/kg/day was 
terminated from the study on Day 6 
due to poor clinical condition.  Two 
additional male dogs at 30 mg/kg/day 
were terminated from the study on 
Day 10 due to extremely reduced 
food consumption and body weight 
loss.  Another high dose male dog 
had transient whole body shaking on 
Days 8 and 9. 
 
Oral 13-week repeat dose dog study:  
One female at 10 mg/kg/day was 
euthanized on Day 74 for welfare 
reasons. Elevated body temperature 
(39.6°C), slightly decreased skin 
turgor, bright/dark red/irregular 
surface of tongue and inner lips, as 
well as friable skin lesions on the limb 
and tail were noted. 
 
Oral 4-wk repeat dose rat study:  
Decreased food consumption was 
observed at 300 mg/kg/day without 
correlated deceases in body weights. 
 
Rat micronucleus and comet study:  
Mortality was observed following 1 to 
3 doses at ≥600mg/kg/day. 
Exclusion criterion #14: 
Active ulcer disease or 
gastrointestinal bleeding at the time 
of screening (positive FOBT at 
screening). 
 
Exclusion criterion #18: 
History or current evidence of any 
serious or clinically significant 
cardiac, gastrointestinal, renal, 
endocrine, neurologic, hematologic or 
other condition that is uncontrolled on 
permitted therapies or that would, in 
the opinion of the Investigator or the 
Medical Monitor, make the participant 
unsuitable for inclusion in this study. 
Scheduled assessments of safety 
labs, including hemoglobin and 
hematocrit. 
 
General safety and tolerability will be 
monitored, and the participant may 
be withdrawn at any time at the 
discretion of the Investigator for 
safety.   


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Revised Text: 
Potential Risk of Clinical 
Significance and Summary 
of Data/Rational for Risk 
Impact on Eligibility Criteria 
Mitigation Strategy 
Investigational Product (IP) [GSK2798745] 
Gastrointestinal:  
Oral 4-wk repeat dose dog study:  
Minimal grade mucosal 
erosion/ulceration in the stomach 
and/or duodenum was observed at 
doses of 3 mg/kg/day and higher. 
The observations were not 
considered to be adverse. 
Oral 4-wk repeat dose rat study:  
Mucosal erosion/ulceration in the 
stomach and/or duodenum was 
observed at 300 mg/kg/day. 
Oral 13-wk repeat dose rat study:  
Minimal grade mucosal erosion in the 
stomach was observed at 60 
mg/kg/day. The observations were 
not considered to be adverse. 
 
Exclusion criterion #14: 
Active ulcer disease or 
gastrointestinal bleeding by history 
within 6 months of screening or by 
exam at the time of screening. 
 
Exclusion criterion #18: 
History or current evidence of any 
serious or clinically significant 
cardiac, gastrointestinal, renal, 
endocrine, neurologic, hematologic or 
other condition that is uncontrolled on 
permitted therapies or that would, in 
the opinion of the Investigator or the 
Medical Monitor, make the participant 
unsuitable for inclusion in this study. 
Scheduled assessments of safety 
labs, including hemoglobin and 
hematocrit. 
 
General safety and tolerability will be 
monitored, and the participant may 
be withdrawn at any time at the 
discretion of the Investigator for 
safety.   


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Potential Risk of Clinical 
Significance and Summary 
of Data/Rational for Risk 
Impact on Eligibility Criteria 
Mitigation Strategy 
Investigational Product (IP) [GSK2798745] 
Mortality and General Health: 
 
Oral 4-wk repeat dose dog study:  
One male dog at 30 mg/kg/day was 
terminated from the study on Day 6 
due to poor clinical condition.  Two 
additional male dogs at 30 mg/kg/day 
were terminated from the study on 
Day 10 due to extremely reduced 
food consumption and body weight 
loss.  Another high dose male dog 
had transient whole body shaking on 
Days 8 and 9. 
 
Oral 13-week repeat dose dog study:  
One female at 10 mg/kg/day was 
euthanized on Day 74 for welfare 
reasons. Elevated body temperature 
(39.6°C), slightly decreased skin 
turgor, bright/dark red/irregular 
surface of tongue and inner lips, as 
well as friable skin lesions on the limb 
and tail were noted. 
 
Oral 4-wk repeat dose rat study:  
Decreased food consumption was 
observed at 300 mg/kg/day without 
correlated deceases in body weights. 
 
Rat micronucleus and comet study:  
Mortality was observed following 1 to 
3 doses at ≥600mg/kg/day. 
Exclusion criterion #14: 
Active ulcer disease or 
gastrointestinal bleeding by history 
within 6 months of screening or by 
exam at the time of screening. 
 
Exclusion criterion #18: 
History or current evidence of any 
serious or clinically significant 
cardiac, gastrointestinal, renal, 
endocrine, neurologic, hematologic or 
other condition that is uncontrolled on 
permitted therapies or that would, in 
the opinion of the Investigator or the 
Medical Monitor, make the participant 
unsuitable for inclusion in this study. 
Scheduled assessments of safety 
labs, including hemoglobin and 
hematocrit. 
 
General safety and tolerability will be 
monitored, and the participant may 
be withdrawn at any time at the 
discretion of the Investigator for 
safety.   
 
 


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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
SPONSOR SIGNATORY: ............................................................................................... 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
TABLE OF CONTENTS ................................................................................................ 13 
1. 
PROTOCOL SUMMARY ........................................................................................ 16 
1.1. 
Synopsis ..................................................................................................... 16 
1.2. 
Schema ...................................................................................................... 19 
1.3. 
Schedule of Activities (SoA) ........................................................................ 20 
1.3.1. 
28 Day – 4 Week Treatment Period ............................................. 20 
1.3.2. 
PK Subset - Intensive PK Sampling Day 7 and Day 28 ................ 24 
1.3.3. 
Additional SoA Notes ................................................................... 25 
2. 
INTRODUCTION .................................................................................................... 26 
2.1. 
Background ................................................................................................ 26 
2.2. 
Study Rationale .......................................................................................... 27 
2.3. 
Benefit/Risk Assessment ............................................................................ 28 
2.3.1. 
Risk Assessment ......................................................................... 28 
2.3.2. 
Benefit Assessment ..................................................................... 35 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 35 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 36 
4. 
STUDY DESIGN .................................................................................................... 36 
4.1. 
Overall Design ............................................................................................ 36 
4.2. 
Scientific Rationale for Study Design .......................................................... 37 
4.3. 
Justification for Dose .................................................................................. 38 
4.3.1. 
Dose Rationale ............................................................................ 38 
4.4. 
End of Study Definition ............................................................................... 39 
5. 
STUDY POPULATION ........................................................................................... 39 
5.1. 
Inclusion Criteria ......................................................................................... 39 
5.2. 
Exclusion Criteria ........................................................................................ 41 
5.3. 
Lifestyle Considerations .............................................................................. 44 
5.3.1. 
Meals and Dietary Restrictions .................................................... 44 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 44 
5.3.3. 
Activity ......................................................................................... 44 
5.4. 
Screen Failures........................................................................................... 45 
6. 
STUDY INTERVENTION ........................................................................................ 45 
6.1. 
Study Intervention Administered ................................................................. 45 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 46 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 46 
6.4. 
Study Intervention Compliance ................................................................... 46 
6.5. 
Concomitant Therapy.................................................................................. 47 
6.5.1. 
Permitted Medications ................................................................. 47 
6.5.2. 
Prohibited Medications ................................................................. 47 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
2 1 2 6 6 9  
1 4  
6. 5. 3.  
O p ht h al mi c S af et y R e s c u e M e di ci n e  ........................................... 4 9  
6. 6.  
D o s e M o difi c ati o n  ....................................................................................... 4 9  
6. 7.  
I nt er v e nti o n aft er t h e E n d of t h e St u d y ........................................................ 4 9  
7.  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  ..................................................................... 4 9  
7. 1.  
Di s c o nti n u ati o n of St u d y I nt er v e nti o n  .......................................................... 4 9  
7. 1. 1.  
Li v er C h e mi str y St o p pi n g Crit eri a  ................................................ 5 0  
7. 1. 2.  
Q T c St o p pi n g Cr it eri a .................................................................. 5 0  
7. 1. 3.  
S y m pt o m s of C ar di a c I s c h e mi a a n d C ar di a c Tr o p o ni n 
St o p pi n g Crit eri a  .......................................................................... 5 1  
7. 1. 4.  
G e n er al St o p pi n g Crit eri a  ............................................................ 5 2  
7. 2.  
P arti ci p a nt Di s c o nti n u ati o n/ Wit h dr a w al fr o m t h e St u d y  ............................... 5 2  
7. 3.  
L o st t o F oll o w U p  ........................................................................................ 5 2  
8.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ..................................................... 5 3  
8. 1.  
S af et y A s s e s s m e nt s  ................................................................................... 5 4  
8. 1. 1.  
P h y si c al E x a mi n ati o n s  ................................................................. 5 4  
8. 1. 2.  
Vit al Si g n s  .................................................................................... 5 4  
8. 1. 3.  
El e ctr o c ar di o gr a m s  ...................................................................... 5 5  
8. 1. 4.  
Cli ni c al S af et y L a b or at or y A s s e s s m e n t s ...................................... 5 5  
8. 1. 5.  
C ol u m bi a S ui ci d alit y S e v erit y R ati n g S c al e ( C S S R S)  .................. 5 5  
8. 1. 6.  
O p ht h al mi c S af et y A s s e s s m e nt s  ................................................. 5 6  
8. 2.  
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  ............................................. 5 7  
8. 2. 1.  
Ti m e P eri o d a n d Fr e q u e n c y f or C oll e cti n g A E a n d S A E 
I nf or m ati o n ................................................................................... 5 7  
8. 2. 2.  
M et h o d of D et e cti n g A E s a n d S A E s  ............................................. 5 8  
8. 2. 3.  
F oll o w -u p of A E s a n d S A E s  ......................................................... 5 8  
8. 2. 4.  
R e g ul at or y R e p ort i n g R e q uir e m e nt s f or S A E s ............................. 5 8  
8. 2. 5.  
Pr e g n a n c y  ................................................................................... 5 8  
8. 2. 6.  
C ar di o v a s c ul ar a n d D e at h E v e nt s  ................................................ 5 9  
8. 3.  
Tr e at m e nt of O v er d o s e  ............................................................................... 5 9  
8. 4.  
P h ar m a c o ki n eti c s  ....................................................................................... 5 9  
8. 5.  
P h ar m a c o d y n a mi c s  .................................................................................... 6 0  
8. 5. 1.  
O pti c al C o h er e n c e T o m o gr a p h y  .................................................. 6 0  
8. 6.  
G e n eti c s  ..................................................................................................... 6 0  
8. 7.  
Bi o m ar k er s  ................................................................................................. 6 0  
8. 8.  
Utili z ati o n a n d H e alt h E c o n o mi c s  ................................................................ 6 0  
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ........................................................................ 6 1  
9. 1.  
St ati sti c al H y p ot h e s e s ................................................................................. 6 1  
9. 2.  
S a m pl e Si z e D et er mi n ati o n  ........................................................................ 6 1  
9. 2. 1.  
S a m pl e Si z e S e n siti vit y  ................................................................ 6 2  
9. 3.  
P o p ul ati o n s f or A n al y s e s  ............................................................................ 6 4  
9. 4.  
St ati sti c al A n al y s e s  ..................................................................................... 6 4  
9. 4. 1.  
Pri m ar y E n d p oi nt s  ....................................................................... 6 4  
9. 4. 2.  
S e c o n d ar y E n d p oi nt  .................................................................... 6 6  
9. 4. 3.  
Ot h er A n al y s e( s) E x pl or at or y E n d p oi nt( s)  .................................... 6 6  
9. 5.  
I nt eri m A n al y s e s ......................................................................................... 6 6  
1 0.  S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L  
C O N SI D E R A TI O N S  ............................................................................................... 6 7  
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10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 67 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 67 
10.1.2. 
Financial Disclosure ..................................................................... 67 
10.1.3. 
Informed Consent Process .......................................................... 68 
10.1.4. 
Data Protection ............................................................................ 68 
10.1.5. 
Dissemination of Clinical Study Data ........................................... 69 
10.1.6. 
Data Quality Assurance ............................................................... 69 
10.1.7. 
Source Documents ...................................................................... 70 
10.1.8. 
Study and Site Start and Closure ................................................. 70 
10.1.9. 
Publication Policy ......................................................................... 71 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 72 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 75 
10.3.1. 
Definition of AE ............................................................................ 75 
10.3.2. 
Definition of SAE .......................................................................... 76 
10.3.3. 
Definition of Cardiovascular Events ............................................. 77 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................... 77 
10.3.5. 
Reporting of SAE to GSK ............................................................. 79 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 81 
10.4.1. 
Definitions: ................................................................................... 81 
10.4.2. 
Collection of Pregnancy Information: ........................................... 83 
10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 84 
10.6. 
Appendix 6: Abbreviations and Trademarks ................................................ 86 
10.7. 
Appendix 7: Protocol Amendment History ................................................... 89 
11. REFERENCES ..................................................................................................... 102 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Diabetic Retinopathy (DR), a complication of diabetes in which high blood sugar levels 
cause damage to retinal blood vessels, is the main cause of all vision loss from age 20-74 
years and is detectable in one third of all diabetics worldwide (one-third of 285 million 
diabetics in 2010). DR is a continuum with Non-Proliferative DR (NPDR) and 
Proliferative DR (PDR) as the two sub-types. Diabetic Macular Edema (DME) may be 
present in either NPDR or PDR and is the main cause for vision loss while PDR is the 
main cause of blindness, in diabetics. 
The pathophysiology of DME is multifactorial involving key pathways, including protein 
kinase C, advanced glycation end production, polyol and hexosamine pathways. The 
common result in the eye is the breakdown of the Blood-Retinal-Barrier (BRB). The 
BRB is the tight junctions between the retinal capillary endothelial cells (internal BRB) 
and the retinal pigmented epithelial cells (external BRB). 
Current treatments focus on addressing BRB breakdown. Non-pharmacologic 
intervention includes laser photocoagulation. Pharmacologic intervention includes 
intraocular corticosteroid implants and intraocular anti-Vascular Endothelial Growth 
Factor (VEGF) injection. Steroid treatments may decrease inflammation and regulate 
endothelial junction proteins and adhesion molecules to have a beneficial effect on the 
BRB. Anti-VEGF treatments may restore cellular junctions and may partially act via 
blockage of calcium influx into endothelial cells caused by activation of VEGF Receptor.   
Transient Receptor Potential Vanilloid 4 (TRPV4) is a non-selective Ca2+ channel that is 
associated with modulation of vascular permeability and is expressed on retinal vascular 
endothelial cells. TRPV4 activation increases endothelial barrier permeability via the 
reorganization of actin cytoskeleton, microtubule disassembly, and disruption of cell-cell 
and cell-matrix adhesion and enhances BRB leak. Conversely, TRPV4 blockers can 
reverse BRB leakiness, as measured by Evans’ blue extravasation, in a diabetic rat model. 
GSK2798745 is a potent and selective oral TRPV4 channel blocker and has the potential 
to reverse BRB leak and treat DME. 
Protocol Title: Study 212669: Phase I, Open-Label, Multi-Center Study to Evaluate 
Safety, Pharmacokinetics and Pharmacodynamics of GSK2798745 after 28 Day Repeat 
Oral Administration to Adults with Diabetic Macular Edema 
Short Title: Study 212669: A Phase I Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of GSK 2798745 in Participants with Diabetic 
Macular Edema 
Rationale: 
GSK2798745 is a potent and selective oral TRPV4 channel blocker being investigated for 
the treatment of DME. GSK2798745 can block in vitro recombinant human TRPV4 
channels with an IC50 of 1.6 to 2.0 nM and can block native human endothelial TRPV4 
channels (in the presence of human whole blood) with an IC50 of 6.5nM.   


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To date, oral GSK2798745 has been administered to healthy participants as single doses 
up to 12.5 mg and for up to 14 daily doses of 5 mg. Oral GSK2798745 has been 
administered to patients with heart failure as a single 2.4 mg dose or as daily 2.4 mg 
doses for 7 days. An oral dose of 4.8 mg followed by a 2.4 mg once daily for an 
additional 6 days (7 days total) has be administered in patients with chronic cough.  
Review of data in healthy participants indicates that there were no clinically significant 
safety concerns with single or repeat administration of GSK2798745. Review of data in 
participants with heart failure and chronic cough indicates that there are no clinically 
significant safety signals or concerns with lab values of potential clinical importance with 
repeat GSK2798745 administration up to 7 days. Of note, 15 participants in the heart 
failure studies were also diabetic and 2 had diabetic retinopathy. There was no impact of 
GSK2798745 on a glucose challenge test in healthy participants. 
Further information regarding GSK2798745 pre-clinical and clinical data is available in 
the Investigator brochure (IB).   
The present study will be the first to evaluate the safety, tolerability, pharmacokinetics 
(PK), and pharmacodynamics (PD) of repeat oral doses of 3.2 mg GSK2798745 
administered to participants with DME.   
Administration of GSK2798745 will be for 28 days. The PD change of interest will be 
change from baseline (CFB) in macular edema as measured by Spectral-Domain Optical 
Coherence Tomography (SD-OCT). 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
To characterize the safety and tolerability of 
GSK2798745 following 28 days of daily oral dose 
administration to adult participants with confirmed 
Diabetic Macular Edema. 
 
To evaluate the pharmacodynamics of 28 daily oral 
doses of GSK2798745 in the study eye of adult 
participants with DME. 
Safety parameters including: complete ophthalmic 
examination, visual acuity, physical examination 
findings, vital sign measurement, clinical lab tests, 
12-lead ECG, clinical monitoring and observation 
and adverse event reporting. 
 
Mean change from baseline in center subfield retinal 
thickness in the study eye as measured by SD-OCT. 
Secondary 
To evaluate the pharmacokinetics of 28 daily oral 
doses of GSK2798745 in adult participants with 
DME. 
Plasma concentrations of GSK2798745, major 
metabolite M1, and derived PK parameters, as data 
permit 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
2 1 2 6 6 9  
1 8  
O bjecti ves  
E n d p oi nts  
E x pl or at or y  
 
O ver all Desi g n:  
St u d y 2 1 2 6 6 9 is a m ulti -ce nter, o p e n -la bel, si n gle ar m, 2 8 -da y  tr eat me nt st u d y. Eac h 
partici pa nt e nr olle d will recei ve a si n gl e dail y 3. 2 m g oral d os e of G S K 2 7 9 8 7 4 5 f or 2 8  
da ys.  T h e st u d y will be c o m p ose d of 3 peri o ds f or all partici pa nts ( Scree ni n g, Treat me nt, 
a n d F oll o w-u p).   
Discl os ure St ate me nt : T his is a si n gle ar m, u n -m as ke d treat me nt st u d y. 
N u m ber of P a rtici p a nts:  
T his is a st u d y i n partici p a nts wit h dia g n ose d Dia b etic Mac ular E de ma . A t l east 2 0 
partici pa nts will be scree ne d a n d e nr olle d t o e ns ure 2 0 e val ua bl e partici pa nts  ca n be 
ac hie ve d at t he e n d of  t h e 2 8 -da y  tr eat me nt peri o d . S u bjects t hat are scree ne d a n d meet 
eli gi bilit y criteria will be e nr olle d i n t he st u d y . A ma xi m u m of 3 0  partici pa nts  ma y be  
e nr olle d. A mi ni m u m of 5  e nr olle d partici p a nts will be c o nse nte d t o part a ke i n t he P K 
s u bset f or i nte nsi ve P K sa m pli n g o n Da y 7 a n d Da y 2 8 (Secti o n 1. 3. 3 ).  
N ote : " E nr olle d" mea ns a partici pa nt's, or t heir le gall y acce pta ble re pres e ntati ve’s, 
a gree m e nt t o partici pate i n a cli nical st u d y f oll o wi n g c o m pleti o n of t he i nf or me d c o nse nt 
pr ocess. P ote ntial partici pa nts w h o are s cree ne d f or t he p ur p ose of deter mi ni n g eli gi bilit y 
f or t he st u d y, b ut d o n ot partici pate i n t he st u d y, are n ot c o nsi dere d e nr olle d, u nless 
ot her wise s pecifie d b y t h e pr ot oc ol.  
I nter ve nti o n Gr o u ps a n d D ur ati o n:  
T he st u d y will be c o m p ose d of 3 peri o ds f or all partic i pa nts ( Scree ni n g, Treat me nt, a n d  
F oll o w -u p). T h e scree ni n g p eri o d ma y occ ur acr oss t w o visits b ut s h o ul d be c o m plete d 
wit hi n 1 4 da y s fr o m t he Baseli ne visit. T he tr eat me nt peri o d is 2 8  da ys . P artici pa nts 
e nr olle d i nt o t he st u d y will recei ve G S K 2 7 9 8 7 4 5 . T h e ma xi m u m da ys a partic i pa nt will 
be i n t he st u d y is a p pr o xi matel y 7 0 . 
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Data Monitoring or other Committee: No 
1.2. 
Schema 
 


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1.3. 
Schedule of Activities (SoA) 
1.3.1. 
28 Day – 4 Week Treatment Period  
Procedure / Study Day: 
 
Screening 
Baseline 
Treatment Period 
Early 
Withdrawal 
(WD) 
Follow-
up 
Day 56 
Week 8 
Notes 
Day 1 
Week 0 
Day 71 
Week 1 
PK-Subset 
Visit Only 
Day 14 
Week 2 
Day 28 
Week 4 
Visit Window 
-1 to -14 
-3 to -1 
1 
6 – 8 
13 – 16 
27 – 30  
 
54 - 58 
Visit window relative to Day 1 (first day 
of dosing at home).  
Screening assessments may be 
conducted across multiple visits, if 
required, but all samples for laboratory 
safety tests to be collected at one visit 
(unless repeats). 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
 
X1 
X 
X 
X 
X 
1 Day 7 for participants in PK Subset 
only  – see PK SoA Section 1.3.3  
Demography 
X 
 
 
 
 
 
 
 
 
Medical History (include substance usage 
& medication history) 
X 
X 
 
 
 
 
 
 
Substances: Drugs, Alcohol, tobacco. 
Review & update at baseline visit. 
See Section 5.3.2 
Complete Physical Examination  
X 
 
 
 
 
 
X 
X 
Including height and weight. See 
Section 8.1.1 
Brief Physical Exam 
 
X 
 
 
X 
X 
 
 
See Section 8.1.1 
12-Lead ECG 
X2 
X 
 
X1 
X 
X1 
X 
X 
Single ECG required at Screening, 
Baseline, Treatment periods, and 
follow-up; Triplicate ECG required at 
WD  
2Any ECG assessments completed 
within the 28 days prior to the start of 
screening may be used to determine 
eligibility.  These assessments must not 


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Procedure / Study Day: 
 
Screening 
Baseline 
Treatment Period 
Early 
Withdrawal 
(WD) 
Follow-
up 
Day 56 
Week 8 
Notes 
Day 1 
Week 0 
Day 71 
Week 1 
PK-Subset 
Visit Only 
Day 14 
Week 2 
Day 28 
Week 4 
have been collected for the purposes of 
this study, but for the routine care of the 
participant.  Any assessments with 
abnormal values may be re-tested 
within the screening window and post-
consent collection would be considered 
the first assessment of that ECG.  
Additional guidance is contained within 
the SRM. 
 
1 Day 7 for participants in PK Subset 
only – see PK SoA Section 1.3.3  
See Section 8.1.3 
Columbia Suicidality Severity Rating 
Scale (CSSRS) 
X 
 
 
X 
X 
X 
X 
X 
Use ‘Baseline’ CSSRS at Screening. 
Use the ‘Since Last Visit’ CSSRS all 
other visits including Follow-up. See 
Section 8.1.5 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
X 
See Section 8.1.2 
Clinical Chemistry, Hematology & UA 
(including Cardiac Troponin, CPK)2 
X 
X 
 
X 
X 
X 
X 
X 
UA baseline, WD and Follow-up only 
2Any laboratory assessments 
completed within the 28 days prior to 
the start of screening may be used to 
determine eligibility.  These 
assessments must not have been 
collected for the purposes of this study, 
but for the routine care of the 
participant.  Any assessments with 
abnormal values may be re-tested 
within the screening window and post-
consent collection would be considered 
the first assessment of that lab.  
Additional guidance is contained within 
the SRM. 


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Procedure / Study Day: 
 
Screening 
Baseline 
Treatment Period 
Early 
Withdrawal 
(WD) 
Follow-
up 
Day 56 
Week 8 
Notes 
Day 1 
Week 0 
Day 71 
Week 1 
PK-Subset 
Visit Only 
Day 14 
Week 2 
Day 28 
Week 4 
HbA1c 
X 
 
 
 
 
 
 
 
Fasting 
FSH / Estradiol 
X 
 
 
 
 
 
 
 
As needed in women of non-
childbearing potential only. See Section 
10.2 and Section 10.4 
Inclusion / Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Dispense Study Medication 
 
X 
 
 
 
 
 
 
Open label.  
Compliance Check for Study Medication 
 
 
 
X 
X 
X 
X 
 
 
First Day of Study Treatment 
 
 
X 
 
 
 
 
 
Site staff will contact each participant 
(or caregiver) on the first dosing day 
(Day 1) to review dosing, to: 1) verbally 
confirm that the participant has begun 
dosing; 2) review and verbally confirm 
proper storage of treatment; 3) remind 
the participant to save all treatment 
containers; 4) inquire about adverse 
events; and 5) answer any other 
questions the participant may have. 
Additional guidance on Day 1 dosing 
can be found in the SRM. 
Dosing in Clinic 
 
 
 
X 
X 
X 
 
 
 
PK – Trough Sampling 
 
 
 
 
 
X 
 
 
All participants pre-dose trough D28. 
On the PK day, participants may have 
light meal prior to visit (see SRM). 
Participants will be dosed at the clinic & 
must not take treatment at home. 
PK – Intensive Sampling  
 
 
 
X 
 
X 
 
 
PK subset only see PK SoA Section 
1.3.3. 
Spectral Domain Optical Coherence 
Tomography (SD-OCT) 
X 
X3 
 
 
X 
X 
X 
X 
3If the date of the screening SD-OCT is 
within 3 days of baseline, the screening 
SD-OCT can be considered as baseline 
SD-OCT 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
2 3  
Pr o c e d ure / St u d y D a y:  
 
S cr e e ni n g  
B a s eli n e  
Tre at m e nt P eri o d  
E arl y 
Wit h dra w al  
( W D) 
F oll o w -
u p  
D a y 5 6  
W e e k 8  
N ot e s  
D a y 1  
W e e k 0  
D a y 7 1  
W e e k 1  
P K -S u b set 
V i sit O nly  
D a y 1 4  
W e e k 2  
D a y 2 8  
W e e k 4  
G e n er al O p ht h al mic Ex a m  
X  
X 3 
 
 
 
X  
X  
X  
3If t h e d at e of t h e scre eni n g g en eral 
o pht h al mic  ex a m  is wit hi n 3 d ays of 
b as eli n e;  t h e scre e ni n g ex a m  c a n b e 
c o nsi d ere d as b as eli n e  
A E  - S A E Ass ess m e nt  
X  
X  
X  
X  
X  
X  
X  
X  
S A Es c oll ect e d fro m t he ti m e of 
c o ns e nt.  A Es c oll ect e d fro m t he ti m e of 
first dos e (s e e S ecti o n 8. 2. 1 ). 
C o nc o m it a nt M e dic ati o n  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
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1.3.2. 
PK Subset - Intensive PK Sampling Day 7 and Day 28  
This SoA details the intensive PK sampling schedule on Day 7 and Day 28. All other assessments detailed on the 28 Day SoA (Section 
1.3.1). The intensive PK sampling is for the PK subset participants only. A minimum of 5 enrolled participants will participate in the PK 
subset. Participants will be evaluated and dosed in the clinic on PK days.  
Day 7 and 28 
Pre-
Dose 
0h 
0.5h 
1h 
2h 
3h 
4h 
6h 
8h 
Notes 
Study Drug Dose 
 
X 
 
 
 
 
 
 
 
On PK days, participant to be dosed at the clinic and must not 
take study treatment at home on that day. 
Plasma PK / M1 Metabolite Sampling  
X 
 
X 
X 
X 
X 
X 
X 
X 
PK subset only. Timepoints relative to dosing 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
See Section 8.1.3 
Vital Signs 
X 
 
 
 
 
 
 
 
 
See Section 8.1.2 
Clinical Chemistry, Hematology (including cardiac 
troponin, CPK) 
X 
 
 
 
 
 
 
 
 
 


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1.3.3. 
Additional SoA Notes 
• 
Study Day 7 is for Participants in the PK Subset only. 
• 
Doses should be taken in the morning with or without food, except on specified PK days when participants may consume a light 
meal prior to the clinic visit. 
• 
The timing of assessments should allow PK samples to be taken as close as possible to the nominal time-point. The actual data and 
time of dose and sampling should be recorded in the electronic case report form (eCRF). 
• 
Participants should agree to and plan to complete all study visits. However, in the exceptional instance where a visit is missed, 
participants should be encouraged to reschedule as soon as possible in order to ensure careful monitoring of participant safety. If it is 
not feasible to reschedule prior to the next planned study visit, then site staff should make extra effort to ensure that the participant 
comes in for that next visit. 
• 
With the exception of PK sampling days where the treatment dose will be taken at the clinic, participants will self-administer the 
study treatment, or obtain dosing assistance from a caregiver, for the duration of the study. The oral tablet should be taken once daily 
in the morning ±2 hours from the Day 1 dose with or without food.  
• 
The timing and number of planned study assessments, including safety, pharmacokinetic, pharmacodynamic assessments may be 
altered during the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to 
ensure appropriate monitoring.  
• 
Any changes in the timing or addition of time points for any planned study assessments as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member and 
then archived in the Sponsor and site study files but will not constitute a protocol amendment. The IRB/IEC will be informed of any 
safety issues that constitute a substantial amendment and require alteration of the safety monitoring scheme or amendment of the 
Informed Consent Form (ICF). These changes will be approved by the IRB/IEC before implementation. 


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2. 
INTRODUCTION 
2.1. 
Background 
Diabetic Retinopathy (DR), a complication of diabetes in which high blood sugar levels 
cause damage to retinal blood vessels, is the main cause of all vision loss from age 20-74 
years and is detectable in one third of all diabetics worldwide (one-third of 285 million 
diabetics in 2010) [Lee, 2015]. DR is a continuum with Non-Proliferative DR (NPDR) 
and Proliferative DR (PDR) as the two sub-types. Diabetic Macular Edema (DME) may 
be present in either NPDR or PDR and is the main cause for vision loss while PDR is the 
main cause of blindness, in diabetics [Lee, 2015]. 
DME has a worldwide estimated prevalence of 21 million and is expected to increase 
with increased incidence of diabetes [Yau, 2012]. The pathophysiology of DME is 
multifactorial with complications of diabetes interacting with and modulating key 
pathways, including protein kinase C, advanced glycation end production, polyol and 
hexosamine pathways [Haritoglou, 2018, Fogli, 2016]. The common result in the eye is 
the breakdown of the Blood-Retinal-Barrier (BRB). The BRB is the tight junctions 
between the retinal capillary endothelial cells (internal BRB) and the retinal pigmented 
epithelial cells (external BRB) [Haritoglou, 2018, Fogli, 2016]. 
Current treatments focus on addressing BRB breakdown. Non-pharmacologic 
intervention includes laser photocoagulation of microaneurysms (focal) and general 
edematous tissue (grid) [Singer, 2016]. Pharmacologic intervention includes intraocular 
corticosteroid implants and intraocular anti-Vascular Endothelial Growth Factor (VEGF) 
injections [Dugel, 2015, Singer, 2016]. Steroid treatments may decrease inflammation 
and regulate endothelial junction proteins and adhesion molecules to have a beneficial 
effect on the BRB [Dugel, 2015]. Anti-VEGF treatments may restore cellular junctions 
and may partially act via blockage of calcium influx into endothelial cells caused by 
activation of VEGF Receptor [Bates, 2010]. 
The dexamethasone and fluocinolone acetonide implants have a long durability of effect 
(6m and 24-36m, respectively) [Dugel 2015]. However, there are side effects including 
implantation complications, increased intraocular pressure (IOP), and cataract formation 
that may necessitate their removal and discontinuation of treatment [Dugel, 2015]. 
Ranibizumab and aflibercept anti-VEGF intraocular injections are approved for monthly 
dosing and also have side effects including increased IOP, ocular pain, floaters, and 
subconjunctival hemorrhage [Blinder, 2017]. 
Although current treatments have efficacy compared to laser or no treatment, 55% of 
patients receiving anti-VEGF treatment and ~80% patients with a steroid implant fail to 
achieve ≥15 letter improvement after 2 or 3 years, respectively [Gonzalez, 2016, Boyer, 
2014]. There is still an opportunity to explore treatments with a better safety and efficacy 
profile, potentially with a route of administration other than intravitreal.  
Transient Receptor Potential Vanilloid 4 (TRPV4) is a non-selective Ca2+ channel that is 
associated with modulation of vascular permeability and is expressed on retinal vascular 
endothelial cells. TRPV4 activation increases endothelial barrier permeability via the 


TMF-14377129 
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reorganization of actin cytoskeleton, microtubule disassembly, and disruption of cell-cell 
and cell-matrix adhesion and enhances BRB leak [Phuong, 2017; Arredondo, 2017]. 
Conversely, TRPV4 blockers can reverse BRB leakiness, as measured by Evans’ blue 
extravasation, in a diabetic rat model [Arredondo, 2017]. Additionally, TRPV4 
modulation can regulate human retinal capillary endothelial cell migration and tube 
formation in vitro, two processes essential to neovascularization associated with BRB 
leak [Wen, 2018].  
2.2. 
Study Rationale 
GSK2798745 is a potent and selective oral TRPV4 channel blocker being investigated for 
the treatment of DME. GSK2798745 can block in vitro recombinant human TRPV4 
channels with an IC50 of 1.6 to 2.0 nM and can block native human endothelial TRPV4 
channels (in the presence of human whole blood) with an IC50 of 6.5 nM.   
To date, oral GSK2798745 has been administered to healthy participants as single doses 
up to 12.5 mg and for up to 14 daily doses of 5 mg. Oral GSK2798745 has been 
administered to patients with heart failure as a single 2.4 mg dose or as daily 2.4 mg 
doses for 7 days. An oral dose of 4.8 mg followed by a 2.4 mg once daily for an 
additional 6 days (7 days total) has be administered in patients with chronic cough.  
Review of data in healthy participants indicates that there were no clinically significant 
safety concerns with single or repeat administration of GSK2798745. Review of data in 
participants with heart failure and chronic cough indicates that there are no clinically 
significant safety signals or concerns with lab values of potential clinical importance with 
repeat GSK2798745 administration up to 7 days. Of note, 15 participants in the heart 
failure studies were also diabetic and 2 had diabetic retinopathy. There was no impact of 
GSK2798745 on a glucose challenge test in healthy participants. 
Further information regarding GSK2798745 pre-clinical and clinical data is available in 
the Investigator brochure (IB) [GSK Document Number 2013N162862_07].  
The present study will be the first to evaluate the safety, tolerability, pharmacokinetics 
(PK), and pharmacodynamics (PD) of repeat oral doses of 3.2 mg GSK2798745 
administered to participants with DME.   
Administration of GSK2798745 will be for 28 days.  The PD change of interest will be 
change from baseline (CFB) in macular edema as measured by Spectral-Domain Optical 
Coherence Tomography (SD-OCT).


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2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably expected adverse events of GSK2798745 may 
be found in the Investigator’s Brochure [GSK Document Number 2013N162862_07]. 
2.3.1. 
Risk Assessment 
All potential risks of GSK2798745 are based on pre-clinical data. No risks have been identified in the clinical studies of GSK2798745 
conducted prior to the effective date of this protocol. 
Potential Risk of Clinical Significance and 
Summary of Data/Rational for Risk 
Impact on Eligibility Criteria 
Mitigation Strategy 
Investigational Product (IP) [GSK2798745] 
Cardiovascular:  
Oral 4-wk repeat dose dog study:  Arterial lesions in 2 male 
dogs at 30 mg/kg/day. One with coronary artery 
inflammation and thymic arteriole inflammation with 
fibroplasia; one with epididymal artery 
degeneration/necrosis with inflammation. 
Cardiac myofiber degeneration/necrosis and inflammation 
was observed in one dog at 30 mg/kg/day. 
Oral 13-wk repeat dose dog study:  Arterial lesions in 1 
male and 1 female dog at 10 mg/kg/day. Male dog with 
epididymal arteriole degeneration/necrosis with 
lymphocytic inflammation; female dog with bladder 
arteriole degeneration/necrosis with lymphocytic 
inflammation. 
 
Exclusion criterion #18: 
History or current evidence of any serious or clinically 
significant cardiac, gastrointestinal, renal, endocrine, 
neurologic, hematologic or other condition that is 
uncontrolled on permitted therapies or that would, in the 
opinion of the Investigator or the Medical Monitor, make 
the participant unsuitable for inclusion in this study. 
 
Exclusion criterion #22: 
QTc >450 msec or QTc > 480 msec in participants with 
bundle branch block. 
 
Exclusion criterion # 32: 
Cardiac troponin at screening > ULN for the assay. 
As the nonclinical observations are not monitorable in the 
clinical, general safety and tolerability will be monitored 
and the participant may be withdrawn at any time at the 
discretion of the Investigator for safety. 
  
Cardiac troponin will be monitored through the study to 
assess general cardiac status. 
 
The GSK2798745 dose was selected to maintain an 
exposure 30-fold or greater below the no effect exposure 
of AUC 513 ng*hr/mL and Cmax 50 ng/mL (observed at 
3 mg/kg/day in the dog 13-wk repeat dose study) 


TMF-14377129 
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29 
Potential Risk of Clinical Significance and 
Summary of Data/Rational for Risk 
Impact on Eligibility Criteria 
Mitigation Strategy 
Investigational Product (IP) [GSK2798745] 
Gastrointestinal:  
Oral 4-wk repeat dose dog study:  Minimal grade mucosal 
erosion/ulceration in the stomach and/or duodenum was 
observed at doses of 3 mg/kg/day and higher. The 
observations were not considered to be adverse. 
Oral 4-wk repeat dose rat study:  Mucosal 
erosion/ulceration in the stomach and/or duodenum was 
observed at 300 mg/kg/day. 
Oral 13-wk repeat dose rat study:  Minimum grade 
mucosal erosion in the stomach was observed at 60 
mg/kg/day. The observations were not considered to be 
adverse. 
 
Exclusion criterion #14: 
Active ulcer disease or gastrointestinal bleeding by history 
within 6 months of screening or by exam at the time of 
screening. 
 
Exclusion criterion #18: 
History or current evidence of any serious or clinically 
significant cardiac, gastrointestinal, renal, endocrine, 
neurologic, hematologic or other condition that is 
uncontrolled on permitted therapies or that would, in the 
opinion of the Investigator or the Medical Monitor, make 
the participant unsuitable for inclusion in this study. 
Scheduled assessments of safety labs, including 
hemoglobin and hematocrit. 
 
General safety and tolerability will be monitored, and the 
participant may be withdrawn at any time at the discretion 
of the Investigator for safety.   


TMF-14377129 
CONFIDENTIAL 
 
 
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Potential Risk of Clinical Significance and 
Summary of Data/Rational for Risk 
Impact on Eligibility Criteria 
Mitigation Strategy 
Investigational Product (IP) [GSK2798745] 
Hepatic:  
Oral 4-wk repeat dose dog study:  In one male dog, focal 
hepatocellular degeneration was observed at 
30 mg/kg/day. 
Oral 7-day repeat dose rat study:  Biliary epithelial 
hypertrophy/hyperplasia and periductal mixed inflammatory 
cell infiltrate into the liver was observed at 300 mg/kg/day. 
Exclusion criterion #15: 
Current or chronic history of liver disease or known hepatic 
or biliary abnormalities (with the exception of Gilbert's 
syndrome or asymptomatic gallstones). 
 
Exclusion criterion #18: 
History or current evidence of any serious or clinically 
significant cardiac, gastrointestinal, renal, endocrine, 
neurologic, hematologic or other condition that is 
uncontrolled on permitted therapies or that would, in the 
opinion of the Investigator or the Medical Monitor, make 
the participant unsuitable for inclusion in this study. 
 
Exclusion criterion #19: 
Alanine transferase (ALT) >1.5x upper limit of normal 
(ULN). 
 
Exclusion criterion #20: 
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is 
acceptable if bilirubin is fractionated and direct bilirubin 
<35%). 
Scheduled assessments of safety labs, including LFTs. 
 
General safety and tolerability will be monitored, and the 
participant may be withdrawn at any time at the discretion 
of the Investigator for safety.   


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Potential Risk of Clinical Significance and 
Summary of Data/Rational for Risk 
Impact on Eligibility Criteria 
Mitigation Strategy 
Investigational Product (IP) [GSK2798745] 
Mortality and General Health: 
Oral 4-wk repeat dose dog study:  One male dog at 30 
mg/kg/day was terminated from the study on Day 6 due to 
poor clinical condition.  Two additional male dogs at 
30 mg/kg/day were terminated from the study on Day 10 
due to extremely reduced food consumption and body 
weight loss.  Another high dose male dog had transient 
whole body shaking on Days 8 and 9. 
Oral 13-week repeat dose dog study:  One female at 
10 mg/kg/day was euthanized on Day 74 for welfare 
reasons. Elevated body temperature (39.6°C), slightly 
decreased skin turgor, bright/dark red/irregular surface of 
tongue and inner lips, as well as friable skin lesions on the 
limb and tail were noted. 
 
Oral 4-wk repeat dose rat study:  Decreased food 
consumption was observed at 300 mg/kg/day without 
correlated deceases in body weights. 
Rat micronucleus and comet study:  Mortality was 
observed following 1 to 3 doses at ≥600mg/kg/day. 
Exclusion criterion #14: 
Active ulcer disease or gastrointestinal bleeding by history 
within 6 months of screening or by exam at the time of 
screening. 
 
Exclusion criterion #18: 
History or current evidence of any serious or clinically 
significant cardiac, gastrointestinal, renal, endocrine, 
neurologic, hematologic or other condition that is 
uncontrolled on permitted therapies or that would, in the 
opinion of the Investigator or the Medical Monitor, make 
the participant unsuitable for inclusion in this study. 
Scheduled assessments of safety labs, including 
hemoglobin and hematocrit. 
 
General safety and tolerability will be monitored, and the 
participant may be withdrawn at any time at the discretion 
of the Investigator for safety.   


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Potential Risk of Clinical Significance and 
Summary of Data/Rational for Risk 
Impact on Eligibility Criteria 
Mitigation Strategy 
Investigational Product (IP) [GSK2798745] 
Musculoskeletal:  
Oral 4-wk repeat dose rat study:  Skeletal myofiber 
necrosis, myofiber degeneration/regeneration, and 
fibroplasia was observed at 300 mg/kg/day. 
Oral 13-wk repeat dose rat study and dog 4- and 13-week 
studies:  No test article related skeletal muscle abnormality 
was noted. 
Exclusion criterion #18: 
History or current evidence of any serious or clinically 
significant cardiac, gastrointestinal, renal, endocrine, 
neurologic, hematologic or other condition that is 
uncontrolled on permitted therapies or that would, in the 
opinion of the Investigator or the Medical Monitor, make 
the participant unsuitable for inclusion in this study. 
Scheduled assessments of safety labs including CPK. 
 
General safety and tolerability will be monitored, and the 
participant may be withdrawn at any time at the discretion 
of the Investigator for safety.   
 
Neurologic:  
Rat micronucleus and comet study:  Convulsions were 
observed at ≥600mg/kg/day, though not related to Cmax 
nor to predictable time from dose administration. 
Rat and dog neurobehavioral function and repeat dosing 
toxicity studies: No test article related and consistent 
effects on neurobehavioral functions were observed. 
Exclusion criterion #16: 
History of stroke or seizure disorder within 1 year of 
screening. 
 
Exclusion criterion #18: 
History or current evidence of any serious or clinically 
significant cardiac, gastrointestinal, renal, endocrine, 
neurologic, hematologic or other condition that is 
uncontrolled on permitted therapies or that would, in the 
opinion of the Investigator or the Medical Monitor, make 
the participant unsuitable for inclusion in this study. 
 
General safety and tolerability will be monitored, and the 
participant may be withdrawn at any time at the discretion 
of the Investigator for safety.   
 


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33 
Potential Risk of Clinical Significance and 
Summary of Data/Rational for Risk 
Impact on Eligibility Criteria 
Mitigation Strategy 
Investigational Product (IP) [GSK2798745] 
Genitourinary:  
Oral 4-wk repeat dose rat study:  Spermatid retention at 
≥60 mg/kg/day. There were no associated degenerative 
changes in the testes or epididymis.  
Oral 13-wk repeat dose rat study:  No spermatogenic 
abnormalities were observed. 
Oral 4-wk and 13-wk repeat dose dog studies:  No 
spermatogenic abnormalities were observed. 
Inclusion criterion #8: 
Male participants must agree to use of contraceptives and 
refrain from donating sperm from first dose until after the 
follow-up visit. 
General safety and tolerability will be monitored, and the 
participant may be withdrawn at any time at the discretion 
of the Investigator for safety.   
 
The GSK2798745 dose was selected to maintain an 
exposure 30-fold or greater below the no effect exposure 
of AUC 513 ng*hr/mL and Cmax 50 ng/mL (observed at 
3 mg/kg/day in the dog 13-wk repeat dose study). The 
exposure will be 40-fold or greater below the rat no effect 
dose. 
 
Immunologic:  
Oral 4-wk repeat dose rat study:  Phospholipid 
accumulation in alveolar macrophages at ≥ 60 mg/kg/day.  
Increased cellularity of sinus macrophages in the 
mesenteric lymph node and macrophage vacuolation in the 
thymus and increased thymus weight at 300 mg/kg/day.  
Ultrastructural appearance of mesenteric lymph nodes 
consistent with phospholipidosis at 300 mg/kg/day.  The 
findings were not associated with degenerative changes. 
Oral 13-wk repeat dose rat study:  No test article related 
immunologic changes.  
Oral 4- and 13-wk repeat dose dog studies:  No test article 
related immunologic changes. 
Exclusion criterion #18: 
History or current evidence of any serious or clinically 
significant cardiac, gastrointestinal, renal, endocrine, 
neurologic, hematologic or other condition that is 
uncontrolled on permitted therapies or that would, in the 
opinion of the Investigator or the Medical Monitor, make 
the participant unsuitable for inclusion in this study. 
 
Exclusion criterion #21: 
Evidence of abnormal clinical laboratory finding prior to 
enrollment that, in the opinion of the Investigator, makes 
the subject unsuitable for the study. 
Scheduled assessments of safety labs, including CBC. 
 
General safety and tolerability will be monitored, and the 
participant may be withdrawn at any time at the discretion 
of the Investigator for safety.   
 
The GSK2798745 dose was selected to maintain an 
exposure 30-fold or greater below the no effect exposure 
of AUC 513 ng*hr/mL and Cmax 50 ng/mL (observed at 
3 mg/kg/day in the dog 13-wk repeat dose study).  The 
exposure will be 40-fold or greater below the rat no effect 
dose. 
 
 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
3 4  
P ot e nti al Ri sk of Cli ni cal Si g nifi c a n ce  
S u m m ar y of D ata/ R ati o n ale f or Ri s k  
Miti g ati o n Str at e g y  
St u d y Pr o c e d ure s  
P hl e b ot o m y  
F ai nti n g, mil d p ai n, br uisi n g, irrit ati o n or r e d n ess at a 
p hl e b ot o my sit e m ay b e ass oci at e d wit h bl o o d dr a ws.  
Ex p eri e nc e d sit e st aff will f oll o w st a n d ar d a p pr o ac h es f or 
m a n a gi n g ev e nts r el at e d t o bl o o d dr a ws.  
P u pil dil ati o n f or O p ht h al m ol o gi c E x a m,
Pot e nti al f or bri ef sti n gi n g wit h ey e dr o p a p plic ati o n.  
S m all risk f or tr a nsi e nt ey e pr ess ur e i ncr e as e, n a us e a, a n d 
ey e p ai n.  
Visi o n m ay b ec o m e t e m p or arily bl urr e d.  
Dil at e d ey es m ay b ec o m e t e m p or arily m or e s e nsitiv e t o 
li g ht. 
Ex p eri e nc e d sit e st aff will f oll o w st a n d ar d a p pr o ac h es f or 
m a n a gi n g ev e nts r el at e d t o ex a m  
Drivi n g or a ny ot h er activiti es w h er e visi o n is i m p act e d is 
n ot r ec o m m e n d e d.  
C o nsi d er av oi di n g bri g ht li g ht or w e ari n g s u n gl ass es  
 
C CI
C CI


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
3 5  
2. 3. 2.  
B e n efit A s s e s s m e nt  
P artici pa nts wit h D M E are n ot e x pecte d t o recei v e a n y direct be nefit as t he st u d y dr u g 
has n ot b ee n pr o v e n t o ha ve efficac y. T he p artici p a nts ma y b e nefit fr o m t he ge neral 
me dical data c ollecte d t hr o u g h st u d y ass ess me nts s uc h as o p ht hal m ol o gic e x a ms, reti nal 
i ma gi n g, cli nical la b orat or y t ests a n d electr ocar di o gra ms (E C Gs ). Partici p ati o n i n t he 
st u d y ma y pr o vi de s o ciet al be nefit t hr o u g h a d v a nci n g de v el o p me nt of ne w oral 
treat me nts i n t his area of disease . 
 
2. 3. 3.  
O v er all B e n efit:  Ri s k C o n cl u si o n  
T he p o p ulati o n f or t he c urre nt st u d y, D M E patie nts w it h ce nter i n v ol ve me nt, was 
selecte d t o all o w f or e x pl orati o n of t he effects of oral G S K 2 7 9 8 7 4 5 o n reti n al t hic k ness. 
D ue t o t he sl o w rate of pr o gessi o n of dise ase, a si g nifica nt l oss of visi o n is n ot e x pecte d 
d uri n g t he le n gt h of t his P hase I st u d y. I n t h e
 a p pr o xi matel y 5 % of patie nts wit h u ntreate d cli nicall y si g nifica nt 
dia betic mac ular e de m a wit h ce nter -i n v ol ve m e nt l ost ≥1 5 letters of visi o n o ver 3 m o nt hs 
Reseac h Gr o u p , 1 9 8 7 ]. 
F urt her m ore, si g nifica nt s p o nta ne o us i m pr o ve me nt i n vis ual ac uit y is n ot e x pecte d d uri n g 
t his st u d y, si nc e i m pr o ve me nts are u nc o m m o n. Less t ha n 3 % of t he partici pa nts o verall 
i n t he
ha d i m pr o ve me nts of 1 5 letters o ver 3  years 
Researc h Gr o u p , 
1 9 8 5 ]. 
Partici pa nts will be m o nit ore d fre q u e ntl y f or e vi d e nce of dis ease pr o gressi o n. At eac h of 
t he st u d y visits, cli nical safet y meas ures, ha v e bee n i nc or p orate d t o m o nit or partici pa nts , 
i ncl u di n g, O C T i ma gi n g a n d vis ual ac uit y m eas ure me nt  at Visits 4 a n d 5 ( Secti o n 1. 3. 1 ) . 
S h o ul d t he disease pr o gress si g nifica ntl y, t he I n vesti gat or ma y c h o ose t o wit h dra wal t he 
s u bject fr o m st u d y p artici pati o n t o a d mi nister sta n dar d of care treat me nt se e Secti o n 
6. 5. 3 . 
Ta ki n g i nt o acc o u nt t he meas ures ta k e n t o mi ni mise ris k t o partici pa nts  i n t his st u d y 
(e. g., d ose sel ecti o n, caref ul partici pa nt selecti o n a n d ris k m o nit ori n g), t he p ote ntial ris ks 
i de ntifie d i n ass ociati o n wit h G S K 2 7 9 8 7 4 5 are j ustifie d b y t he a ntici pate d be nefits t hat 
ma y b e aff or de d t o partici pa nts wit h  D M E.  
C CI
C CI
C CI
C CI
C CI


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
3 6  
3.  
O B J E C TI V E S A N D E N D P O I N T S 
O bj e cti ve s  
E n d p oi nt s  
Pri m ary  
T o c h ar act eriz e t h e s af ety a nd t ol er a bility of 
G S K 2 7 9 8 7 45 f oll o wi n g 28 d ays  of d aily or al dos e 
a d mi nistr ati o n t o a d ult p artici pa nts wit h c o nfir m e d 
Di a b etic M ac ul ar E d e m a.  
 
T o ev alu at e th e p h ar m aco dy na mics of 28  d aily or al 
d os es of G S K 2 79 8 7 4 5 i n t he st u dy ey e of ad ult 
p articip a nts wit h D M E.  
S af ety p ar a m et ers i ncl u di n g: co m pl ete o p hth al mic 
ex a min ati on, vis u al ac uity, p hysic al ex a mi nati o n 
fi n di n gs, vit al si gn m e as ur e m ent, cli nical l ab t ests, 
1 2 -l e a d E C G, cli nic al m o nit orin g a n d obs erv ati o n 
a n d a dv ers e ev e nt re p ortin g.  
 
M e a n ch a n g e fr o m bas eli n e i n c e nt er s u bfiel d r eti n al 
t hickn ess i n th e stu dy ey e as m e as ured by S D -O C T.  
S e c o n d ary  
T o ev alu at e th e p h ar m acoki netics of 2 8 daily or al 
d os es of G S K 2 79 8 7 4 5 i n a dult p artici p a nts wit h 
D M E.  
Pl as m a c o nc e ntr ati o ns of G S K 2 7 9 8 7 4 5, m aj or 
m et a b olit e M 1, a nd d eriv e d P K p ar a m et ers, as d at a 
p er mit  
E x pl or at or y  
 
4.  
S T U D Y D E SI G N  
4. 1.  
O v er all D e si g n  
T his is a m ulti -ce nter, o p e n -la bel, si n gle ar m, 2 8 -da y  tr eat me nt st u d y. T he st u d y will be 
c o m p ose d of 3 peri o ds f or all partici pa nts ( Scree ni n g, Treat me nt, a n d F oll o w -u p).   
Eac h partici pa nt will:  
•  b e scree ne d (s cree ni n g ma y b e c o n d u cte d acr oss m ore t ha n 1 visit);  
•  h a ve a 2 8 -d a y  treat me nt peri o d; 
•  a n d, ha ve a f oll o w -u p visit (a p pr o xi matel y 2 8 da ys after t he fi nal d ose). 
Eac h partici pa nt e nr olle d will  recei ve a si n gl e dail y 3. 2 m g oral d ose of G S K 2 7 9 8 7 4 5 f or 
2 8 da ys . 
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212669 
37 
Figure 1 
Study Design Overview 
 
 
4.2. 
Scientific Rationale for Study Design 
This is a multi-center study of repeat oral administration of 3.2 mg of GSK2798745 daily 
for 28 days.  
The study will be open label. Placebo is not needed for powering the primary endpoint of 
SD-OCT. Additionally, initial participant safety and tolerability has previously been 
assessed in multiple placebo-controlled trials. The populations assessed included subjects 
with diabetes and diabetic retinopathy. There is no specific safety signal we are 
anticipating that would require discrimination between an active and placebo population. 
The primary objectives are to determine 1) safety and tolerability of GSK2798745, and 2) 
the effect of GSK2798745 on the mean change from baseline in macular thickness as 
measured by SD-OCT after 28 days of dosing. Measurements will be taken at specified 
study visits as detailed in the SoA (Section 1.3). At a minimum the screening, baseline 
and 28-day SD-OCT images will be read by a central reading center. 
Eligible participant must start treatment within 14 days of screening. Eligibility for each 
participant will be based only on one eye, which will be designated as the study eye. If 
both eyes qualify for the study, the study eye will be determined by the Investigator based 
on macular thickness and visual acuity as outlined in the SRM. 
The study eye will be examined for changes over the life of the study. As this 
investigational treatment is systemic, the fellow eye will be examined in tandem to 
provide additional safety data. The same assessments will be performed for the study eye 
and fellow eye. The duration of treatment will be 28 days. Participants will return for a 
follow-up visit approximately 28 days after the last dose of study medication. 
Safety will be assessed by complete ophthalmic examination, vital sign measurement, 
clinical laboratory tests, clinical monitoring and adverse event reporting. 
Pharmacodynamic assessments will include SD-OCT measurements of the central retinal 
thickness, during screening, on-treatment and follow-up visits. 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
3 8  
Vis ual ac uit y usi n g 
 c h art rea di n g 
will be meas ure d at s pecifie d visits as per t he S o A ( Secti o n 1. 3 ). Reti nal m or p h ol o g y will 
be assesse d b y S D -O C T,
4. 3.  
J u stifi c ati o n f or D o s e  
4. 3. 1.  
D o s e R ati o n al e  
O nce dail y d osi n g wit h 3. 2 m g ta blet G S K 2 7 9 8 7 4 5 will be a d mi nistere d i n t his st u d y. 
T he a vera ge s yste mic e x p os ure ( Ca v) o ver t he o n ce  dail y d osi n g i nter val wit h 3. 2 m g is 
e x pecte d t o be ar o u n d 8 n g/ m L  [ 9 5 % CI: 3. 5 –  1 7. 5] w hic h w o ul d be ass oci ate d wit h 
s yste mic tar get T R P V 4 i n hi biti o n of ~ 7 0 % [ 9 5 % CI: 4 6 %-8 5 %]. T he T R P V 4 p ote nc y 
(I C 5 0) of G S K 2 7 9 8 7 4 5 ra n ge fr o m 2. 1 t o 3. 2 n g/ m L bas e d o n i n vitr o h u ma n cell li nes, 
a n i n vi v o P K -P D rat p ul m o nar y e de ma m o d el a n d e x vi v o h u ma n u m bilical vei n 
e n d ot helial cell ( H U V E C) assa ys usi n g bl o o d fr o m heart fail ure patie nts d ose d wit h 
G S K 2 7 9 8 7 4 5 [G S K D oc u me nt N u m ber 2 0 1 3 N 1 6 2 8 6 2 _ 0 7 ]. As G S K 2 7 9 8 7 4 5 is hi g hl y 
li p o p hilic (l o g D7. 4 = 3. 1 4) wit h g o o d p er mea bilit y, a relati vel y hi g h tiss ue -t o-plas ma rati o 
of t he dr u g is e x pecte d i n t he c h or oi d a n d reti nal e pit helial barriers i nt o t he oc ular 
vasc ular e n d ot helial ca pillaries.  
E vi de nce f o r tra nslati o nal T R P V 4 tar get e n ga ge m e nt i n dia betic mac ular e de ma has bee n 
de m o nstrate d usi n g a p ot e nt t o ol T R P V 4 i n hi bit or. T R P V 4 bl oc ka de usi n g t he p ote nt a n d 
selecti ve i n hi bit or G S K 2 1 9 3 8 7 4 gi ve n i ntra vitreall y re v erse d B R B lea k i n dia betic rats 
[Arre d o n d o , 2 0 1 7 ]. It is n ota ble per G S K i nter n al data t hat G S K 2 1 9 3 8 7 4 is 
a p pr o xi matel y 1 0 -ti mes less p ote nt t ha n G S K 2 7 9 8 7 4 5 f or s yst e mic T R P V 4 i n hi biti o n 
usi n g rat P K -P D p ul m o n ar y e de m a m o del . F urt her e vi de nce of tra nsl ati o nal T R P V 4 
tar get e n ga ge me nt is pr o vi de d wit h t he T R P V 4 i n hi bit or H C -0 6 7 0 4 7 gi ve n i ntra -
perit o neall y ( 1 0 m g/ k g dail y f or o v er 1 m o nt h) i n a m o use m o del of gl a uc o ma a n d 
s h o we d s ustai ne d i n hi biti o n of i ntra-oc ular press ure c o m para ble t o baseli ne le vels 
[R ys ka m p , 2 0 1 6 ]. H C-0 6 7 0 4 7 is ~ 1 0 -f ol d less p ote nt t ha n G S K 2 7 9 8 7 4 5 i n cell li nes 
e x pressi n g m o use a n d h u ma n rec o m bi na nt T R P V 4 [E veraerts , 2 0 1 0 ], h o we ver n o 
s yste mic P K data wit h H C-0 6 7 0 4 7 are a vaila ble t o all o w  f or tra nslati o nal cr oss-s pecies 
c o m paris o n t o G S K 2 7 9 8 7 4 5.     
T he i nte n de d d osi n g re gi me n als o li mits t he dail y ceili n g h u ma n e x p os ure at i n di vi d ual 
partici pa nt le vel t o 3 0 -f ol d bel o w t he e x p os ure o bs er ve d at t he n o o bs er ve d a d verse effect 
le vel ( N O A E L) d ose of 3 m g/ k g/ d fr o m t he 3 -m o nt h d o g safet y st u d y. T h e pr o p ose d 
cli nical d ose of 3. 2 m g o n ce dail y G S K 2 7 9 8 7 4 5 is selecte d s o t hat n o partici pa nt 
i nte nti o nall y e x cee ds t he dail y A U C of 5 1 3 n g * hr/ m L a n d C ma x  of 5 0  n g /m L. T h e 
li keli h o o d of o ne or m ore partici pa nts of t he 2 0 partici pa nts t o be d ose d wit h t his re gi me n 
e x cee di n g t h e t hres h ol d is liste d i n Ta ble 1  bel o w:  
C CI
C CI


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
3 9  
T a bl e 1  
Pr e di ct e d e x p o s ur e, pr o b a bilit y of e x c e e di n g t hr e s h ol d a n d 
pr e di ct e d T R P V 4 i n hi biti o n aft er or al d o s e s of 3. 2 m g d ail y 
a d mi ni st er e d t o 2 0 p arti ci p a nt s  
P er c e nt a g e 
s y st e mi c T R P V 4 
bl o c k a d e o v er 2 4 h  
( m e di a n [ 9 5 % PI]) 
Pr e di ct e d e x p o s ure  
( m e di a n [ 9 5 % PI]) 
% Pr o b a bilit y t h at ≥1 of 20 
p arti ci p a nt s will e x ce e d t he 
t o xi c o ki n etic li mit1 
A U C 0 – 2 4  h  
( n g.h/ m L)  
C m a x  
( 5 0 n g/ m L)  
A U C 0 – 2 4  h  
( 5 1 3 n g. h/ m L)  
C m a x  
( 5 0 n g/ m L)  
7 0 % 
 [ 4 6 % –  85 %]  
1 9 5  
[ 8 5–4 20] 
1 5  
[ 8– 25] 
0. 9 4  
0  
PI:  pr e dict e d i nt erv al.   
1. T h e p erc e nt a g e of t h e 5 0 0 si m ul at e d st u di es ( of 2 0 s u bj ects e ac h) i n w hic h ≥1 s u bj ect exc e e ds t h e t oxic oki n etic 
limit.  
N O T E: R ecr uit m e nt is pl a n n e d t o e ns ur e t h at 2 0 p artici p a nts will  b e  ev al u a bl e  a ft er 2 8 d ays of d osi n g. Sh o ul d  3 0 
p artici p a nts b e r ecr uit e d a n d all c o m pl et e, t h e % pr o b a bility of exc e e di n g t h e li mit g o es d o w n f or t h e A U C t o 0. 8 4 % a n d 
r e m ai ns 0 % f or C m ax.  
4. 4.  
E n d of St u d y D efi niti o n  
A partici pa nt is c o nsi dere d t o ha ve c o m plet e d t he st u d y if he/s he h as c o m plete d all 
p hases of t he st u d y i ncl u di n g t he f oll o w-u p visit  a n d last sc he d ule d  pr oce d ure s s h o wn i n 
t he Sc he d ule of A cti vities. 
T he e n d of t he st u d y is d ef i ne d as t he d ate of t he l ast sc he d ule d pr o ce d ure s h o w n i n t he 
Sc he d ule of A cti vities f or t he last pa rtici pa nt i n t h e trial gl o b all y. 
5.  
S T U D Y P O P U L A TI O N  
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr ollme nt  criteria, als o 
k n o w n as pr ot oc o l wai v ers or e x e m pti o ns, is n ot per mitte d. A d here nce t o t h e e ntr y 
criteria a n d t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A ( Secti o n 
1. 3 ) are esse ntial. 
5. 1.  
I n cl u si o n Crit eri a 
Partici pa nts a n d t he parti ci pa nt s’ st u d y e ye are eli gi ble t o be i ncl u d e d i n t he st u d y o nl y if 
all of t he f oll o wi n g criteria a p pl y:  
A G E  
1.  At least 1 8 t o 75  years of a ge i ncl usi ve, at t he ti me of si g ni n g t he i nf or m e d c o nse nt.  
 
T Y P E O F P A R TI CI P A N T  A N D DI A G N O SI S I N C L U DI N G DI S E A S E S E V E RI T Y   
2.  Dia g n osis of di a betes mellit us (t y p e 1 or t y pe 2) . 
3.  C o nfir mati o n of D M E wit h ce nter i n v ol ve me nt i n at least o ne e ye, i ncl u di n g t h o se 
wit h f ocal or diff us e D M E as deter mi ne d b y I n vesti gat or-d eter mi ne d 
 
C CI
C CI


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
4 0  
T Y P E O F P A R TI CI P A N T  A N D DI A G N O SI S I N C L U DI N G DI S E A S E S E V E RI T Y   
4.  Reti nal t hic ke ni n g ( D M E ) i n v ol vin g t he ce nter of t he f o vea i n t he st u d y e ye as 
defi ne d b y I n v esti gat or-d eter mi ne d S D -O C T ce ntr al s u bfiel d t hic k ness > 3 4 0 micr o ns 
f or Hei del b er g S pectr alis or > 3 2 0 f or Zeiss Cirr us ; if b ot h e yes are eli gi ble, t he e ye 
wit h t he greater O C T ce nter s u bfiel d sc o re is selecte d as t he st u d y e ye if all ot her 
criteria are met. S D -O C T assess me nts f or i n di vi d ual patie nts m ust be ta ke n wit h t he 
sa me mac hi ne t hr o u g h o ut t he d urati o n of t he st u d y.  
5.  
l etter sc ore of 8 0  letter or w orse 
( S nelle n e q ui vale nt ~ 2 0/2 5 ) or w orse i n t he st u d y e ye.  
6.  Safe t o wit h h ol d treat me nt of t he st u d y e ye wit h laser p h ot oc oa g ulati o n, i ntra vitreal 
ster oi d i njecti o n, or i ntra vitreal V E G F i n hi bit or f or t he d urati o n of t he st u d y.  
A s u bject wit h a cli nical a b n or m alit y or la b orat or y para meter(s) w hi c h is/are n ot 
s pecificall y liste d i n t he i ncl usi o n or e x cl usi o n criteria, o utsi de t he refere nce ra n ge f or t he 
p o p ulati o n bei n g st u die d ma y b e i ncl u de d o nl y if t he I n vesti gat or i n c o ns ult ati o n wit h t he 
Me dical M o nit or  a gr ee a n d d oc u me nt t hat t he fi n di n g is u nli kel y t o i ntr o d uce a d diti o nal 
ris k fact ors a n d will n ot i nterfere wit h t he st u d y pr oce d ures.  
 
W EI G H T  
7.  B o d y wei g ht ≥5 0 k g  a nd b o d y mass i n de x ( B MI) wit hi n t he ra n ge 1 8 t o 4 3 k g / m2 
(i ncl usi ve) at scree ni n g. 
 
S E X  
8.  Mal e or Fe male  
a. M ale p artici p a nts:  
Male partici pa nts are eli gi ble t o partici pate if t he y a gree t o t he f oll o wi n g first d ose of 
st u d y treat me nt u ntil t he f oll o w-u p visit.  
•  Refrai n fr o m d o n ati n g s p er m  
P L U S eit her:  
•  
Be a bsti ne nt fr o m heter ose x ual or h o m ose x ual i nte rc o urse as t heir preferre d a n d 
us ual lifest yle (a bsti ne nt o n a l o n g ter m a n d persiste nt basis) a n d a gree t o r e mai n 
a bsti ne nt  
O R  
•  
M ust a gree t o use c o ntrace pti o n/ barrier as detaile d bel o w:  
•  
A gree t o use a male c o n d o m a n d fe male p art ner t o use a n a d diti o nal hi g hl y 
effecti ve c o ntr ace pti ve m et h o d wit h a fail ure rate of < 1 % per year as 
descri be d i n A p p e n di x  4   
•  
S h o ul d als o be a d vise d of t he be nefit f or a fe male part ner t o use a hi g hl y 
effecti ve met h o d of c o ntrace pti o n as a c o n d o m ma y brea k or l ea k  w he n 
ha vi n g se x ual i nterc o urse wit h a w o ma n of c hil d beari n g p ot e ntial w h o is n ot 
c urre ntl y pre g na nt  
C CI


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
4 1  
S E X  
 
b.  Fe m ale p artici p a nts:  
A fe male p artici pa nt is eli gi ble t o partici pat e if s he is n ot pre g n a nt, n ot breastfee di n g 
a n d n ot of c hil d be ar i n g p ote nti al as defi ne d i n A p pe n di x  4 . T he I n vesti gat or is 
res p o nsi ble f or re vie w of me dical hist or y, m e nstr u al hist or y, a n d rece nt se x ual 
acti vit y t o decrease t he ris k f or i ncl usi o n of a w o ma n wit h a n earl y u n d etecte d 
pre g na nc y . 
C o n trace pti ve use b y me n or w o me n s h o ul d be c o nsiste nt wit h l ocal re g ul ati o ns 
re gar di n g t he m et h o ds of c o ntrace pti o n f or t h ose p artici pati n g i n cli nical st u dies. 
 
I N F O R M E D C O N S E N T 
9.  S u bject is willi n g a n d a bl e t o ret ur n f or all st u d y visits a n d t o c o m pl y wit h  all 
pr ot oc ol re q uire m e nts a n d pr oce d ures.  
1 0.  Ca pa ble of gi vi n g si g n e d i nf or me d c o nse nt as d es cri be d i n A p pe n di x 1  w hic h 
i ncl u des c o m plia nce wit h t he re q uire m e nts a n d restricti o ns liste d i n t he c o nse nt f or m 
a n d i n t his pr ot oc ol.  
 
5. 2.  
E x cl u s i o n Crit eri a  
Partici pa nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
M E DI C A L C O N DI TI O N S –  O C U L A R  
1.  A d diti o nal e ye disease i n t he st u d y e ye t hat i n t he o pi ni o n of t he I n v esti gat or  c o ul d 
c o m pr o mise assess me nt of S D -O C T, 
or i ma gi n g of t he p ost eri or p ole b y
, 
 or is li kel y t o re q uir e i nter ve nti o n d uri n g t h e st u d y (e. g., 
cataract, gla uc o m a wit h d oc u me nte d vis ual fiel d l oss, isc he mic o ptic ne ur o pat h y, 
reti nitis pi g me nt osa). 
2.  Hist or y of c h or oi dal ne o vasc ulariza ti o n i n t he st u d y e ye, or c urre nt c h or oi dal 
ne o vasc ularizati o n i n t he fell o w e ye re q uiri n g treat me nt.  
3.  Acti ve P D R i n t he st u d y e ye or u ntr eate d acti ve P D R i n t he fell o w e ye.  
4.  Is c he mic ma c ul o pat h y o n 
defi ne d as a t otal area of ca pilla r y 
l oss greater t hat 2-dis c areas ( > 5 m m 2) wit hi n t he E T D R A mac ular gri d or a f o veal 
a vasc ular z o ne great est li near dia met er of > 1 0 0 0 micr o ns.  
5.  I ntr a oc ular s ur ger y or l as er p h ot oc oa g ulati o n i n t h e st u d y e ye wit hi n 9 0 da y  of d osi n g 
w hic h mi g ht co m pr o mise asse ss me nt of S D-O C T,  
 or i ma gi n g of t he p osteri or 
p ole b y
 All o we d i n f ell o w e ye. 
6.   Use of i ntra vitreal ra ni bi z u ma b or be vaciz u ma b wit hi n 4 2 da ys ( 6 wee ks), or 
afli berce pt wit hi n 5 6 da ys ( 8 wee ks) of d osi n g i n t he st u d y e ye. Allo we d i n fell o w 
e ye.  
7.  Use of i ntra oc ular ster oi ds i n t he st u d y e ye wit hi n 1 8 0 da ys of d osi n g. All o we d i n 
C CI
C CI
C CI
C CI
C CI
C CI


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MEDICAL CONDITIONS – OCULAR 
fellow eye. 
8. Use of or expected need for intravitreal or intraocular treatment in the study eye 
during course of the study. Allowed in fellow eye. 
9. Use of any systemically administered anti-angiogenic agent (e.g., bevacizumab, 
sunitinib, cetuximab, sorafenib, pazopanib), approved or investigational, within 
6 months of dosing. 
10. Evidence of vitreomacular traction as determined by the Investigator. 
11. Uncontrolled intraocular pressure >22 mmHg in the study eye despite treatment with 
glaucoma medication. 
12. Within 6 months prior to the Screening Visit, use of medications known to be toxic to 
the retina, lens or optic nerve (e.g., deferoxamine, chloroquine/hydroxychloroquine, 
chlorpromazine, phenothiazines, tamoxifen, interferons and ethambutol) or are 
implicated in the development of macular edema (e.g. thiazolidinediones, 
fingolimod). 
 
MEDICAL CONDITIONS - NON-OCULAR 
13. Uncontrolled diabetes as indicated by HbA1c >12% at screening. 
14. Active ulcer disease or gastrointestinal bleeding by history within 6 months of 
screening or by exam at the time of screening  
15. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
16. History of stroke or seizure disorder within 1 year of screening. 
17. Participant who, in the Investigator’s opinion, poses a significant suicide risk.  
Evidence of serious suicide risk may include any history of suicidal behaviour and/or 
any evidence of suicidal ideation on any questionnaires e.g., Type 4 or 5 on the 
CSSRS in the last 6 months (assessed at screening). 
18. History or current evidence of any serious or clinically significant cardiac, 
gastrointestinal, renal, endocrine, neurologic, hematologic, infectious or other 
condition that is uncontrolled on permitted therapies or that would, in the opinion of 
the Investigator or the Medical Monitor, make the participant unsuitable for 
inclusion in this study. 
19. Alanine transferase (ALT) >1.5x upper limit of normal (ULN).  
20. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
21. Evidence of abnormal clinical laboratory finding prior to enrollment that, in the 
opinion of the Investigator, makes the subject unsuitable for the study. 
22. QTc >450 msec or QTc >480 msec in participants with bundle branch block. 
NOTES: The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method. It is either 


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MEDICAL CONDITIONS - NON-OCULAR 
machine-read or manually over-read. 
The specific formula used to determine eligibility and discontinuation for an 
individual participant should be determined prior to initiation of the study. In other 
words, several different formulas cannot be used to calculate the QTc for an 
individual participant and then the lowest QTc value used to include or discontinue 
the participant from the trial. 
 
PRIOR / CONCOMITANT MEDICATIONS 
23. Unless permitted per Section 6.5, 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 drug, unless in the opinion of the 
Investigator and GSK Medical Monitor the medication will not interfere with the 
study procedures or compromise participant safety.   
Note:  Stable use of some medications and standard multi-vitamins (with only 
vitamins and minerals, and no plant extracts or herbal additives) may be permitted if 
the dose is stable for at least 3 months prior to Day 1, and the medication was 
prescribed for an indication other than DME.  The dose should remain constant 
throughout the study.  Changes in dose are not permitted, unless required for safety 
or tolerability.  Paracetamol at doses of ≤2 grams/day is permitted for use any time.  
 
24. Use of a listed precluded medication, including strong inhibitors or inducers of 
cytochrome P450 (CYP) 3A or p-glycoprotein (Section 6.5.2), within the restricted 
timeframe relative to the first dose of the study treatment. 
 
PRIOR / CONCURRENT CLINICAL TRIAL EXPERIENCE 
25. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 months from screening. 
26. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day. 
27. Current enrollment, or past participation within the last 60 days, of any clinical study 
involving an investigational study intervention, or any other type of medical 
research, before signing of consent for this study. 
 
DIAGNOSTIC ASSESSMENTS  
28. Positive human immunodeficiency virus (HIV) antibody test. 
29. Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months 
prior to first dose of study intervention.  
30. Positive Hepatitis C antibody test result at screening or within 3 months prior to 
starting study intervention.  


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DIAGNOSTIC ASSESSMENTS  
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained 
31. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study intervention. 
NOTE: Test is optional and participants with negative Hepatitis C antibody test are 
not required to also undergo Hepatitis C RNA testing 
32. Cardiac troponin at screening > ULN for the assay. 
 
OTHER EXCLUSIONS 
33. 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. 
34. Regular substance abuse including drug and/or alcohol consumption within 6 months 
prior to the study. Alcohol consumption is defined as: An 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.  
 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
Participants are not permitted to consume red wine, Seville oranges, grapefruit or 
grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices 
from 7 days before the start of study treatment until the end of study treatment. The 
exception to this is that regular orange juice is allowed anytime except 2 hours prior 
through 2 hours after study treatment dose.  
5.3.2. 
Caffeine, Alcohol, and Tobacco 
• 
Participants participating in the PK subset on Day 7 and Day 28 and for all 
participants on Day 28 will abstain from ingesting caffeine- or xanthine-containing 
products (e.g., coffee, tea, cola drinks, and chocolate) for 8 hours before the start of 
dosing until after collection of the final pharmacokinetic sample. 
• 
Participants who use tobacco products (including alternate delivery devices such as 
vaporizers) or alcohol will be instructed that use of such tobacco products or alcohol 
will not be permitted while they are in the clinical unit. Stable use of nicotine patches 
will be allowed at all times.  
5.3.3. 
Activity 
Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light recreational 
activities (e.g., walking). 


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5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs. 
Participants may be rescreened once only after consultation and agreement with the 
Medical Monitor. If rescreening is performed, participants must be assigned a different 
unique subject identification number for the rescreening, and all screening procedures 
must be repeated. See the study reference manual (SRM) for more details.   
In the event of out-of-range results of safety tests, the tests may be repeated once within 
the screening window. If a retest result is again outside the reference range and 
considered clinically significant by the Investigator and GSK Medical Monitor, the 
subject will be considered a screen failure. 
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 Administered 
Study Treatment Name: 
GSK2798745 
Dosage formulation: 
White to almost white, round, film-coated tablet.   
Unit dose strength: 
3.2 mg 
Route of Administration: 
Oral 
Dosing instructions: 
One tablet to be taken per day. All doses to be taken with a glass 
of water (~240 mL) at about the same time each day (2 hours 
relative to dosing on Day 1).  
Packaging and Labelling: 
GSK2798745 tablets will be provided in high-density 
polyethylene (HDPE) bottles with child-resistant closures that 
include induction-seal liners.  Each bottle will be labelled as 
required per country requirement.  
Manufacturer: 
GSK 
 


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6.2. 
Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must confirm appropriate temperature conditions as 
detailed in SRM have been maintained during transit for all study treatment received 
and any discrepancies are reported and resolved before use of the study treatment. 
2. Only participants enrolled in the study may receive study treatment and only 
authorised site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the Investigator and authorised site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.  
5. Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.   
6. A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
Investigator, where this is required by local laws, or is available upon request from 
GSK. 
 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
• 
This is a single arm, open-label study. 
• 
Assessments are objective measures and should have limited risk of bias.  
• 
The PD endpoints are based on studies with the same population and will also 
minimize bias. 
• 
The study will use Pre-Coded numbers provided to the site.  
• 
Participants will be assigned a unique number in ascending numerical order at each 
study site. The number encodes the participant’s assignment to the single arm study, 
according to the schedule generated prior to the study by the Statistics Department at 
GSK. Each participant will be dispensed study intervention, labeled with his/her 
unique number, throughout the study. 
6.4. 
Study Intervention Compliance 
• 
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 


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administering the study intervention. Study site personnel will examine each 
participant’s mouth to ensure that the study intervention was ingested. 
• 
When participants self-administer study intervention(s) at home, compliance with 
GSK2798745 will be assessed by direct questioning and counting returned 
tablets/capsules, etc. during the site visits and documented in the source documents 
and CRF.   
• 
A record of the number of GSK2798745 tablets dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and 
compliance records. Intervention start and stop dates, including dates for intervention 
delays and/or dose reductions will also be recorded in the CRF. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, some 
vitamins, and/or herbal supplements), approved by the Investigator, in consultation with 
the GSK Medical Monitor, that the participant is receiving at the time of enrolment, or 
receives during the study, must be recorded along with: 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.5.1. 
Permitted Medications 
Paracetamol at doses of ≤2 grams/day is permitted for use any time during the study. 
Other concomitant medication will be considered on a case by case basis by the 
Investigator in consultation with the GSK Medical Monitor. An exception is that rescue 
treatment is allowable in the fellow eye at any time during the study, see Section 6.5.3. 
Stable use of some medications may be permitted if the dose is stable for at least 3 
months prior to Day 1, and the medication was prescribed for an indication other than 
DME. The dose should remain constant throughout the study. Changes in dose are not 
permitted, unless required for safety or tolerability. These will be considered on a case by 
case basis by the Investigator in consultation with the GSK Medical Monitor. 
6.5.2. 
Prohibited Medications 
Except for the permitted medication noted above and those approved by the Investigator 
in consultation with the GSK Medical Monitor (Section 6.5.1, participants must abstain 
from taking prescription and non-prescription drugs (including some vitamins and dietary 
or herbal supplements), within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the first dose of study treatment until 
completion of the follow-up visit, unless in the opinion of the Investigator and GSK 
Medical Monitor the medication will not interfere with the study. 


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During the study, participants should not use drugs that are strong inhibitors or inducers 
of Cytochrome P450 (CYP) 3A4 or p-glycoprotein (P-gp), because they may alter 
GSK2798745 concentrations. The list of background therapy/drugs may be modified 
based on emerging data. These include, but are not limited to, those listed in Table 2. 
Table 2 
Strong Inducers/Inhibitors of CYP3A4 and P-gp 
Antiretrovirals: 
atazanavir, danoprevir, elvitegravir, fosamprenavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, tipranavir, 
boceprevir 
Antibiotics: 
clarithromycin, telithromycin, troleandomycin, rifampin 
Oral antifungals: 
ketoconazole, itraconazole, voriconazole 
Antidepressant 
nefazadone  
Immunosuppressant 
Cyclosporine 
Anti-Epileptic 
carbamazepine, phenytoin 
 
GSK2798745 has weak CYP3A4 inhibition potential. It is possible that concentrations of 
drugs that are substrates of CYP3A4 may be increased. HMG-CoA reductase inhibitors, 
such as atorvastatin and simvastatin, are examples of CYP3A4 substrates that might be 
taken by the eligible participants. Participants being treated with simvastatin will be 
allowed to participate in the study, as long as their dose is 20 mg once daily. 
Participants being treated with >20 mg once daily simvastatin will be considered on a 
case basis by the Investigator in consultation with the GSK Medical Monitor. Participants 
being treated with atorvastatin of any therapeutic dose are allowed to participate in the 
study. Pharmacokinetic data in three patients with refractory cough on GSK2798745 co-
administered with chronic oral atorvastatin 20 mg dose under steady state condition did 
not reveal any clinically relevant pharmacokinetic interactions for both atorvastatin and 
its major metabolite para-hydroxyatorvastatin [GSK Document Number 
2018N386129_00]. The Investigators may also consider substitutions of these 
medications. 
 
It is strongly recommended that participants avoid using drugs that are sensitive 
substrates of Cytochrome P450 (CYP) 3A4 and/or P-gp or that have a low therapeutic 
index because concentrations of these substrates may be increased by GSK2798745. If 
co-administration of medications with interaction potential with GSK2798745 is 
necessary, Investigators should monitor participants for safety risks or consider 
substitutions of these medications.   
All concomitant medications may be reviewed by the Medical Monitor and it will be up 
to the discretion of the Investigator in consultation with the GSK Medical Monitor, 
whether the medication can be continued, and/or the participant can participate in the 
study. 


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6.5.3. 
Ophthalmic Safety Rescue Medicine 
At any time during the study, including the follow-up period, the subject may be 
withdrawn and rescue treatment (standard of care) administered based on the clinical 
judgment of the Investigator. 
Rescue treatment should strongly be considered for participants who have experienced in 
the study eye: 
• A loss of greater than 5 letters from baseline in visual acuity maintained at 2 
consecutive visits and/or 
• An increase from baseline in SD-OCT center subfield thickness >60 microns or 
>15% 
Intervention in the fellow eye with rescue medication is allowable at any point and does 
not require withdraw from the study. 
The study site will institute and supply rescue medication at the discretion of the 
Investigator or physician treating the patient. GSK will not supply the rescue medication.  
Subjects requiring rescue treatment in the study eye will be withdrawn from the study and 
follow early withdraw procedures as per the SoA (Section 1.3). 
6.6. 
Dose Modification 
No dose modifications are permitted without submission of an amendment to the 
protocol. 
6.7. 
Intervention after the End of the Study 
Participants will not receive any additional treatment from GSK after completion of the 
study, because the indication being studied is not life threatening or seriously debilitating. 
The Investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition. 
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 except to complete with early 
withdraw visit 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).  If subjects are prematurely discontinued from the study prior to 
completing the primary endpoint 28-day dosing period, additional replacement 


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participants may be enrolled at the discretion of the Sponsor in consultation with the 
Investigator.  Replacement participants may be enrolled until the protocol defined sample 
size is achieved. 
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: 
• a participant meets one of the conditions outlined in the algorithm 
• 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.  
Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal. 
Refer to Section 10.5 for required Liver Safety Actions and Follow up Assessments  
7.1.2. 
QTc Stopping Criteria 
If a participant meets either bulleted criterion below, two further ECG recordings should 
be done (obtained over a brief [e.g. 5 to 10 minute] recording period). A participant who 
meets either bulleted criterion, based on the average of the triplicate ECG readings, will 
be withdrawn from study treatment: 
• 
QTc > 500 msec OR Uncorrected QT >600 msec 


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• 
Change from baseline of QTc >60 msec 
For participants with underlying bundle branch block, follow the discontinuation criteria 
listed below: 
Baseline QTc with Bundle Branch Block Discontinuation QTc with Bundle 
Branch Block 
<450 msec 
> 500 msec 
450 – 480 msec 
≥ 530 msec 
 
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the participant has been enrolled. 
• 
For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well. 
• 
Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis. Safety ECGs and other non-protocol specified 
ECGs are an exception.   
7.1.3. 
Symptoms of Cardiac Ischemia and Cardiac Troponin Stopping 
Criteria 
7.1.3.1. 
Symptomatic Participant: 
If a participant experiences symptoms of cardiac ischemia, (e.g. chest pain, increased 
shortness of breath, and diaphoresis), cardiology consultation should be obtained 
immediately.  GSK2798745 should be discontinued permanently. The participant should 
be evaluated by a cardiologist and undergo any clinically appropriate testing. The 
participant should be followed up until symptoms are resolved. 
7.1.3.2. 
Asymptomatic Participant: 
Cardiac troponin will be measured pre-dose and at specific time points during the 
treatment period as specified in the SoA (Section 1.3). If any cardiac troponin assessment 
is >ULN or >2 times the participant’s baseline value (Day -1), the participant should be 
assessed for symptoms of cardiac ischemia (as above). If the participant is asymptomatic, 
the participant can continue in the study after discussion with the Medical Monitor and 
close monitoring for symptoms. 
7.1.3.3. 
Study Intervention Restart or Rechallenge After Liver Stopping Criteria 
Met 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 


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7.1.4. 
General Stopping Criteria 
If the same or identifiably similar moderate or severe AE, considered reasonably 
attributable to study intervention in the opinion of the Investigator, occur in more than 4 
participants, then dosing will be temporarily halted, and no further participants will be 
enrolled or dosed until a full safety review of the study has taken place.  Relevant 
reporting and discussion with the Medical Monitor, relevant site personnel, and the 
IRB/IEC will take place before resumption of enrollment or dosing. 
If the same or identifiably similar SAE, considered reasonably attributable to study 
intervention in the opinion of the Investigator, occurs in more than 2 participants, then 
dosing will be temporarily halted, and no further participants will be enrolled or dosed 
until a full safety review of the data has taken place. Relevant reporting and discussion 
with the Medical Monitor, relevant site personnel, and the IRB/IEC will take place before 
resumption of enrollment or dosing.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• 
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 (Section 1.3) 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. 
• 
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. 


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• 
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 as a whole are handled as part of 
Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the SoA (Section 1.3) and SRM, are essential and required for study conduct. 
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the SoA (Section 1.3) and SRM. 
The following points must be noted:  
• If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order: 
o 12-lead ECG 
o vital signs 
o blood draws 
• Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time. 
• The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic or other assessments may be altered during 
the course of the study based on newly available data (e.g., to obtain data closer to 
the time of peak plasma concentrations) to ensure appropriate monitoring.  
• The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File which is approved by the relevant GSK 
study team member and then archived in the study Sponsor and site study files, 
but this will not constitute a protocol amendment.  
• The IRB/IEC and Investigators will be informed of any safety issues that require 
alteration of the safety monitoring scheme or amendment of the ICF. 


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• Immediate safety concerns should be discussed with the Sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study drug. 
• All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the time frame defined in the SoA (Section 
1.3). 
• 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 (Section 1.3). 
8.1.1. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, measuring weight, and 
assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems.   
• 
A brief physical examination will include, at a minimum, measuring weight, and 
assessments of the skin, lungs, cardiovascular system, and abdomen (liver and 
spleen). 
• 
Height will be measured at screening only. 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.1.2. 
Vital Signs 
• 
Vital signs include systolic and diastolic blood pressure and pulse and will be 
measured in semi-supine position after 5 minutes rest. Manual techniques will be 
used only if an automated device is not available. 
• 
Temperature will also be measured as a vital sign but will not require positioning or 
rest prior to measuring. 


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• 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 
pulse and 3 blood pressure measurements (3 consecutive blood pressure readings 
will be recorded at intervals of at least 1 minute). The average of the 3 blood 
pressure readings will be recorded on the CRF. 
8.1.3. 
Electrocardiograms 
• 
12-lead ECG will be obtained using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals. Refer to Section 7 for 
QTc withdrawal criteria and additional QTc readings that may be necessary. 
• 
Single 12-lead ECGs will be obtained for trial eligibility and will be obtained as 
outlined in the SoA (Section 1.3).  
• 
Withdrawal of participants is to be based on an average QTc value of triplicate 
ECGs.  If an ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs 
over a brief period of time and then use the averaged QTc values of the 3 ECGs to 
determine whether the participant should be discontinued from the study.  
8.1.4. 
Clinical Safety Laboratory Assessments 
• 
Refer to Appendix 2 (Section 10.2) 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 to 10 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline or are no longer 
considered significantly abnormal by the Investigator or Medical Monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the aetiology should be identified, and the Sponsor 
notified. 
• 
All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3).  
  
8.1.5. 
Columbia Suicidality Severity Rating Scale (CSSRS) 
Based on preclinical studies that have been conducted, GSK2798745 is considered to be a 
central nervous system (CNS)-active drug. There has been some concern that some CNS-
active drugs may be associated with an increased risk of suicidal thinking or behaviour 
when given to some patients with certain conditions. Although GSK2798745 has not 
been shown to be associated with an increased risk of suicidal thinking or behaviour, 
GSK considers it important to monitor for such events. 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
5 6  
Partici pa nts bei n g tr eate d wit h G S K 2 7 9 8 7 4 5 s h o ul d be assesse d a n d m o nit ore d 
a p pr o priatel y f or s uici dalit y a n d u n us ual c ha n ges i n be ha vi o ur. C o nsi derati o n s h o ul d be 
gi ve n t o disc o nti n ui n g G S K 2 7 9 8 7 4 5 i n partici pa nts w h o e x perie nce si g ns of s uici dal 
i deati o n or be ha vi o ur. Fa milies of partici pa nts bei n g treate d wit h G S K 2 7 9 8 7 4 5 s h o ul d be 
alerte d a b o ut t he n ee d t o m o nit or s u bjects f or t he e mer ge nce of u n us ual c ha n ges i n 
be ha vi o ur, as w ell as t he e mer ge n ce of s uici d al i deati o n a n d be h a vi o ur, a n d t o re p ort s uc h 
s y m pt o ms i m me diatel y t o t he st u d y I n v esti gat or.  
T he C S S R S is a meas ure of s uici dal i deati o n a n d be ha vi o ur, wit h de m o nstrate d 
pre dicti ve vali dit y a n d relia bil it y. Secti o ns of t he C S S R S i ncl u de s uici dal i deati o n, 
i nte nsit y of i deati o n, s uici dal be ha vi o ur, a n d act ual s uici de atte m pt(s). T he C S S R S 
assesses lifeti me a n d c urre nt s uici dal t h o u g hts a n d be ha vi o urs acr oss t hese cate g ories 
base d o n a n i ncreasi n g se verit y  of a 1 - t o 5-rati n g scale. T he s e mi-str uct ure d 
q uesti o n naire is c o m plete d b y a tr ai ne d a n d e x perie nce d n e ur ol o gist, ps yc hi atrist, or 
ne ur o ps yc h ol o gist, or a n ot her trai ne d a n d e x perie nce d pers o n a p pr o ve d b y t he S p o ns or, 
w h o ma y b e t he Pri nci pal I n v esti gat or or a s u b -I n v esti gat or f or t he st u d y. See S R M f or 
details of t he scale.  
At scree ni n g, t he ‘ Baseli ne’ C S S R S q uesti o n naire will be c o m plete d. At all ot her ti me -
p oi nts, t he ‘ Si nce Last Visit’ C S S R S q uesti o n naire will be use d (see Secti o n 1. 3 , S O A ). 
S h o ul d s uici dalit y or u n us ual c ha n ges i n be h a vi o ur occ ur, t h e I n vesti gat or will refer t he 
partici pa nt f or a p pr o priat e e val uati o n a n d treat me nt.  
8. 1. 6.  
O p ht h al mi c S af et y A s s e s s m e nt s  
8. 1. 6. 1.  
R efr a cti o n a n d Vi s u al A c uit y  
•  
Refracti o n a n d vis u al ac uit y will  be meas ure d usi n g el ectr o nic 
vis ual ac uit y 
c harts (e V A wit h  
 or sta n dar d  
 vis ual ac uit y c harts  (li g ht b o x wit h 
c harts). 
•  
Refracti o n a n d vis u al ac uit y assess me nts m ust be t a ke n wit h t he sa me met h o d of 
assess me nt (i.e.
) t hr o u g h o ut t he d urati o n of t he st u d y. See t he 
S R M f or m ore details.    
•  
Refracti o n a n d vis u al ac uit y meas ure me nts m ust be perf or me d b y a n e x a mi ner t hat 
has bee n a p pr o priatel y tr ai ne d.  
•  
 i ncl u di n g refracti o n, will be deter mi ne d at defi ne d 
st u d y visits (see Secti o n 1. 3 , S O A ). 
8. 1. 6. 2.  
G e n er al O p ht h al mi c E x a mi n ati o n  
A c o m plete e ye e x a m will be perf or m e d per t h e S o A ( Secti o n 1. 3 ) a n d will i ncl u de t he 
f oll o wi n g: 
•  E x a mi nati o n of e ye c ol or  (scree ni n g o nl y), e yeli ds a n d las hes (i ncl u di n g 
Mei b o mia n gla n ds)  
•  P u pil m otilit y a n d c o nfr o ntati o n vis ual fiel d e xa mi nati o n  
C CI
C CI
C CI
C CI
C CI
C CI


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
5 7  
•  Slit la m p e val uati o n of a nteri or oc ular str u ct ures (i ncl u di n g c o nj u ncti va, tear fil m, 
c or nea a n d fl u orescei n st ai ni n g, a nt eri or c h a m ber, iris, le ns a n d a nteri or vitre o us)  
•  I ntr a oc ular press ure meas ure me nt 
•  Dilate d F u n d us E x a mi nati o n (I n dir ect o p ht hal m os c o p y a n d slit la m p 
bi o micr osc o p y)  
8. 2.  
A d v er s e E v e nt s  a n d S eri o u s A d v er s e E v e nt s  
T he defi niti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x 3 . 
A Es  will be re p orte d b y t he partici pa nt ( or, w he n a p pr o priate, b y a care gi v er, s urr o gate, 
or t he partici pa nt's le gall y a ut h orize d re pres e ntati ve).  
T he I n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, 
a n d re p orti n g e v e nts t h at meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble f or 
f oll o wi n g u p A Es t hat are seri o us, c o nsi dere d relate d t o t he st u d y i nter ve nti o n or t he 
st u d y, or t hat c a use d t he partici pa nt t o disc o nti n ue t he st u d y i nter ve nti o n a n d st u d y (see 
Secti o n 7 ).  
8. 2. 1.  
Ti m e P eri o d a n d Fr e q u e n c y f or C oll e cti n g A E a n d S A E 
I nf or m ati o n 
•  
All S A Es will be c ollecte d fr o m t he start of i nter ve nti o n u ntil t he f oll o w-u p visit at 
t he ti me p oi nts s pecifie d i n t he S o A  ( Secti o n 1. 3 ). H o we ver, a n y S A Es assesse d as 
relate d t o st u d y partici pati o n (e. g., st u d y i nter ve nti o n, pr ot oc ol-ma n date d pr oce d ures, 
i n vasi ve tests, or c ha n ge i n e xisti n g t hera p y) or relate d t o a G S K pr o d u ct will be 
rec or de d fr o m t he ti me a partici pa nt c o nse nts t o partici pate i n t he st u d y. 
•  
All A Es will be c ollecte d fr o m t he start of i nter ve nti o n u ntil t he f oll o w -u p visit at t he 
ti me p oi nts s pecifie d i n t he S o A  ( Secti o n 1. 3 ). 
•  
Me dical occ urre n ces t hat be gi n b ef ore t he start of st u d y i nter ve nti o n b ut aft er 
o btai ni n g i nf or me d c o nse nt will be rec or de d o n t he Me dical Hist or y/ C urre nt Me dical 
C o n diti o ns secti o n of t he case re p ort f or m ( C R F) n ot t he A E secti o n.  
•  
All S A Es will be rec or de d a n d re p ort e d t o t he S p o ns or or desi g nee i m me di atel y a n d 
u n der n o cir c u msta nce s h o ul d t his e x cee d 2 4 h o urs, as i n dicate d i n A p pe n di x 3 . T he 
I n v esti gat or will s u b mit a n y u p d ate d S A E data t o t he S p o ns or wit hi n 2 4  h o urs of it 
bei n g a vaila ble.  
•  
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k A Es or S A Es after t he c o ncl usi o n of 
t he st u d y partici pati o n. H o we ver, if t h e I n vesti gat or lear ns of a n y S A E, i ncl u di n g a 
deat h, at a n y ti me after a partici pa nt has bee n disc har ge d fr o m t he st u d y, a n d he/s he 
C CI


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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 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 IRB/IEC 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.  
• 
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 partners of male participants will be collected 
after the start of study intervention and until the follow-up visit. 
• 
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. 


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8.2.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 3 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion.   
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
8.3. 
Treatment of Overdose 
For this study, any dose of GSK2798745 greater than 3.2 mg (i.e., ≥2 tablets of 3.2 mg) 
within a 24-hour time period  4 hours will be considered an overdose. 
GSK does not recommend specific treatment for an overdose. The Investigator (or 
physician in charge of the participant at the time) will use clinical judgment to treat any 
overdose. 
In the event of an overdose, the Investigator or treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK2798745 can no longer be detected systemically (at least 5 days). 
3. Obtain a plasma sample for PK analysis within 24 h from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
Decisions regarding dose interruptions 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 2 mL will be collected for measurement of plasma 
concentrations of GSK2798745 and its metabolite GSK3526876 as specified in the SoA 
(Section 1.3). Details of sample collection, processing, storage and shipping procedures 
are provided in the SRM. 
• 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 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
6 0  
sa m pli n g ma y be altere d d uri n g t he c o urse of t he st u d y base d o n ne wl y a v aila ble 
data (e. g., t o o btai n dat a cl oser t o t h e ti me of pea k plas ma c o nce ntrati o ns) t o 
e ns ure a p pr o priate m o nit ori n g.  
•  I nstr u cti o ns f or t he c ollecti o n a n d ha n dli n g of bi ol o gical sa m ples will be pr o vi de d 
b y t he S p o ns or. T h e act u al date a n d ti me ( 2 4 -h o ur cl oc k ti me) of eac h sa m ple will 
be rec or de d.  
•  Sa m pl es will be use d t o e val uate t he P K of G S K 2 7 9 8 7 4 5  a n d G S K 3 5 2 6 8 7 6 . 
sa m ples c ollecte d f or a n al yses of G S K 2 7 9 8 7 4 5  a n d G S K 3 5 2 6 8 7 6  plas ma 
c o nce ntr ati o n ma y als o b e use d t o e val uat e safet y or efficac y as pects r elate d t o 
c o ncer ns arisi n g d uri n g or after t h e st u d y.  
•  P K a nal ysis will be perf or me d u n der t he c o ntr ol of I n Vitr o/I n Vi v o Tra nslati o n 
(I VI V T)/ a n d T hir d-Part y Res o urci n g ( T P R) / Gla x o S mit h Kli ne.  Plas ma 
c o nce ntr ati o ns of G S K 2 7 9 8 7 4 5  a n d G S K 3 5 2 6 8 7 6  will be deter mi ne d usi n g t he 
c urre ntl y a p pr o ve d bi oa n al ytical me t h o d ol o g y. Ra w data will be arc hi ve d at t he 
bi oa nal ytical site ( detaile d i n t he S R M).  
8. 5.  
P h ar m a c o d y n a mi c s  
8. 5. 1.  
O pti c al C o h er e n c e T o m o gr a p h y  
•  
S D -O C T i ma ges/sca ns will be c ollecte d at  s pecifie d visits (see Secti o n 1. 3 , S o A ). 
•  
Q ua ntitati ve a n d q ualifie d assess me nts will be o btai ne d b y a n a p pr o priatel y trai ne d 
p h ot o gra p her/tec h nicia n u si n g S D-O C T e q ui p me nt t hat has bee n a p pr o ve d b y a 
ce ntral r ea d er.  
•  
I ma ges will be e v al uate d b y t he I n vesti gat or f or pr ot oc ol i ncl usi o n/e xcl usi o n criteria 
a n d safet y m o nit ori n g.  I ma ges will be se nt t o a n d e val uate d b y a ce ntr al rea di n g 
ce nter at t he e n d of t he st u d y f or p har m ac o d y na mi c effect.  
8. 6.  
G e n eti c s  
Ge netics are n ot e v al uate d i n t his st u d y.  
8. 7.  
Bi o m ar k er s  
Bi o mar kers are n ot e val u ate d i n t his st u d y.  
8. 8.  
Utili z ati o n a n d H e alt h E c o n o mi c s  
Healt h Ec o n o mics/ Me dic al Res o urce Utilizati o n a n d Healt h Ec o n o mics  para meters are 
n ot e val uate d i n t his st u d y.  
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T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
6 1  
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
Statis tical a nal yses will b e perf or me d b y, or u n d er t he direct a us pices of, Bi ostatistics, 
Gla x o S mit h Kli ne.  
Re p orti n g of st u d y dat a will be perf or me d i n acc or da nce wit h a p plica ble G S K a n d/ or 
c o ntract r esearc h or ga niz ati o n ( C R O) sta n dar ds.   
C o m plete details of t he pla n ne d statistical a nal yses will be pr o vi de d i n t he Statistical  
A nal ysis Pla n ( S A P).  
9. 1.  
St ati sti c al H y p ot h e s e s  
T he c o -pri mar y o bjecti ve of t his st u d y is t o esti mate t he treat me nt effect o n mea n c ha n ge 
fr o m baseli ne i n c e nter s u bfiel d reti nal t hic k ness i n t he st u d y e ye as me as ure d b y S D-
O C T at 2 8  da ys . 
 
T o e ns ure hi g h pr o b a bilit y of acc urate decisi o n ma ki n g ar o u n d t he c ha n ge at Da y 2 8 i n 
S D O C T , t he decisi o n criteria are defi n e d as: 
⎯  “ P ositi ve” if Pr o b[ C F B i n O C T @ 2 8  da ys > 7 0 μ m  decrease | dat a] > 8 0 % a n d  
⎯ “ Ne gati ve” if Pr o b[ C F B i n O C T @ 2 8  da ys  < 9 5 μ m decreas e  | data] > 9 0 %. 
If neit her P ositi ve n or Ne gati ve criteri o n are meet, a n e val uati o n of t he
will be perf or m e d.  A p ositi ve o utc o me will be c o n cl u de d if t he 
after c o m pleti n g 2 8 da ys of d osi n g is 3 letters or 
greater as r e vie we d i n t h e c o nte xt of all a vaila ble P D data.  
F urt her details of t he a n al ysis will be i ncl u de d i n t he re p orti n g a n d a nal ysis pla n  
d oc u me nt ( S A P).  
9. 2.  
S a m pl e Si z e D et er mi n ati o n  
A mi ni m u m 2 0 partici pa nts wi ll be scree ne d a n d e nr olle d s uc h t hat 2 0 e v al ua ble 
partici pa nts ca n b e ac hi e ve d at e n d of 2 8  d a ys.   
A sta n dar d de vi ati o n of 7 5 µ m i n S D -O C T mea n c ha n ge fr o m b aseli ne at 2 8  da ys h as 
bee n c o nsi dere d bas e d o n t he varia bilit y o bs e r ve d i n t he Place b o ar m fr o m Dara pla di b 
st u d y [G S K D oc u me nt N u m ber 2 0 1 1 N 1 1 2 1 9 8 _ 0 1 ]. T he statistical o perati n g 
c haracteristics of t he crit eria gi ve n t hes e ass u m pti o ns are prese nte d i n Fi g ure 2 . 
 
 
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Figure 2 
Operating Characteristics curves for SD-OCT (µm) 
 
 
 
 
From the above Figure 2, considering 20 subjects and standard deviation of 75 μm, 
• if the true mean change from baseline in SD-OCT at 28 days as 95 μm then, the 
probability of a positive study outcome is 74.2%. 
• if the true mean change from baseline in SD-OCT at 28 days as 0 μm (no change) 
then, the study outcome is always negative. 
• the minimum observed value of change from baseline in 28 days that would meet 
the criteria for a positive outcome is 84 μm and the maximum observed value of 
change that would meet the criteria for a negative outcome is 73.3 μm. 
• If the true mean CFB is less than 70 μm then the maximum risk of getting a false 
positive outcome is 20%. If the true mean CFB is greater than 95 μm then the 
maximum risk of getting a false-negative outcome is 10%. 
 
9.2.1. 
Sample Size Sensitivity 
The sensitivity of different variability estimates and sample sizes on the probabilities of 
study outcomes such as Positive, Negative and Inconclusive were evaluated in Table 3 
below: 


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Table 3 
Sample Size Sensitivity Calculations 
Standard 
deviation 
(μm) 
Sample 
Size 
True 
Change  
(μm) 
Probability 
of Positive 
outcome1 
Probability of 
Negative 
outcome2 
Probability of neither 
positive nor negative  
outcome 
75 
15 
0 
0% 
100% 
0% 
70 
20% 
50.4% 
29.6% 
95 
67.3% 
10% 
22.7% 
20 
0 
0% 
100% 
0% 
70 
20% 
58.3% 
21.7% 
95 
74.2% 
10% 
15.8% 
25 
0 
0% 
100% 
0% 
70 
20% 
65% 
15% 
95 
79.5% 
10% 
10.5% 
30 
0 
0% 
100% 
0% 
70 
20% 
70.7% 
9.3% 
95 
83.7% 
10% 
6.3% 
80 
15 
0 
0% 
100% 
0% 
70 
20% 
47.2% 
32.8% 
95 
64.4% 
10% 
25.6% 
20 
0 
0% 
100% 
0% 
70 
20% 
54.6% 
25.4% 
95 
71.1% 
10% 
18.9% 
25 
0 
0% 
100% 
0% 
70 
20% 
61.1% 
18.9% 
95 
76.5% 
10% 
13.5% 
30 
0 
0% 
100% 
0% 
70 
20% 
66.6% 
13.4% 
95 
80.8% 
10% 
9.2% 
1 - Positive if Prob[ Δ > 70 | data]  > 80% 
2 - Negative if Prob[ Δ < 95 | data] > 90% 


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9.3. 
Populations for Analyses 
The following populations are defined: 
Population 
Description 
Screened 
All participants who were screened for eligibility. 
Enrolled 
All participants who passed screening and entered the study.  
 
Note: screening failures (who never passed screening even if rescreened) and 
participants screened but never enrolled into the study (Reserve, Not Used) are 
excluded from the Enrolled population as they did not enter the study. 
Safety 
All enrolled participants who received at least one dose of study treatment. 
PD 
All participants in the Safety population who had at least 1 post-baseline non-missing 
PD assessment. 
PK 
All participants in the Safety population who will have intensive PK sampling on 
Day 7 and Day 28 per Section 1.3.3 (PK Subset). 
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled.  
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. 
9.4.1. 
Primary Endpoints 
9.4.1.1. 
Safety Analyses  
The primary analyses are to evaluate safety and tolerability of GSK2798745 following 28 
days of daily oral dose administration to adult participants with confirmed Diabetic 
Macular Edema. The safety population will be used for the primary analyses.  
Endpoint 
Statistical Analysis Methods 
Primary 
Safety and tolerability data comprising of  
• complete ophthalmic examination 
• visual acuity 
• physical examination findings 
• adverse events (clinical monitoring and observation) 
• clinical laboratory safety data  


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Endpoint 
Statistical Analysis Methods 
• vital signs  
• 12 lead ECGs  
 
Will be presented in tabular and/or graphical format and summarized descriptively 
according to GSK’s Integrated Data Standards Library (IDSL) standards. 
9.4.1.2. 
Pharmacodynamics (PD) Analysis 
All PD analyses will be performed on the PD Population. 
Endpoint 
Statistical Analysis Methods 
Primary 
Mean change from baseline in center subfield retinal thickness in the study eye as 
measured by SD-OCT at 28 days  
 
PD data will be presented in graphical and/or tabular form and will be summarized 
descriptively by days/weeks. 
 
A Bayesian probability model will be used to analyse the mean change from 
baseline in OCT at Day 28.  
 
Normal distribution is assumed for the change in OCT. 
Let xi, i=1, 2, …., n, denotes i.i.d observations of mean change from baseline at 
Day 28 of the ith subject, 
 
such that xi ~ N (µ, σ2), i=1, 2, …, n, where µ is the mean, σ2 is the known 
variance,  
therefore  = 
 ~ N (µ, 
) and let =75 µm. 
A non-informative prior distribution of µ will be considered as µ~N (µ0, σ02), 
where µ0=0 and σ02=1010. 
The study decision criteria will be evaluated based on the following posterior 
distribution of µ|
2:  
µ|
2 ~N ( 
, 
)
N ( ,  
) 
Evidence of an effect on 28-day OCT will be evaluated based on the posterior 
probabilities. 
 
Details of the final analysis will be included in the SAP. 
 
 
 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
6 6  
9. 4. 2.  
S e c o n d ar y E n d p oi nt  
9. 4. 2. 1.  
P h ar m a c o ki n eti c ( P K) A n al y s e s  
All P K a nal ys es will be perf or me d o n t h e P K P o p ulati o n.  
E n d p oi nt  
St ati sti c al A n al ysi s M et h o d s  
S ec o nd ary  
P h ar mac oki netic a n alysis will b e t he r es po nsi bility of t he Cli nic al P har mac ol o gy 
M o d eli n g a nd Si m ul ati on De p art m ent, ( C P M S), Gl axo S mit h Kli n e.  
 
N o n -li n e ar mix e d effect m eth o ds will b e us ed to a n alyse all t he pl as ma 
G S K 27 9 87 45 dr ug l ev els bas e d o n t h e co m bi ne d i nte nsiv e a nd s p arse P K 
s a m pli n g sc h e dul es i n this p ati ent po p ulati o n. I n divi d ual p a rticip a nt P K 
p a r a m eters (i ncl u di n g a bsor pti o n r at e, or al cl e ara nc e a nd or al v olu m e of 
distri b uti o n) wit h t he associ at e d i nt er -an d i ntra -i n divi d ual v aria bility will b e 
esti m at e d. P op ul ati o n P K par a m et er si m ul ati on will b e a p pli ed t o esti m ate t he 
i n divi d u al p ati ent C max a nd A U C ov er dosi n g i nt erv al.   
 
Pl as m a M 1 m eta b olite c o nce ntr ati on -ti m e d at a will be a n alyz e d by n o n-
c o m p art m e ntal m et h o ds.  
 
F ull descri pti o n a n d te c h nic al details of pla n ne d P K a nal ysis will be descri be d eit her as 
a d d-o n t o t he statistical a nal ysis pla n o r as a sta n d-al o ne p o p ulati o n P K, P K -P D  a nal ysis 
pla n.  
9. 4. 3.  
Ot h er A n al y s e( s)  E x pl or at or y E n d p oi nt( s)  
9. 5.  
I nt eri m A n al y s e s 
As t his is a n o pe n -la bel st u d y, data will be re vie we d o n a n o n g oi n g basis a n d ma y b e 
s hare d e xter nall y t o s u pp ort disc ussi o n wit h re g ul at or y a ge n cies.  
After a p pr o xi matel y 8 partici pa nts c o m plete d t he Da y 2 8 visit, O C T a n d  
ata will 
be a nal yse d o n a n o n g oi n g basis t o assess f utilit y a n d t he st u d y ma y be t er mi nate d earl y if 
t he f utilit y criteri a are met. A d diti o nal e n d p oi nts ma y b e re vi e we d as well if necessar y. 
F ull details will be pr o vi de d i n t he i nteri m a nal ysis c harter.  
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) 
Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the Investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC 
• Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 


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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 or his/her legally authorized representative and answer all questions 
regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
Participants who are rescreened are required to sign a new ICF. 
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 the study intervention or about the study disease; publish the results of these 
research efforts; work with government agencies or insurers to have the study 
intervention approved for medical use or approved for payment coverage.  
The ICF contains a separate section that addresses the use of participant data and 
remaining images for optional further research. The Investigator or authorised designee 
will inform each participant of the possibility of further research not related to the 
study/disease. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A 
separate tick box will be required to document a participant's agreement to allow any 
participant data and/or images to be used for further research not related to the 
study/disease. Participants who decline further research will tick the corresponding “No” 
box. 
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.  


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• 
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 will be 
provided reasonable access to statistical tables, figures, and relevant reports and will 
have the opportunity to review the complete study results at a GSK site or other 
mutually-agreeable location. 
• 
GSK will also provide the Investigator with the full summary of the study results. 
The Investigator is encouraged to share the summary results with the study subjects, 
as appropriate. 
• 
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 eCRF 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). 


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• 
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.  
• 
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 eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The Investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available. 
• 
Definition of what constitutes source data can be found in Section 10.1.7. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the first participant is screened in the clinical 
study. 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the Investigator 
• 
Discontinuation of further study 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 


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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 
subject and should assure appropriate subject therapy and/or follow-up 
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 multi-center 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 
All protocol required laboratory assessments, as defined in Table 4, must be conducted in 
accordance with the Laboratory Manual, and Protocol SoA. Laboratory requisition forms 
must be completed, and samples must be clearly labelled with the participant number, 
protocol number, site/centre number, and visit date. Details for the preparation and 
shipment of samples will be provided by the laboratory and are detailed in the SRM or 
the laboratory manual. Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments. 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.   
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.   
• 
The tests detailed in Table 4 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. 
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. 


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Table 4 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin (MCH)  
Mean corpuscular hemoglobin 
concentration (MCHC) 
 
WBC Count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell 
(RBC) Count 
WBC Count 
(absolute) 
Reticulocyte 
Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
Blood urea 
nitrogen (BUN) 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT)  
Total and 
direct bilirubin 
Creatinine 
Chloride 
Alanine 
Aminotransferase 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)  
Uric Acid 
Glucose 
(fasting/non-
fasting)2 
Bicarbonate 
Gamma-Glutamyl 
Transferase (GGT) 
Albumin 
Sodium 
Calcium 
Alkaline phosphatase 
Total Protein 
Bile Acids 
Creatinine 
phosphokinase 
(CPK) 
 
 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other Tests 
• Cardiac troponin 
Other 
Screening 
Tests 
• HbA1c (Screening only. Fasting) 
• Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)Serology [(HIV antibody, hepatitis B surface 
antigen [HBsAg], and hepatitis C virus antibody)] -- if second generation 
Hepatitis C antibody positive, a hepatitis C antibody Chiron RIBA immunoblot 
assay (or other third generation immunoassay) or Hepatitis C Virus RNA test 
(either quantitative or qualitative) should be reflexively performed on the same 
sample to confirm the result)  
• Urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 
 


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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.  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. Glucose will be fasting for all screening only.  Glucose can be non-fasting for all other time points. 
 


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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. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 


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Events NOT Meeting the AE Definition  
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
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 
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 


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A SAE is defined as any untoward medical occurrence that, at any dose: 
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. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
 
10.3.4. 
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, with the exception of the 
participant number, will be redacted on the copies of the medical records before 


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AE and SAE Recording 
submission to GSK. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
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 make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• 
The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 


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Assessment of 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. 
 
10.3.5. 
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. 
• 
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 GSK Medical Monitor/SAE coordinator by telephone. 
• 
Contacts for SAE reporting can be found in SRM. 


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SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the GSK Medical Monitor or the SAE coordinator. 
• 
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: 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenopausal female with ONE of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of participant’s 
medical records, medical examination, or medical history interview. 
2. Postmenopausal female: 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) and estradiol level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH and estradiol measurement is 
insufficient.  
• 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Male participants 
• 
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined time 
frame in Section 5.1  
• 
Are abstinent from heterosexual or homosexual intercourse as their usual and 
preferred lifestyle (abstinent on a long term and persistent basis) and agree to 
remain abstinent  
• 
Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 5 when having penile-vaginal 


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intercourse with a woman of childbearing potential and should also be advised 
of the benefit for a female partner to use a highly effective method of 
contraception as a condom may break or leak. 
• 
Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the protocol-defined time frame in Section 5.1.  
• 
In addition, male participants must refrain from donating sperm from the time of first 
dose of study treatment until the follow-up visit. 
Table 5 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation 
• oral 
• intravaginal  
• transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• injectable  
Highly Effective Methods That Are User Independent  
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)  
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)  
NOTES:  
a. 
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies.  


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10.4.2. 
Collection of Pregnancy Information: 
Male participants with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male participants who receive study intervention. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.  
• 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 
• 
Generally, follow-up will be 12 months following the estimated delivery date. Any 
termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  


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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  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf  
Phase 1 liver chemistry stopping criteria and required follow up assessments  
Liver Chemistry Stopping Criteria – Liver Stopping Event 
 
ALT-absolute 
 
ALT≥3xULN 
If ALT≥3xULN AND bilirubin1,2  2xULN (>35% direct bilirubin) OR 
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 
• Immediately discontinue study intervention 
• Report the event to GSK within 24 hours 
• Complete the liver event case report form (CRF), 
and complete an SAE data collection tool if the 
event also meets the criteria for an SAE2 
• Perform liver chemistry event follow up 
assessments  
• Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline (see 
MONITORING below) 
• 
Do not restart/rechallenge participant with study 
intervention unless allowed per protocol and GSK 
Medical Governance approval is granted (see 
below).   
• 
If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
intervention and continue participant in the study 
for any protocol specified follow up assessments  
 
 
 
• 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, within 
24h 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 case report 
form (CRF) 
• Record use of concomitant 
medications on the concomitant 
medications CRF page including 
acetaminophen, herbal remedies, 


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MONITORING: 
If ALT≥3xULN AND bilirubin  2xULN or INR >1.5:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) and 
perform liver event follow up assessments within 
24 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 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 
other over the counter medications. 
• Record alcohol use on the liver event 
alcohol intake CRF page 
If ALT≥3xULN AND bilirubin  2xULN 
or INR >1.5: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins. 
• 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 M (IgM) antibody; HbsAg and HBcAb; Hepatitis CRNA; Cytomegalovirus 
IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing); Hepatitis E IgM antibody  
4. PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
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. 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
8 6  
1 0. 6.  
A p p e n di x 6 : A b br e vi ati o n s a nd Tr a d e m ar k s  
A b br e vi ati o n s  
A E  
A d verse E v e nt  
A L T  
Ala ni ne a mi n otra nsferas e  
A S T  
As partate a mi n otra nsferase  
A U C  
Area u n d er c o n ce ntr ati o n -ti me c ur ve 
B MI  
B o d y mass i n de x  
B R B  
Bl o o d -Reti nal -Barrie r 
B U N  
Bl o o d urea nitr o ge n  
Ca 2 + 
Calci u m  
Ca v  
A vera ge plas ma c o n ce ntr ati o n  
C F B  
C ha n ge fr o m bas eli ne  
CI  
C o nfi de nce I nter val  
C ma x  
Ma xi m u m o bser ve d plas ma c o nce ntr ati o n  
C N S  
Ce ntral Ner v o us S yste m  
C O N S O R T  
C o ns oli date d Sta n dar ds of Re p orti n g Trials  
C O P D  
C hr o nic O bstr ucti ve P ul m o nar y Diseas e  
C P K  
Creati ni ne p h os p h o ki nas e  
C R F  
Case Re p ort F or m  
C V  
Car di o vasc ular  
C S S R S  
C ol u m bia S uici dalit y Se verit y Rati n g Scal e  
C Y P  
C yt o c hr o me P 4 5 0  
C Y P 3 A 4  
C yt o c hr o me P 4 5 0 3 A 4  
D M  
Dia betes Mellit us  
D M E  
Dia betic Mac ul ar E de m a  
D N A  
De o x yri b o n ucleic aci d  
D R  
Dia betic Reti n o pat h y  
E C G  
Electr ocar di o gra m  
e C R F 
Electr o nic case re p ort f or m  
E V A  
Electr o nic Vis ual A c uit y  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S H  
F ol licle Sti m ulati n g H or m o ne 
F U  
F oll o w -u p  
G C P  
G o o d Cli nical Practice  
G C S P  
Gl o bal Cli nical Safet y a n d P har mac o vi gila nce  
G G T  
Ga m ma Gl uta m yltra nsferase  
GI  
Gastr oi ntesti nal  
G L P  
G o o d La b orat or y Practice  
G S K  
Gla x o S mit h Kli ne  
H b A 1c  
Gl ycate d He ma gl o bi n  
C CI
C CI
C CI
C CI


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HBsAg 
Hepatitis B surface antigen 
hCG 
Human Chorionic Gonadotropin 
HDPE 
High-density polyethylene 
HIV 
Human Immunodeficiency Virus 
HPLC 
High performance liquid chromatography 
h/hr 
Hour(s) 
HR 
Heart Rate 
HRT 
Hormonal replacement therapy 
HUVEC 
Human umbilical vein endothelial cell 
IB 
Investigator’s Brochure 
IC50 
50% maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
IDSL 
Integrated Data Standards Library 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IOP 
Intraocular pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IU 
International Unit 
IVIVT 
In Vitro/In Vivo Translations 
Kg 
Kilogram 
KO 
Knockout 
LDH 
Lactate dehydrogenase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligrams 
mL 
Milliliter 
mmHg 
Millimeter of Mercury 
MSDS 
Material Safety Data Sheet 
Msec 
Milliseconds 
NOAEL 
No observed adverse effect level 
nM 
Nano Molar 
OCT 
Optical Coherence Tomography 
PD 
Pharmacodynamic 
PDR 
Proliferative diabetic retinopathy 
P-gp 
p-glycoprotein 
PK 
Pharmacokinetic 
QTcB 
QT duration corrected for heart rate by Bazett’s formula 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
RBC 
Red Blood Cells 
RNA 
Ribonucleic Acid 


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SAE 
Serious Adverse Event(s) 
SAP 
Statistical Analysis Plan 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SOA 
Schedule of Activities 
SRM 
Study Reference Manual 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TPR 
Third Party Resourcing 
TRPV4 
Transient receptor potential vanilloid 4  
UA 
Urinalysis 
ULN 
Upper Limit of Normal 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White blood cells 
WD 
Withdrawal 
WOCBP 
Women of Child Bearing Potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
None 
 
MedDRA 
 
 
SAS 
 
 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
8 9  
1 0. 7.  
A p p e n di x 7: Pr ot o c ol A m e n d m e nt Hi st or y  
 
D O C U M E N T HI S T O R Y  
List dates of ori gi n al pr ot oc ol a n d all a me n d me nts i n re verse c hr o n ol o gical or der . 
D o c u m e nt  
D at e  
D N G N u m b er  
A m e n d m ent 0 4  
1 1 -N O V -2 0 2 1  
T M F - 1 4 0 7 3 2 5 4  
A m e n d m ent 0 3  
2 4 -M A R -2 0 2 1  
T M F -1 1 8 7 44 9 9  
A m e n d m ent 0 2 
2 8 -O C T -2 0 2 0  
2 0 1 9 N 4 0 4 0 30 _ 0 2  
A m e n d m ent 0 1  
1 1 -M A Y -2 0 2 0  
2 0 1 9 N 4 0 4 0 30 _ 0 1 
Ori gi nal Pr ot oc ol  
1 9 S E P 2 0 1 9  
2 0 1 9 N 4 0 4 0 30 _ 0 0 
 
A me n d me nt 0 4  1 1 -N O V -2 0 2 1  
O ver all R ati o n a le f or t he A me n d me nt:  T h e f ell o w e ye
 i ncl usi o n criterio n  was 
i ncl u de d i n t he ori gi n al pr ot oc ol w here a n 8  w eek o pt -i n peri o d was all o we d, res ulti n g i n 
a t otal p ote ntial d osi n g d urati o n of 3  m o nt hs .  T he criteri o n was t o e ns ure t he fell o w e ye 
was u nli kel y t o pr o gress o ver t hat 3  m o nt hs peri o d.  T he criteri o n  is bei n g re m o ve d si nce 
mi ni mal disease pr o gressi o n  is e x pecte d wit hi n t he c urre nt 2 8-da y  d osi n g p eri o d .  N ote 
t hat treat me nt f or D M E is all o wa ble at a n y ti me w hile o n st u d y i n t he fell o w e ye. A 
si n gle E C G re places ma n dat or y  tri plicate E C G m eas ure m e nt at scree ni n g t o deter mi ne 
eli gi bilit y.  If a s u bject is wit h dra w n f or a cli nicall y si g nifica nt Q Tc val ue , E C G 
wit h dra wal meas ure me nts will still re q uire c ollecti o n i n  tri plicate per pr ot oc ol.  
W here t he  A me n d me nt A p plies:  
T his pr ot oc ol A me n d me nt 4  a p plies t o all c o u ntries a n d sites partici pati n g i n t he st u d y. 
T a ble of S pecific C h a n ges:  
N O T E: f or P R E VI O U S T E X T, t he c o nte nt is e x actl y as i n t he ori gi n al; f or R E VI S E D 
T E X T, te xt delete d fr o m t he ori gi nal h as  a d otte d u n derli ne a n d te xt a d de d has a s oli d 
u n derli ne.  
S e cti o n # a n d 
N a m e  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
P a g e 1  
A d d e d U S I N D n u m b er ( #)  
I N D n u m b er w a s mi s si n g 
fr o m t h e titl e p a g e 
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T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
9 0  
S e cti o n # a n d 
N a m e  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
5. 1 I n cl u si o n 
Crit eri a  
Pr e vi o u s T e xt:  
l ett er s c or e of 8 0 l ett er or w or s e 
( S n ell e n e q ui v al e nt ~ 2 0/ 2 5) or w or s e i n 
t h e st u d y e y e. T h e n o n -st u d y f ell o w e y e 
s h o ul d b e e q ui v al e nt or b ett er at 
B a s eli n e, pr e -d o s e.  
R e vi s e d T e xt:  
l ett er s c or e of 8 0 l ett er or w or s e 
( S n ell e n e q ui v al e nt ~ 2 0/ 2 5) or w or s e i n 
t h e st u d y e y e.  
T h e n o n -st u d y, f ell o w e y e 
crit eri o n i s  b ei n g r e m o v e d 
si n c e mi ni m al di s e a s e 
pr o gr e s si o n i s e x p e ct e d 
wit hi n t h e c urr e nt 2 8  d a y s  
d o si n g p eri o d . T r e at m e nt f or 
D M E i n t h e f ell o w e y e 
r e m ai n s all o w a bl e at a n y 
ti m e w hil e o n st u d y. 
S e cti o n 1. 3  
 
 
 
S e cti o n 8. 1. 3  
 
Pr e vi o u s T e xt:  
Tri pli c at e  E C G r e q uir e d at S cr e e ni n g  & 
W D  
R e vi s e d t e xt:  
Si n gl e E C G re q uir ed at Scr eeni n g, B as elin e, 
Tr e at m e nt p eri ods, an d f oll o w -u p; Tri plic ate 
E C G r e q uir e d at  W D  
 
Pr e vi o u s T e xt  B ull et 2 : 
•  
Tri pli c at e  1 2 -l e a d E C G s will b e 
o bt ai n e d f or tri al eli gi bilit y. T hr e e 
i n di vi d u al E C G tr a ci n g s s h o ul d b e 
o bt ai n e d a s cl o s el y a s p o s si bl e i n 
s u c c e s si o n, b ut n o m or e t h a n 
2  mi n ut e s a p art. T h e f ull s et of 
tri pli c at e s s h o ul d b e c o m pl et e d in 
l e s s t h a n 4 mi n ut e s.  
•  
Si n gl e 1 2 -l e a d E C G will b e o bt ai n e d 
a s o utli n e d i n t h e S o A ( S e cti o n 1. 3).  
 
R e vi s e d T e xt  B ull et 2 : 
•  
Si n gl e  1 2 -l e a d E C G s will b e 
o bt ai n e d f or tri al eli gi bilit y a n d will 
b e o bt ai n e d a s o utli n e d i n t h e S o A 
( S e cti o n 1. 3).  
 
T h e tri pli c at e E C G 
m e a s ur e m e nt at s cr e e ni n g 
t o d et er mi n e eli gi bilit y a n d 
f or m o nit ori n g t hr o u g h o ut 
t h e st u d y ar e r e d u c e d t o a 
si n gl e E C G r e a di n g . If a 
s u bj e ct i s wit h dr a w n f or a 
cli ni c all y si g nifi c a nt Q T c 
v al u e, E C G wit h dr a w al 
m e a s ur e m e nt s will still 
r e q uir e c oll e cti o n i n tri pli c at e 
p er pr ot o c ol.  ( B ull et 2)  
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 10.3.2 
Previous Text: 
A SAE is defined as any untoward 
medical occurrence that, at any dose: 
Revised Text: 
An SAE is defined as any untoward 
medical occurrence that, at any dose, 
meets one or more of the criteria listed: 
As per latest protocol 
template following SAE 
definition has been updated 
Section 10.3.5 
Removed the requirement of SAE 
reporting in Electronic case form (eCRF) 
within 72 hours 
Removal of additional step 
of eCRF check. 
 
 
DOCUMENT HISTORY 
List dates of original protocol and all amendments in reverse chronological order. 
Document 
Date 
DNG Number 
Amendment 03 
24-MAR-2021 
TMF-11874499 
Amendment 02 
28-OCT-2020 
2019N404030_02 
Amendment 01 
11-MAY-2020 
2019N404030_01 
Original Protocol 
19 SEP 2019 
2019N404030_00 
 
Amendment 03  
Overall Rationale for the Amendment:  This Protocol Amendment 03 is being 
implemented to remove the 8-week Opt-in period as well as address several 
administrative revisions.  
Where the Amendment Applies: 
This protocol Amendment 3 applies to all countries and sites participating in the study. 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
9 2  
T a ble of S pecific C h a n ges:  
N O T E: f or P R E VI O U S T E X T, t he c o nte nt is e x actl y as i n t he ori gi n al; f or R E VI S E D 
T E X T, te xt delete d fr o m t he ori gi nal h as a d otte d u n derli ne a n d te xt a d de d ha s a s oli d 
u n derli ne.  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
M ulti ple Secti o ns:  
1. Pr ot oc ol S u m mar y  
2. I ntr o d ucti o n  
3. O bj ecti ves a n d 
E n d p oi nts  
4. St u d y Desi g n  
8. St u d y Assess me nts 
a n d Pr oce d ures  
9. Statistical 
C o nsi derati o ns  
Re m o val of 8 -wee k o pt -i n peri o d b o d y te xt, 
ta bles a n d sc he matics. T his i ncl u des pr ot oc ol 
c o nte nt t hat s olel y s u p p orts t he c o n d uct of 
t he 8-wee k o pt -i n peri o d. 
T he Pr ot oc ol 2 1 2 6 6 9 was 
desi g ne d t o be a 2 8 -da y P hase 
1 b safet y st u d y wit h a n o pt -i n 
8 -wee k e xte nsi o n t o e x pl ore 
p har mac o d y na mics a n d 
safet y/t olera bilit y be y o n d 2 8 
da ys.  T he pri mar y e n d p oi nts 
were at t he 2 8 -da y visit. 
Re m o val of t he 8 -wee k o pt -i n 
peri o d retai ns f oc us o n t he 
pri mar y o bj ecti ves, safet y, 
t olera bilit y a n d 
p har mac o d y na mics at 2 8 -da ys 
a n d better ali g n s wit h a P hase 
1 b safet y st u d y desi g n. T he 
c ha n ge was pr o m pte d, i n part, 
b y fee d bac k d uri n g re g ulat or y 
re vie w w he n o pe ni n g a n 
i n vesti gati o nal ne w dr u g (I N D) 
i n t he U nite d States. 
O bj ecti ves a n d 
E n d p oi nts T a bles  
1. 1  S y n o psis  
3 O bj ecti ves a n d 
E n d p oi nts  
Re m o val of E x pl orat or y E n d p oi nt.  
P R E VI O U S T E X T:  
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Section # and Name 
Description of Change 
Brief Rationale 
1.3.1 Schedule of 
Assessments 
Reference and linking to protocol sections 
pertaining to confirmation of non-
childbearing status for women. 
PREVIOUS TEXT: 
As needed in women of non-childbearing 
potential only 
REVISED TEXT: 
As needed in women of non-childbearing 
potential only. See Section 10.2 and Section 
10.4 
 
Administrative change. 
4.3.1. Dose Rationale 
Correction of unit Cmax unit to ng/mL 
PREVIOUS TEXT: 
The proposed clinical dose of 3.2mg once 
daily GSK2798745 is selected so that no 
participant intentionally exceeds the daily 
AUC of 513 ng*hr/mL and Cmax of 50 
ng.hr/mL. 
REVISED TEXT: 
The proposed clinical dose of 3.2mg once 
daily GSK2798745 is selected so that no 
participant intentionally exceeds the daily 
AUC of 513 ng*hr/mL and Cmax of 50 ng/mL 
50 ng.hr/mL  
Administrative correction in 
text body. 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
9 4  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
9. 1 Statistical 
H y p ot heses  
C ha n ge d t he c o nte xt of re vie w t o 2 8 -da y 
data.  
P R E VI O U S T E X T:  
If neit her P ositi ve n or Ne gati ve criteri o n are 
meet, a n e val uati o n of t he
will be perf or me d. A 
p ositi ve o utc o me will be c o ncl u de d if t he 
after 
c o m pleti n g 3 -m o nt hs of d osi n g is greater 
t ha n 6 letters. 
R E VI S E D T E X T:  
If neit her P ositi ve n or Ne gati ve criteri o n are 
meet, a n e val uati o n of t he
 will be perf or me d.  A 
p ositi ve o utc o me will be c o ncl u de d if t he 
after 
c o m pleti n g 2 8 da ys 3 -m o nt hs of d osi n g is 3 
letters or greater is greater t ha n 6 letters as 
re vie we d i n t he c o nte xt of all a vaila ble P D 
data.  
Wit h t he re m o val of t he 8 -wee k 
o pt -i n peri o d, t he criteria t o 
re vie w
 letter sc ore 
was a dj uste d t o reflect a 2 8 -da y 
t hres h ol d. Give n t he lar ge 
varia bilit y e x pecte d f or 2 8 -da y 
t he e ntiret y of t he 2 8-
da y P D data will be use d i n 
a d diti o n t o t he 
f or 
decisi o n ma ki n g s h o ul d neit her 
P ositi ve n or Ne gati ve criteri o n 
be met.  
 
9. 2 Sa m ple Size 
Deter mi nati o n  
C orrecti o n of pr o ba bilit y of a p ositi ve st u d y 
o utc o me val ue t o ali g n wit h Fi g ure 2 a n d 
T a ble 3  
P R E VI O U S T E X T:  
• if t he tr ue mea n c ha n ge fr o m baseli ne i n 
S D -O C T at 2 8 da ys as 9 5 μ m t he n, t he 
pr o ba bilit y of a p ositi ve st u d y o utc o me is 
7 1. 1 %.  
R E VI S E D T E X T:  
• if t he tr ue mea n c ha n ge fr o m baseli ne i n 
S D -O C T at 2 8 da ys as 9 5 μ m t he n, t he 
pr o ba bilit y of a p ositi ve st u d y o utc o me is 
7 1. 1 % 7 4. 2 %.  
A d mi nistrati ve c orrecti o n. 
Pre vi o us te xt c orres p o n de d 
wit h a sta n dar d de viati o n of 8 0 
μ m f or a sa m ple size of 2 0. 
U p date d t o sta n dar d de viati o n 
of 7 5 μ m f or a sa m ple size of 
2 0 t o ali g n wit h Fi g ure 2  
 
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T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
9 5  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1 1. Refere nces  
P u blicati o n dat e c orrecti o n.  
P R E VI O U S T E X T:  
D u gel, P U, et al. 2 0 1 6. “ De xa met has o ne 
i ntra vitreal i m pla nt i n t he treat me nt of 
dia betic mac ular e de ma.” Cli nical 
O p ht hal m ol o g y, 9: 1 3 2 1 – 1 3 3 5.  
R E VI S E D T E X T:  
D u gel, P U, et al. 2 0 1 5  2 0 1 6 . 
“ De xa met has o ne i ntra vitreal i m pla nt i n t h e 
treat me nt of dia betic mac ular e de ma.” 
Cli nical O p ht hal m ol o g y, 9: 1 3 2 1 – 1 3 3 5.  
A d mi nistrati ve c orrecti o n of 
refere nce p u blicati o n date. 
 
T he Pr ot oc ol A me n d me nt S u m mar y of C ha n ges T a ble f or t he c urre nt a me n d me nt is 
l ocate d directl y b ef ore t he Ta ble of C o ntents ( T O C).  
D O C U M E N T HI S T O R Y  
List dates of ori gi n al pr ot oc ol a n d all a me n d me nts i n re verse c hr o n ol o gical or der . 
D o c u m e nt  
D at e  
D N G N u m b er  
A m e n d m ent 0 2  
2 8 -O C T -2 0 2 0  
2 0 1 9 N 4 0 4 0 30 _ 0 2  
A m e n d m ent 0 1  
1 1 -M A Y -2 0 2 0  
2 0 1 9 N 4 0 4 0 30 _ 0 1 
Ori gi nal Pr ot oc ol  
1 9 S E P 2 0 1 9  
2 0 1 9 N 4 0 4 0 30 _ 0 0 
 
A me n d me nt 0 2  2 8 -O C T -2 0 2 0  
O ver all R ati o n ale f or t he A me n d me nt:  T his Pr ot oc ol A me n d me nt 0 2  is bei n g 
i m ple me nte d t o a dj ust s pecific i ncl usi o n a n d e x cl usi o n criteria  a n d clarif y t he assess me nt 
wi n d o w f or Baseli ne S pectral -D o mai n O ptical C o here nce T o m o gra p h y ( S D -O C T), 
 a n d O p ht hal mic e x a ms. 
W here t he A me n d me nt A p plies:  
T his Pr ot oc ol A me n d me nt 2 a p plies t o all c o u ntries a n d sites partici pati n g i n t he st u d y.  
T a ble of S pecific C h a n ges:  
N O T E: f or P R E VI O U S T E X T, t he c o nte nt is e x actl y as i n t he ori gi n al; f or R E VI S E D 
T E X T, te xt delete d fr o m t he ori gi nal h as a d otte d u n derli ne a n d te xt a d de d has a s oli d 
u n derli ne.  
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T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
9 6  
Secti o n # a n d 
N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 3. 1: 2 8 Da y –  
4 W ee k 
Treat me nt 
P eri o d  
Clarificati o n of B aseli ne assess me nt wi n d o w f or 
S D -O C T i n Sc he d ule of Assess me nts ( S o A) N otes 
c ol u m n  
N E W T E X T  
If t he date of t he scree ni n g S D-O C T is wit hi n 3 
da ys of baseli ne, t he scree ni n g S D -O C T ca n be 
c o nsi dere d as baseli ne  S D -O C T  
Pr o vi di n g clarit y t o S o A. 
Mi ni mal b i ol o gical c ha n ges 
e x pecte d wit hi n a 3 -da y 
ti mefra me. 
1. 3. 1: 2 8 Da y –  
4 W ee k 
Treat me nt 
P eri o d  
Clarificati o n of B aseli ne assess me nt wi n d o w f or 
i n S o A N otes c ol u m n  
N E W T E X T  
If t he date of t he scree ni n g
is wit hi n 3 da ys 
of baseli ne, t he scree ni n g
ca n be c o nsi dere d 
as baseli ne
Pr o vi di n g clarit y t o S o A. 
Mi ni mal bi ol o gical c ha n ges 
e x pecte d wit hi n a 3 -da y 
ti mefra me.  
1. 3. 1: 2 8 Da y –  
4 W ee k 
Treat me nt 
P eri o d  
Clarificati o n of B aseli ne assess me nt wi n d o w f or 
Ge neral O p ht hal mic E xa m i n S o A N otes c o l u m n  
N E W T E X T  
If t he date of t he scree ni n g ge neral o p ht hal mic 
e xa m is wit hi n 3 da ys of baseli ne, t he scree ni n g 
e xa m ca n be c o nsi dere d as baseli ne  
Pr o vi di n g clarit y t o S o A. 
Mi ni mal bi ol o gical c ha n ges 
e x pecte d wit hi n a 3 -da y 
ti mefra me.  
5. 1: I ncl usi o n 
Crit eria, 
, # 5 
U p date d I ncl usi o n Criteria t o all o w partici pa nts 
wit h better visi o n t o e nr ol i n t he st u d y  
P R E VI O U S T E X T  
letter sc ore of 6 8  letter or w orse ( S nelle n e q ui vale nt 
~ 2 0/ 5 0 ) or w orse i n t he st u d y e ye. T he no n -st u d y 
fell o w e ye s h o ul d be ≥ 7 3 letters or better at Da y 1 
pre -d ose.  
R E VI S E D T E X T  
letter sc ore of 8 0  letter or w orse ( S nelle n e q ui vale nt 
~ 2 0/ 2 5 ) or w orse i n t he st u d y e ye. T he n o n-st u d y 
fell o w e ye s h o ul d be e q ui vale nt  or better at 
B aseli ne , pre -d ose . 
T he ori gi nal rati o nal f or t his 
criteri o n was t o e ns ure 
s ufficie ntl y i m pacte d visi o n i n 
t he st u d y e ye t o ha ve a better 
o p p ort u nit y t o o bser ve 
i m pr o ve me nt. It was als o t o 
e ns ure a p pr o xi matel y e q ual or 
better visi o n i n t he fell o w e ye.  
As t he 
i s n ot t he 
pri mar y e n d p oi nt, c ha n gi n g t he 
criteri o n will e na ble a better 
o p p ort u nit y t o e nr ol patie nts 
f or t he pri mar y e n d p oi nt of 
O C T.  T he ne w w or di n g 
mai ntai ns t hat t he fell o w e ye 
has e q ual or better visi o n t ha n 
t he treat me nt e ye. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.2 Exclusion 
Criteria, anti-
VEGF SOC, #6 
Updated Exclusion Criteria to decrease anti-VEGF 
washout period 
PREVIOUS TEXT 
Use of intravitreal ranibizumab, bevacizumab or 
aflibercept in the study eye within 90 days of 
dosing. Allowed in fellow eye. 
REVISED TEXT 
Use of intravitreal ranibizumab or bevacizumab 
within 42 days (6 weeks), or aflibercept within 56 
days (8 weeks) of dosing in the study eye. Allowed 
in fellow eye. 
Decreasing the required anti-
VEGF wash-out period to 
better align with prescribing 
labels and treatment practices. 
Amendment [01]: 11-May-2020 
Overall Rationale for the Amendment 
In relation to the Coronavirus SARS-CoV-2 (COVID-19) pandemic, this Protocol 
Amendment 01 serves to clarify exclusion criteria and include the allowance of 
replacement participants, add protocol defined laboratory tests, as well as address several 
administrative revisions. 
Where the Amendment Applies: 
This protocol Amendment 1 applies to all sites participating in the study. 
Table of Specific Changes: 
NOTE: for PREVIOUS TEXT, the content is exactly as in the original; for REVISED 
TEXT, text deleted from the original has a dotted underline and text added has a solid 
underline. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3.1: 28 Day – 4 
Week Treatment 
Period 
Added wording to Day 1 Dosing Notes 
section.  
NEW TEXT: 
Additional guidance on Day 1 dosing 
can be found in the SRM. 
Updated Notes section to direct sites 
to Study Reference Manual (SRM) 
for guidance on how to conduct Day 
1 dosing. 
1.3.2:  8-Week Opt-
in Treatment Period 
Troponin Laboratory test added to Week 
6 (Day 42) and Week 10 (Day 70) to 
monitor troponin levels.  
The additional troponin collections 
were added for the opt-in period to 
keep the maximum between-testing 
interval as 2 weeks, consistent with 
the 28-day primary dosing period 


T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
9 8  
Secti o n # a n d 
N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
ma xi m u m i nter val.  
1. 3. 2:  8 -W ee k O pt -
i n Treat me nt P eri o d 
A d de d 1 2 -Lea d E C G assess me nt at t he 
Da y 1 1 2 F oll o w -u p t o ali g n wit h t he 
Da y 5 6 F oll o w -u p assess me nts.  
T y p o gra p hical err or i n t he ori gi nal 
pr ot oc ol.  
4. 2:  Scie ntific 
Rati o nale f or St u d y 
Desi g n  
U p date d secti o n t o all o w vis ual ac uit y 
assess me nt via eit her
P R E VI O U S T E X T:  
Vis ual ac uit y usi n g
c hart rea di n g will be 
meas ure d at s pecifie d visits as per t he 
S o A  
 
R E VI S E D T E X T:  
Vis ual ac uit y usi n g
 
c hart 
rea di n g will be meas ure d at s pecifie d 
visits as per t he S o A  
A d mi nistrati ve c ha n ge per Pr ot oc ol 
N ote t o file date d 0 3 F E B 2 0 2 0 
pr o vi di n g clarificati o n t o pr ot oc ol 
w or di n g t o all o w Cli nical Sites t o 
meas ure vis ual ac uit y per c urre nt 
sta n dar d of care. 
5. 2:  E xcl usi o n 
Criteria, Me dical 
C o n diti o nal –  N o n -
Oc ular, # 1 8  
U p date d e xcl usi o n criteria t o s pecificall y 
pr o hi bit eli gi bilit y of i nfecti o us 
partici pa nts.  
P R E VI O U S T E X T  
1 8.  
Hist or y or c urre nt e vi de nce of 
a n y seri o us or cli nicall y si g nifica nt 
car diac, gastr oi ntesti nal, re nal, 
e n d ocri ne, ne ur ol o gic, he mat ol o gic or 
ot her c o n diti o n t hat is u nc o ntr olle d o n 
per mitte d t hera pies or t hat w o ul d, i n t he 
o pi ni o n of t he I n vesti gat or or t he 
Me dical M o nit or, ma ke t he partici pa nt 
u ns uita ble f or i ncl usi o n i n t his st u d y.  
 
R E VI S E D T E X T:  
1 8.  
Hist or y or c urre nt e vi de nce of 
a n y seri o us or cli nicall y si g nifica nt 
car diac, gastr oi ntesti nal, re nal, 
e n d ocri ne, ne ur ol o gic, he mat ol o gic, 
i nfecti o us or ot her c o n diti o n t hat is 
u nc o ntr olle d o n per mitte d t her a pies or 
T he e xisti n g p hrase ‘ or ot her 
c o n diti o n t hat is u nc o ntr olle d o n 
per mitte d t hera pies or t hat w o ul d, i n 
t he o pi ni o n of t he I n vesti gat or or t he 
Me dical M o nit or, ma ke t he 
partici pa nt u ns uita ble f or i ncl usi o n i n 
t his st u d y’ d oes ha ve i nfecti o n wit hi n 
its sc o pe.  H o we ver, gi ve n t he c urre nt 
pa n de mic, i nfecti o n is bei n g 
e m p hasize as a s pecific cate g or y.  
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T M F -1 4 3 7 7 1 2 9  
C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
9 9  
Secti o n # a n d 
N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
t hat w o ul d, i n t he o pi ni o n of t he 
I n vesti gat or or t he Me dical M o nit or, 
ma ke t he partici pa nt u ns uita bl e f or 
i ncl usi o n i n t his st u d y. 
5. 2:  E xcl usi o n 
Criteria, Me dical 
Ot her E xcl usi o ns, # 
3 4  
U p date d e xcl usi o n criteria t o clarif y 
e xcl usi o n of partici pa nts wit h hist or y of 
re g ular s u bsta nce a b use i ncl u di n g dr u g 
a n d/ or alc o h ol.  
P R E VI O U S T E X T:  
3 4.  
Re g ular alc o h ol c o ns u m pti o n 
wit hi n 6 m o nt hs pri or t o t he st u d y 
defi ne d as: A n a vera ge wee kl y i nta ke of 
> 1 4 u nits. O ne u nit is e q ui val e nt t o 8 g 
of alc o h ol: a half -pi nt ( ~ 2 4 0 ml) of beer, 
1 glass ( 1 2 5 ml) of wi ne or 1 ( 2 5 ml) 
meas ure of s pirits.  
 
R E VI S E D T E X T:  
3 4.  
Re g ular s u bsta nce a b use 
i ncl u di n g dr u g a n d/ or alc o h ol 
c o ns u m pti o n wit hi n 6 m o nt hs pri or t o 
t he st u d y. Alc o h ol c o ns u m pti o n is 
defi ne d as: A n a vera ge wee kl y i nta ke of 
> 1 4 u nits. O ne u nit is e q ui val e nt t o 8 g 
of alc o h ol: a half -pi nt ( ~ 2 4 0 m l) of beer, 
1 glass ( 1 2 5 ml) of wi ne or 1 ( 2 5 ml) 
meas ure of s pirits.  
A d mi nistrati ve c ha n ge t o ali g n 
w or di n g wit h assess me nts i n 
Sc he d ule of Acti vities ( S o A).  
7. 1: Disc o nti n uati o n 
of St u d y 
I nter ve nti o n 
U p date d secti o n t o all o w f or 
re place me nt p artici pa nts. 
N E W T E X T:  
If s u bj ects are pre mat urel y disc o nti n ue d 
fr o m t he st u d y pri or t o c o m pleti n g t he 
pri mar y e n d p oi nt 2 8 -da y d osi n g peri o d, 
a d diti o nal re place me nt partici pa nts ma y 
be e nr olle d at t he discreti o n of t he 
S p o ns or i n c o ns ultati o n wit h t he 
I n vesti gat or.  Re place me nt partici pa nts 
ma y be e nr olle d u ntil t he pr ot oc ol 
defi ne d sa m ple size is ac hie ve d.  
Gi ve n t he c urre nt pa n de mic a n d 
hi g her ris k of dr o p -o ut, t he se cti o n is 
m o difie d t o all o w f or re place me nt 
partici pa nts t o e ns ure s ufficie nt 
partici pa nts are a vaila b le f or 
e val uati o n of t he pri mar y 2 8 -da y 
e n d p oi nt.  
8. 1. 7. 1:  Refracti o n 
a n d Vis ual Ac uit y  
U p date d secti o n t o all o w vis ual ac uit y 
assess me nt via eit her
A d mi nistrati ve c ha n ge per Pr ot oc ol 
N ote t o file date d 0 3 F E B 2 0 2 0, 
pr o vi di n g clarificati o n t o pr ot oc ol 
w or di n g t o all o w Cli nical Sites t o 
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C O N FI D E N TI A L  
 
 
2 1 2 6 6 9  
1 0 0  
Secti o n # a n d 
N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
 
P R E VI O U S T E X T:  
• 
Refracti o n a n d vis ual ac uit y 
will be meas ure d usi n g electr o nic 
vis ual ac uit y c harts (e V A).  
 
R E VI S E D T E X T:  
• 
Refracti o n a n d vis ual ac uit y 
will b e meas ure d usi n g electr o nic 
vis ual ac uit y c harts (e V A wit h 
) or sta n dar d 
vis ual 
ac uit y c harts (li g ht b o x wit h
c harts).  
• 
Refracti o n a n d vis ual ac uit y 
assess me nts m ust be ta ke n wit h t he sa me 
met h o d of assess me nt (i.e. 
 or 
 t hr o u g h o ut t he d urati o n of t he 
st u d y. See t he S R M f or m ore details.   
meas ure vis ual ac uit y per c urre nt 
sta n dar d of care. 
1 0. 2:  Cli nical 
La b orat or y T ests  
U p date d secti o n t o re m o ve refere nce t o 
ser u m or uri ne pre g na nc y testi n g per 
S o A.  
P R E VI O U S T E X T:  
Ser u m  or uri ne pre g na nc y tests s h o ul d 
be perf or me d as per t he S o A ( Secti o n 
1. 3). A d diti o nal ser u m or uri ne 
pre g na nc y tests ma y be perf or me d, as 
deter mi ne d necessar y b y t he I n vesti gat or 
or re q uire d b y l ocal re g ulati o n, t o 
esta blis h t he a bse nce of pre g na nc y at 
a n y ti me d uri n g t he partici pa nt's 
partici pati o n i n t he st u d y.  
R E VI S E D T E X T:  
A d diti o nal Ser u m or uri ne pre g na nc y 
tests ma y be perf or me d, as det er mi ne d 
necessar y b y t he I n vesti gat or or re q uire d 
b y l ocal re g ulati o n, t o esta blis h t he 
a bse nce of pre g na nc y at a n y ti me d uri n g 
t he partici pa nt's partici pati o n i n t he 
st u d y. 
A d mi nistrati ve c ha n ge t o ali g n 
re q uire me nt f or r o uti ne pre g na nc y 
testi n g t o t he Sc he d ule of 
Assess me nts. W o me n of 
C hil d beari n g p ote ntial are n ot 
eli gi ble t o partici pate i n t he st u d y; 
t heref ore, r o uti ne pre g na nc y t esti n g is 
n ot re q uire d per t he S o A. Pre g na nc y 
testi n g ma y be perf or me d as 
deter mi ne d necessar y b y t he 
I n vesti gat or or l ocal re g ulati o ns t o 
esta blis h a bse nce of pre g na nc y.  
1 0. 2:  Cli nical 
U p date d A p pe n di x 2, T a ble 4: Pr ot oc ol -
Re q uire d Safet y La b orat or y 
C orrecti o n d ue t o i nc o m plete 
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101 
Section # and 
Name 
Description of Change 
Brief Rationale 
Laboratory Tests 
Assessments to detail additional protocol 
required laboratory tests. 
template table. 
10.6 Abbreviations 
and Trademarks 
Updated Appendix 6: Abbreviations and 
Trademarks to include additional 
abbreviations and remove irrelevant 
abbreviations and trademarks. 
Administrative change 
11: References 
Updated Arrendondo reference to 
correct author name. 
PREVIOUS TEXT: 
Arredondo, ZD, et al. (2017). “Dual 
contribution of TRPV4 antagonism in 
the regulatory effect of vasoinhibins on 
blood-retinal barrier permeability: 
diabetic milieu makes a difference.” 
Scientific Reports, 7: 13094. 
 
REVISED TEXT: 
Arredondo, Zamarripa D, et al. (2017). 
“Dual contribution of TRPV4 
antagonism in the regulatory effect of 
vasoinhibins on blood-retinal barrier 
permeability: diabetic milieu makes a 
difference.” Scientific Reports, 7: 
13094. 
Administrative change to accurately 
reflect author reference. 


TMF-14377129 
CONFIDENTIAL 
 
 
212669 
102 
11. 
REFERENCES 
Arredondo Zamarripa D, et al. (2017). “Dual contribution of TRPV4 antagonism in the 
regulatory effect of vasoinhibins on blood-retinal barrier permeability: diabetic milieu 
makes a difference.” Scientific Reports, 7: 13094. 
Bates, DO. 2010. “Vascular endothelial growth factors and vascular permeability.” 
Cardiovascular Research, 87, 262-271. 
Blinder, KJ, et al. 2017. “Anti-VEGF treatment of diabetic macular edema in clinical 
practice: effectiveness and patterns of use (ECHO study report 1).” Clinical 
Ophthalmology, 11:393-401. 
Boyer, DS, et al. 2014. “Three-Year, Randomized, Sham-Controlled Trial of 
Dexamethasone Intravitreal Implant in Patients with Diabetic Macular Edema.” 
Ophthalmology, 121:1904-1914.  
Dugel, PU, et al. 2015. “Dexamethasone intravitreal implant in the treatment of diabetic 
macular edema.” Clinical Ophthalmology, 9: 1321–1335. 
Early Treatment Diabetic Retinopathy Study (ETDRS) Research Group. 
Photocoagulation for Diabetic Macular Edema. Early Treatment Diabetic Retinopathy 
Study Report 1. Arch Ophthalmology 1985: 103: 1796 – 1806. 
Early Treatment Diabetic Retinopathy Study (ETDRS) Research Group. 
Photocoagulation for Diabetic Macular Edema. Early Treatment Diabetic Retinopathy 
Study Report 4. International Ophthalmology Clinics 1987: 27(4): 256-272. 
Everaerts, W, et al. 2010. “Inhibition of the cation channel TRPV4 improves bladder 
function in mice and rats with cyclophosphamide-induced cystitis.” PNAS 107:44 
Fogli, S, et al.  2016. “Pathophysiology and pharmacological targets of VEGF in diabetic 
macular edema.” Pharmacological Research, 103:149–157. 
Fragala, MS, Kaufman HW, Meigs JB, Niles JK, McPhaul MJ, “Consequences of the 
COVID-19 Pandemic: Reduced Hemoglobin A1c Diabetes Monitoring.”  Population 
Health Management, 2021; 24(1) 8-10. 
Gonzalez, VH, et al. 2016. “Early and Long-Term Responses to Anti–Vascular 
Endothelial Growth Factor Therapy in Diabetic Macular Edema: Analysis of Protocol I 
Data.” American Journal of Ophthalmology, 172: 72-79. 
GSK Document Number 2011N112198_01 Study DM2115403 A phase 2, multi-
national, multi-centre, double masked, randomised, placebo controlled, parallel-group 
study to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics and 
efficacy of darapladib administered for 3 months to adult subjects with diabetic macular 
edema with centre involvement, 2011-Oct-11 


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GSK Document Number 2013N162862_07. Investigator’s Brochure (IB) for 
GSK2798745. Version 08, 2020-June-10. 
GSK Document Number 2018N386129_00. Study 207702 A placebo-controlled, double-
blind (sponsor open), randomised, crossover study to assess the efficacy, safety, and 
tolerability of GSK2798745 in participants with chronic cough, 2018-June-18 
Haritoglou, C, et al. 2018. “Pathophysiology of diabetic macular edema – a background 
for current treatment modalities.” Expert Review of Ophthalmology, 13(5): 273-281. 
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; 37:1779-84. 
Lee, R, et al. 2015. “Epidemiology of diabetic retinopathy, diabetic macular edema and 
related vision loss.” Eye and Vision, 2:17, DOI: 10.1186/s40662-015-0026-2, 25 pages. 
Phuong, TTT, et al. 2017 “Calcium influx through TRPV4 channels modulates the 
adherens contacts between retinal microvascular endothelial cells.” J Physiol, 595: 6869-
6885. 
Ryskamp, D. A. et al. 2016 “TRPV4 regulates calcium homeostasis, cytoskeletal 
remodeling, conventional outflow and intraocular pressure in the mammalian eye.” Sci. 
Rep. 6, 30583; doi: 10.1038/srep30583 
Samuels, TA, Bolen S, Yeh HC, Abuid M, Marinopoulos SS, Weiner JP, “Missed 
Opportunities in Diabetes Management: A Longitudinal Assessment of Factors 
Associated with Sub-optimal Quality.”  Journal of General Internal Medicine, 2008; 
23(11)1770-1777. 
Singer, MA, et al. (2016). “Diabetic macular edema: it is more than just VEGF.” F1000 
Research, 2015, 5(F1000 Faculty Rev):1019, DOI: 10.12688/f1000research.8265.1, 6 
pages. 
Wen, L, et al. (2018). “TRPV4 regulates migration and tube formation of human retinal 
capillary endothelial cells.” BMC Ophthalmol. 18: 38. 
Yau, JWY, et al. 2012. “Global Prevalence and Major Risk Factors of Diabetic 
Retinopathy.” Diabetes Care, 35:556–564. 

SAP_001.pdf: 
 
CONFIDENTIAL 
 
 
 
212669 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Statistical and Analysis Plan (SAP) 
 
Title 
: Statistical and Analysis Plan for Reporting and Analysis 
Plan for Phase I, Open-Label, Multi-Center Study to 
Evaluate Safety, Pharmacokinetics and Pharmacodynamics 
of GSK2798745 after 28 Day Repeat Oral Administration 
to Adults with Diabetic Macular Edema 
Compound Number  : GSK2798745 
Clinical Study 
Identifier 
: 212669 
Effective Date  
: 21 Jun 2022 
 
Description: 
 The purpose of this SAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 212669.  
 This SAP will be provided to the study team members to convey the content of 
the final statistical analysis deliverable. 
 Details of mock shells for all endpoints are provided in accompanying Shell 
document and Appendix 11. 
 
Copyright 2022 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.   
 
 
 


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
2  
 
S A P  A ut h or(s):  
 
A ut h or  
 Bi ostatistics (I Q VI A, A B D U, A ustralia) 
 
S A P  Te a m Re vie ws:  
 
S A P  Te a m Re vie w C o nfir m ati o ns ( Met h o d: E -m ail)  
Re vie wer  
Pr oject P h ysicia n, Me di cal M o nit or ( Disc o ver y M e dici ne)  
( Disc o ver y Me dici n e) 
 
Ma na ger Statistics ( Bi ostatistics) 
, De v -
C G O -R x G C D -Res pirat or y & S pecialt y  ( Gl o bal Cli nical Scie nces a n d Deli ver y) 
 
 C P M S 
 
 Earl y  P hase A n d Cell & Ge ne T hera p y, P har m a Safet y  
Pri nci pal Pr o gra m mer / A nal yst, Bi ostatistics 
 
Cli nic al St atistics a n d Cli nic al Pr o gr a m mi n g Li ne A p pr o v als:  
Cli nic al St atistics & Cli nic al Pr o gr a m mi n g Li ne A p pr o v als ( Met h o d: Vee v a V a ult 
T M F e Si g n at ure)  
A p pr o ver  
, Bi ost atistics 
 
Pr o gra m mi n g Lea der, Bi ostatistics  
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
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C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
3  
 
T A B L E O F C O N T E N T S   
P A G E   
1.  
I N T R O D U C TI O N ...................................................................................................... 5  
2.  
S U M M A R Y O F K E Y P R O T O C O L I N F O R M A TI O N  .................................................. 5  
2. 1.  
C h a n g e s t o t h e Pr ot o c ol D efi n e d St ati sti c al A n al y si s Pl a n  ............................ 5  
2. 2.  
St u d y O bj e cti v e( s) E n d p oi nt( s)  ..................................................................... 7  
2. 3.  
St u d y D e si g n  ................................................................................................ 8  
2. 4.  
St ati sti c al H y p ot h e s e s / St ati sti c al A n al y s e s  ................................................. 9  
3.  
P L A N N E D A N A L Y S E S  .......................................................................................... 1 0  
3. 1.  
I nt eri m A n al y si s .......................................................................................... 1 0  
3. 2.  
E n d of Tr e at m e nt P eri o d A n al y si s/I nt eri m A n al y si s of 2 8 D a y S D -
O C T a n d
.......................................................................................... 1 0  
3. 3.  
Fi n al A n al y s e s  ............................................................................................ 1 0  
4.  
A N A L Y SI S P O P U L A TI O N S  ................................................................................... 1 1  
4. 1.  
Pr ot o c ol D e vi ati o n s  ..................................................................................... 1 2  
5.  
C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S A N D D A T A H A N D LI N G 
C O N V E N TI O N S  ..................................................................................................... 1 3  
5. 1.  
St u d y Tr e at m e nt & S u b -gr o u p Di s pl a y D e s cri pt or s  ..................................... 1 3  
5. 2.  
B a s eli n e D efi niti o n s  .................................................................................... 1 3  
5. 5.  
Ot h er C o n si d er ati o n s f or D at a A n al y s e s a n d D at a H a n dli n g 
C o n v e nti o n s  ................................................................................................ 1 3  
6.  
S T U D Y P O P U L A TI O N A N A L Y S E S  ....................................................................... 1 5  
6. 1.  
O v er vi e w of Pl a n n e d St u d y P o p ul ati o n A n al y s e s  ........................................ 1 5  
7.  
S A F E T Y A N A L Y S E S  ............................................................................................. 1 6  
7. 1.  
A d v er s e E v e nt s A n al y s e s  ........................................................................... 1 6  
7. 2.  
A d v er s e E v e nt s of S p e ci al I nt er e st A n al y s e s  .............................................. 1 7  
7. 3.  
Cli ni c al L a b or at or y A n al y s e s  ....................................................................... 1 7  
7. 4.  
Ot h er S af et y A n al y s e s  ................................................................................ 1 7  
8.  
P H A R M A C O KI N E TI C A N A L Y S E S  ......................................................................... 1 8  
8. 1.  
P h ar m a c o ki n eti c A n al y s e s  .......................................................................... 1 8  
8. 1. 1.  
P h ar m a c o ki n eti c A n al y si s F or I nt e n si v e P K S a m pli n g  ................. 1 8  
8. 1. 2.  
P o p ul ati o n of I nt er e st  ................................................................... 1 9  
8. 1. 3.  
St ati sti c al A n al y s e s / M et h o d s  ..................................................... 1 9  
9.  
P H A R M A C O D Y N A MI C A N A L Y S E S ....................................................................... 2 0  
9. 1.  
Pri m ar y P h ar m a c o d y n a mi c A n al y s e s  .......................................................... 2 0  
9. 1. 1.  
E n d p oi nt / V ari a bl e s  ..................................................................... 2 0  
9. 1. 2.  
S u m m ar y M e a s ur e  ...................................................................... 2 0  
9. 1. 3.  
P o p ul ati o n of I nt er e st  ................................................................... 2 0  
9. 1. 4.  
Str at e g y f or I nt er c urr e nt ( P o st -R a n d o mi z ati o n) E v e nt s  ................ 2 0  
9. 1. 5.  
St ati sti c al A n al y s e s / M et h o d s  ..................................................... 2 1  
9. 2.  
E x pl or at or y P h ar m a c o d y n a mi c A n al y s e s  .................................................... 2 2  
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C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
4  
 
1 0.  R E F E R E N C E S  ....................................................................................................... 2 4  
1 1.  A P P E N DI C E S  ........................................................................................................ 2 5  
1 1. 1.  A p p e n di x 1: E x cl u si o n s fr o m P er Pr ot o c ol P o p ul ati o n  ................................. 2 5  
1 1. 2.  A p p e n di x 2: S c h e d ul e of A cti viti e s  .............................................................. 2 6  
1 1. 3.  A p p e n di x 3: A s s e s s m e nt Wi n d o w s  ............................................................. 2 8  
1 1. 3. 1.  
D efi niti o n s of A s s e s s m e nt Wi n d o w s f or A n al y s e s  ........................ 2 8  
1 1. 4.  A p p e n di x 4: St u d y P h a s e s a n d Tr e at m e nt E m er g e nt A d v er s e 
E v e nt s  ........................................................................................................ 2 9  
1 1. 4. 1.  
St u d y P h a s e s  .............................................................................. 2 9  
1 1. 5.  A p p e n di x 5: D at a Di s pl a y St a n d ar d s & H a n dli n g C o n v e nti o n s  .................... 3 0  
1 1. 5. 1.  
R e p orti n g Pr o c e s s  ....................................................................... 3 0  
1 1 . 5. 2. 
R e p orti n g St a n d ar d s  .................................................................... 3 0  
1 1. 5. 3.  
R e p orti n g St a n d ar d s f or P h ar m a c o ki n eti c  .................................... 3 1  
1 1. 6. 
A p p e n di x 6: D eri v e d a n d Tr a n sf or m e d D at a  ............................................... 3 2  
1 1. 6. 1.  
G e n er al  ........................................................................................ 3 2  
1 1. 6. 2.  
St u d y P o p ul ati o n  .......................................................................... 3 2  
1 1. 6. 3.  
P h ar m a c o d y n a mi c  ....................................................................... 3 2  
1 1. 7. 
A p p e n di x 7: R e p orti n g St a n d ar d s f or Mi s si n g D at a  ..................................... 3 3  
1 1. 7. 1.  
S af et y  .......................................................................................... 3 3  
1 1. 7. 2.  
Pr e m at ur e Wit h dr a w al s  ................................................................ 3 3  
1 1. 7. 3.  
H a n dli n g of Mi s si n g D at a  ............................................................. 3 3  
1 1. 8.  A p p e n di x 8: V al u e s of P ot e nti al Cli ni c al I m p ort a n c e  ................................... 3 4  
1 1. 8. 1.  
L a b or at or y V al u e s  ........................................................................ 3 4  
1 1. 8. 2.  
Vit al Si g n s  .................................................................................... 3 5  
1 1. 8. 3.  
E C G  ............................................................................................. 3 5  
1 1. 8. 4 O p ht h al mi c E x a mi n ati o n V al u e s of P ot e nti al Cli ni c al 
I m p ort a n c e ................................................................................... 3 5  
1 1. 9.  A p p e n di x 9: A b br e vi ati o n s & Tr a d e m ar k s  ................................................... 3 7  
1 1. 9. 1.  
A b br e vi ati o n s  ............................................................................... 3 7  
1 1. 9. 2.  
Tr a d e m ar k s  ................................................................................. 3 9  
1 1. 1 0.  A p p e n di x 1 0: Li st of D at a Di s pl a y s .............................................................. 4 0  
1 1. 1 0. 1.  D at a Di s pl a y N u m b eri n g  .............................................................. 4 0  
1 1. 1 0. 2.  M o c k E x a m pl e S h ell R ef er e n ci n g  ................................................ 4 0  
1 1. 1 0. 3.  D eli v er a bl e s  ................................................................................. 4 0  
1 1. 1 0. 4.  St u d y P o p ul ati o n T a bl e s  .............................................................. 4 1  
1 1. 1 0. 5.  S af et y T a bl e s  ............................................................................... 4 3  
1 1. 1 0. 6.  S af et y Fi g ur e s  ............................................................................. 4 7  
1 1. 1 0. 7.  P h ar m a c o ki n eti c T a bl e s  ............................................................... 4 8  
1 1. 1 0. 8.  P h ar m a c o d y n a mi c T a bl e s  ........................................................... 4 9  
1 1. 1 0. 9.  P h ar m a c o d y n a mi c Fi g ur e s  .......................................................... 5 2  
1 1. 1 0. 1 0.  I C H Li sti n g s ................................................................................. 5 4  
1 1. 1 0. 1 1.  N o n -I C H Li sti n g s .......................................................................... 5 6  
1 1. 1 1.  A p p e n di x 1 1: E x a m pl e M o c k S h ell s f or D at a Di s pl a y s  ................................ 6 1  
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
5  
 
1.  
I N T R O D U C TI O N  
 
T he p ur p ose of t his statistical a n d a nal ysis pla n ( S A P ) is t o descri be t he pla n ne d a nal yses 
a n d o ut p ut t o be i ncl u de d i n t he Cli nical St u d y Re p ort  f or Pr ot oc ol 2 1 2 6 6 9.  
 
Pr ot o c ol R e vi si o n C hr o n ol o g y:  
Ori gi nal D ocu m e nt N u m b er : 20 1 9 N 4 0 4 0 3 0_ 0 0  
D at e d: 1 9 -S e p -20 1 9 
V ersi o n: Ori gi n al  
Ori gi nal D ocu m e nt N u m b er : 20 1 9 N 4 0 4 0 3 0_ 0 1  
D at e d: 1 1 -May -2 0 20 
V ersi o n: A m e n d m e nt 0 1  
Ori gi nal D ocu m e nt N u m b er: 20 1 9 N 4 0 4 0 3 0_ 0 2 
D at e d: 2 8 -Oct -2 02 0 
V ersi o n: A m e n d m e nt 0 2  
Ori gi nal D ocu m e nt N u m b er: T M F -1 1 8 7 44 9 9  
D at e d: 2 4 -Mar -2 0 2 1  
V ersi o n: A m e n d m e nt 0 3  
Ori gi nal D ocu m e nt N u m b er: T M F -1 4 0 7 32 5 4  
D at e d: 1 1 -N O V -2 02 1 
V ersi o n: A m e n d m e nt 0 4  
Ori gi nal D ocu m e nt N u m b er: T M F -1 4 3 7 71 2 9  
D at e d: 2 -F e b -20 2 2 
V ersi o n: A m e n d m e nt 0 5  
  
It is n ote d t hat G S K ter mi nate d t his st u d y d ue t o t he f utilit y a nal ysis as d escri be d  i n 
Secti o n  3. 1  of t his S A P. T he S A P details t he a nal ysis t hat is pla n ne d bas e d o n t he 
s p o ns or’s decisi o n t o ter mi nate t he st u d y. 
2.  
S U M M A R Y O F K E Y P R O T O C O L I N F O R M A TI O N   
2. 1.  
C h a n g e s t o t h e Pr ot o c ol D efi n e d St ati sti c al A n al y si s Pl a n   
 
T a bl e 1  
C h a n g e s t o Pr ot o c ol D efi n e d A n al y si s Pl a n   
Pr ot o c ol  
R e p orti n g & A n al y si s Pl a n  
St ati sti c al A n al y si s Pl a n  
St ati sti c al A n al y si s Pl a n  
R ati o n al e f or C h a n g e s  
S ecti o n 9.4. 1.2. 
P h ar mac ody n a mics ( P D) A n alysis  
 
A B ayesi a n pr o b a bility m o del will 
b e use d t o a n alys e t he m e an 
c h a ng e fr o m b as eli ne i n O C T at 
D ay 2 8.  
S ecti o n 9.1. 5. St atistic al 
M et h o dol o gy S pecific ati on  
 
T h e pri m ary a nalysis is 
c h a ng e d t o a Bay esi an 
R e p e at e d M e as ur e 
A n alysis.  
A r e p eat e d m e asur es m od el 
will all o w t o m o d el d ata 
c oll ect e d at all visits i n a 
si n gl e m o del an d d o es n ot 
r e q uire a n assu m pti on t hat 
t h e S D is kn o w n.  
S ecti o n 9.3  
P o p ulati o ns f or An alysis  
 
M o difi e d S af ety Po p ulati o n h as 
b e en i ncl u d e d  in S A P. 
S ecti o n 4  
A n alysis P op ul ati o ns  
 
T h e m o difi ed Saf ety 
P o p ulati o n i ncl u d es “ All 
s u bj ects i n t he Saf ety 
p o pul ati on excl udi n g 
s u bj ects fro m Sit e n u m ber: 
Sit e nu m b er 
was cl os ed 
pr e m at ur ely d u e t o 
si g nific a nt q uality iss u es. 
S p ecific ally, th e f oll o wi n g 
w er e o bserv e d:  
 
 Pr ot oc ol n on -c o m pli a nc e 
 I C F d efici e ncies 
 I nv esti gati o nal Pr od uct 
d osi n g c o ncer ns  
 I n a de qu ate s o urce 
d oc u m ent atio n a n d 
m ulti pl e s o urc e 
d oc u m ent at io n 
P P D
P P D


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
6  
 
Pr ot o c ol  
R e p orti n g & A n al y si s Pl a n  
St ati sti c al A n al y si s Pl a n  
St ati sti c al A n al y si s Pl a n  
R ati o n al e f or C h a n g e s  
d efici e nci es / 
i nc o nsist enci es 
 Si g nific a nt del ay i n th e 
C R A’s acc ess t o t he 
El ectr o nic M edic al 
R ec or ds ( E M R).  
 
B as e d o n t hes e fin di ngs, 
t h e site 
 d at a ar e 
c o nsi d er ed i n q uesti o n a nd 
i nc o m pl et e. T h e A nalysis 
P o p ulati o n d efi niti o ns a nd 
r es ult a nt D at a Dis pl ays 
h av e b ee n a dj uste d to 
a d dr ess t h ese 
c o nsi d er ati o ns. 
 
All s af ety a nd r el ev a nt stu dy 
p o pul ati on t abl es will b e 
u n dert ak en usi ng th e 
M o difi e d S af ety Set. 
S el ect ed s af ety ( Over all a nd 
Oc ul ar A E a nd S A Es) will 
b e r e pe ate d f or t he full 
s af ety p op ul ati on. 
A p p en dix 1 0 a n d 1 1  
R e d ucti ons i n th e n u m ber 
of t a bl es, listi ngs a n d 
fi g ur es 
D u e t o st udy t er mi n atio n d ue 
t o f utility, t h e n u mb er of 
T F Ls b ei ng pr ese nte d h as 
b e en r e duc e d  
S ecti o n 9  
B ay esi an r e pe ate d mix e d 
m o d el c ha n ge d t o 
B ay esi an mix e d m od el  
D u e t o t e r mi n ati on, a n alysis 
will n o w o nly c onsi d er th e 
b as eli ne a nd 2 8 D ay visit. 
D ay 1 4  n o  lo n ger i ncl u de d in 
fi n al m o del 
P P D


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
7  
 
2. 2.  
St u d y O bj e cti v e( s) E n d p oi nt( s)   
 
O bj e cti ve s  
E n d p oi nt s  
Pri m ar y  
Pri m ar y  
 
T o c h ar act eriz e t h e s af ety a nd 
t ol er a bility of G S K 2 7 9 8 7 45 
f oll o wi ng 2 8 d ays of d aily oral d os e 
a d mi nistr ati o n t o a d ult s u bj ects wit h 
c o nfir m e d Di a betic M ac ul ar Ed e m a 
( D M E). 
 
S af ety p ar a m et ers i ncl u di n g: co m pl ete o p hth al mic 
ex a min ati on, vis u al ac ui ty, p hysic al ex a mi nati o n fi n di n gs, 
vit al si g n m e as ur e me nts, cli nic al l a b tests, 1 2-le a d E C G, 
cli nic al m o nit ori ng a n d obs ervati o n a nd a dv ers e ev e nt 
r e p orti n g. 
 
T o ev alu at e th e p h ar m aco dy na mics 
of 2 8  d aily or al d os es of 
G S K 2 7 9 8 7 45 i n th e stu dy ey e of 
a d ult su bj ects with D M E. 
 
M e a n ch a n g e fr o m bas eli n e i n c e nt er s u bfiel d r eti n al 
t hickn ess i n th e stu dy ey e as m e as ure d by S D-O C T.  
S e c o n d ar y  
S e c o n d ar y  
 
T o ev alu at e th e p h ar m acoki netics 
of 2 8 d aily or al d os es of 
G S K 2 7 9 8 7 45 i n ad ult s u bjects wit h 
D M E.  
 
Pl as m a c o nc e ntr ati o ns of G S K 2 7 9 8 7 4 5, m aj or m et ab olite 
M 1, a n d d eriv e d P K p ar a m et ers, as dat a p er mit . 
E x pl orat ory  
E x pl or at ory  
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
8  
 
2. 3.  
St u d y D e si g n   
 
O v er vi e w of St u d y D e si g n a n d Ke y F e at ur e s  
 
De si g n 
F e at ure s  
 
St u dy 2 1 26 6 9 is a m ulti -c e nt er, o p e n-l ab el, si n gl e ar m, 2 8-d ay tr e at me nt  stu dy. T h e 
st u dy will be c o m p os e d of 3 peri o ds for all s u bj ects ( Scr e enin g, Tr e at me nt, an d F oll o w-
u p). T h e scr e e ni n g peri o d m ay occ ur acr oss mor e t h an o n e  visit. Th e tr e at m e nt p eri o d 
is 2 8 days. T h e f oll o w-u p visit will b e ap pr oxi m ately 2 8 d ays aft er t h e fi n al d os e . 
 
 
At l e ast 2 0 p artici pa nts will be scr e e ne d a n d e nr oll e d t o e ns ur e 2 0 eval u a bl e 
p articip a nts c a n b e ac hi ev e d a t t h e e n d of t h e 2 8-d ay tr e at me nt p eri od. S u bjects t h at 
ar e scr ee n e d an d me et eli gi bility criteri a will b e e nr oll e d i n t he st u dy. A m axi mu m of 3 0 
p articip a nts m ay b e enr olle d. A mi ni m u m of 5 e nr oll e d p artici p a nts will be c o ns e nte d t o 
p art ak e i n t h e P K s u bset f or i nt e nsiv e P K s a m plin g o n D ay 7 a n d D ay 28 . 
 
 
If s u bjects ar e pr e m at ur ely disc o nti nu e d fr o m t h e st u dy pri or t o c o mpl etin g t h e pri mary 
e n d p oi nt 2 8 -d ay d osi n g p eri o d, a d ditio n al re pl ac e m ent s ubj ects may b e e nr oll e d at t h e 
discr eti o n of t h e S po ns or i n co ns ult ati o n with t h e Inv esti g ator.  R e pl ace m e nt s u bj ects 
m ay b e e nr oll e d until th e pr otoc ol d efi n e d s a mpl e siz e is ac hiev e d.  
D o si n g  
 
E ac h s ubj ect e nr oll e d will r ec eiv e a si n gl e d aily 3. 2 mg or al dos e of G S K 2 7 9 8 74 5 f or 
2 8 d ays . 
Ti m e & 
E v e nt s  
 
R ef er t o  A p p e ndix  2: Sc h ed ul e  of Activiti es  ( S o A) 
Tre at m e nt 
As si g n m e nt  
 
T his is a si n gl e ar m, o p e n -l a bel tr e at m e nt st u dy. E ac h s u bject e nr oll e d will r ec eive a 
si n gle d aily 3.2 m g or al dos e of G S K 2 7 9 8 74 5 f or 28 d ays . 
I nt eri m 
A n al y si s  
 
As t his is an o p e n-l a b el st udy, d at a will b e r evi e w e d on a n ong oi n g basis a n d m ay 
b e  s h ar ed exter n ally t o s u p port discussi o n with r e g ul at ory a ge nci es.  
 
Aft er a p pr oxi m ately 8 p artici pants c o m pl et e d t h e D ay 2 8 visit, O C T a n d 
d at a 
will b e an alys e d o n a n o n g oing b asis t o ass ess futility an d t he st u dy m ay b e 
t er mi n ate d e arly if t h e f utility crit eri a are m et. Ad ditio n al e n d poi nts m ay b e 
r evi e w e d as w ell if n ec ess ary.  
F ull d etails will b e pr ovi d ed i n th e i nt eri m a nalysis c h arter.  
 
 
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
9  
 
2. 4.  
St ati sti c al H y p ot h e s e s  / St ati sti c al A n al y s e s   
 
T he first c o -p ri mar y o bje cti ve of t his st u d y is t o esti mate t he treat me nt effect o n mea n 
c ha n ge fr o m baseli ne i n ce nter s u bfi el d reti nal t hic k ness i n t he s t u d y e ye as meas ure d b y 
S D -O C T at 2 8 da ys.  
 
T o e ns ure hi g h pr o b a bilit y of acc urate decisi o n ma ki n g ar o u n d t he c ha n ge at Da y 2 8 i n 
S D -O C T, t he decisi o n criteria are defi n e d as:  
 
 “ P ositi ve” if Pr o b [ C F B i n O C T @ 2 8 da ys > 7 0 μ m decrease| dat a] > 8 0 % a n d 
“Ne g ati ve” if Pr o b  [ C F B i n O C T @ 2 8 da ys < 9 5 μ m decrease| dat a] > 9 0 %. 
 
If neit her P ositi ve n or Ne gati ve criteri o n are meet, a n e val uati o n of t he  
mea n 
c ha n ge fr o m baseli ne will be perf or m e d.  A p ositi ve o utc o me will be c o n cl u de d if t he 
mea n c ha n ge fr o m b ase li ne i n 
 after c o m pleti n g 2 8 da ys of d osi n g is 3 letters or 
greater as r e vie we d i n t h e c o nte xt of all a vaila ble P D data .  
 
T he s ec o n d c o-pri mar y o bjecti ve is t o e val uate safet y of a n d t olera bilit y of t he treat me nt 
f oll o wi n g 2 8 da ys of dail y oral d ose ad mi nistrati o n t o a d ult s u bjects wit h c o nfir me d 
D M E , he nce n o f or mal h y p ot hesis will be teste d . 
 
T he sec o n d ar y o bjecti ve is to e val uate t he p har mac o ki netics of 2 8 dail y oral d oses of 
G S K 2 7 9 8 7 4 5  a n d relat e d M 1 meta b olite i n a d ult st u d y s u bjects a n d d eri ve c orres p o n di n g 
P K para meters . He n ce, n o f or mal h y p ot hesis will be teste d.  
C CI
C CI
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
1 0  
 
3.  
P L A N N E D A N A L Y S E S   
3. 1.  
I nt eri m A n al y si s  
 
After a p pr o xi matel y 8 partici pa nts c o m plete d t he Da y 2 8 visit, O C T a n d 
data will 
be a nal yse d o n a n o n g oi n g basis t o assess f utilit y a n d t he st u d y ma y be t er mi nate d earl y if 
t he f utilit y criteri a are met. A d diti o nal e n d p oi nts ma y b e re vi e we d as well if necessar y.  
F ull details will be pr o vi de d i n t he i nteri m a nal ysis c harter . T he o n g oi n g i nteri m a nal yses 
will be t he res p o nsi bilit y of G S K Bi ostatistics . 
 
3. 2.  
E n d of Tr e at m e nt P eri o d A n al y si s /I nt eri m A n al y si s  of 2 8 D a y 
S D -O C T  a n d
 
 
A preli mi nar y s u m mar y of 2 8 -da y S D -O C T a n d 
bas e d o n u nclea n e d data will be 
perf or me d after t he c o m pleti o n of t he f oll o wi n g se q ue ntial ste ps:  
 
1.  A mi ni m u m of 2 0 s u bjects ha ve c o m plete d t he 2 8-da y treat me nt peri o d a n d 
pr o vi de d e val ua bl e assess me nt s of S D -O C T a n d
at bas eli ne a n d at Da y 2 8.  
2.  T he s o urce d ata of S D -O C T fr o m t he Rea di n g Ce nter a n d eC R F d ata of
 
De m o gra p h y, E x p os ure, Dis p ositi o n a n d Pr ot oc ol De viati o n is recei ve d as S A S 
datasets. Data n ee ds t o b e as clea n as p ossi ble, si nce t his a nal ysis will be d o ne 
bef ore fi nal data clea ni n g a n d data bas e l oc k/freeze ( D B L/ D B F)  of t he st u d y.  
T he  e n d-of -treat me nt i nteri m a nal ysis will be t he res p o nsi bilit y of I Q VI A Statistics a n d 
Pr o gra m mi n g F u ncti o ns.  
 
3. 3.  
Fi n al A n al y s e s   
 
T he fi nal st u d y a nal yses will be perf or me d after t he c o m pleti o n of t he f oll o wi n g 
se q ue ntial ste ps: 
 
1.  A ll e nr olle d s u bjects ha v e c o m plete d t he st u d y . 
2.  All re q uire d dat a base cle a ni n g acti vities ha ve bee n c o m plete d a n d fi nal d ata base l oc k 
( DB L ) has  bee n declare d b y D ata Ma n a ge me nt . 
3.  T he  dr y r u n s ha v e  bee n c o m plete d pri or t o t he D B L  f or re vi e w b y t he st u d y tea m.  
T hese a n al ys es will be t he res p o nsi bilit y of I Q VI A Statistics a n d Pr o gra m mi n g 
F u ncti o ns.  
 
C CI
C CI
C CI
C CI
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
1 1  
 
4.  
A N A L Y SI S P O P U L A TI O N S   
 
P o p ul ati o n  
D efi niti o n / Crit eri a  
A n al y s e s E v al uat e d  
Scr e e n e d  
All s u bj ects w h o w er e scr e en ed f or eligi bility 
 
Scr e e n f ail ur es  
E nr oll e d  
All s u bj ects w h o p ass ed scr e eni n g a nd ar e 
eli gi bl e f or t h e st u dy wit h i nte nsi o n t o d ose .  
 
N ot e scr e eni n g f ailur es ( wh o nev er p ass e d 
scr e e ni n g ev e n if r escr e e n ed) a n d s u bj ects 
scr e e ne d b ut n ev er e nr oll e d int o t h e stu dy ar e 
excl ud e d fr o m t h e Enr oll ed p op ul ati on as t h ey 
di d n ot e nt er t he st udy.  
 
St u dy p o pul ati o ns   
S af ety   
All e nr oll e d s u bj ects w ho r ec eiv e d at l e ast o n e 
d os e of st u dy tr e at m e nt.  
 
St u dy P o p ul ati on  
 
S el ect e d S af ety T a bl es  
 
P o p ul atio n a n d Saf ety 
listin gs 
  
M o difie d S af ety   
All s u bj ects i n t h e S af ety p op ul ati o n  excl u d in g 
s u bj ects fro m Sit e  n u mb er:
 
S el ect e d St u dy 
P o p ul atio n  
 
S af ety T a bl es  
 
S o m e s el ect ed listi ngs 
r e p e at e d 
P h ar m ac ody n a mic 
( P D) 
All s u bj ects i n t h e mo difie d S af ety p o pul ati o n 
w h o h a d at l e ast 1 p ost -b aselin e n o n -missi n g 
P D ass ess m e nt . 
 
P h ar m ac ody n a mics 
a n alysis  
P h ar m ac oki n etic 
( P K) 
A ll p artici p a nts i n t h e mo dified S af ety 
p o p ul ati o n for w h o m a p har m ac oki n etic 
s a m pl e w as o btai n e d a n d a n alys e d.  
 
P h ar m ac oki n etic 
a n alysis  
I nt e nsiv e 
P h ar m ac oki n etic 
( P K) 
All s u bj ects i n t h e mo difie d S af ety p o pul ati o n 
w h o h a d i nte nsiv e P K sa m pli ng o n D ay 7 a n d 
D ay 2 8 p er s ecti o n 1. 3. 3 of t he pr ot ocol . 
 
I nt e nsiv e 
P h ar m ac oki n etic 
a n alysis  
N ot e: " Enr oll e d" m e a ns a p artici p a nt's, or t h eir l e g ally acc e pt a bl e r e pr es e nt ativ e’s, a gr e e m e nt t o p artici p at e i n a 
cli nic al st u dy f oll o wi n g c o m pl eti o n of t h e i nf or m e d c o ns e nt pr oc ess. P ot e nti al p artici p a nts w h o ar e scr e e n e d 
f or t h e p ur p os e of d et er mi ni n g eli gi bility f or t h e st u dy, b ut d o n ot p artici p at e i n t h e st u dy, ar e n ot c o nsi d er e d 
e nr oll e d.  
R ef er t o A p p e n dix 1 0 : List of D at a Dis pl ays w hic h d et ails t h e p o p ul ati o n us e d f or e ac h dis pl ay. 
* T his Sit e N u m b er
h a d s eri o us q u ality iss u es, m ulti pl e pr ot oc ol vi ol ati o ns a n d t h er ef or e n ot d e e m e d r eli a bl e.  
 
 
 
P P D
P P D


 
CONFIDENTIAL 
 
 
 
212669 
 
12 
 
4.1. 
Protocol Deviations  
 
A protocol deviation is any noncompliance with the clinical trial protocol or Good 
Clinical Practice (GCP).  The noncompliance may be either on the part of the subject, the 
site’s PI, or the study site staff. Any subject enrolled who does not meet eligibility criteria 
will be considered an enrolment deviation.   
 
Important protocol deviations, including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. 
 
Exclusion from the analysis sets due to a deviation will be determined programmatically 
using the criteria described in the table of Analysis populations above. These deviations 
will not be included in the SDTM dataset but will be programmed in the protocol 
deviation analysis (ADaM) dataset. This dataset will be the basis for the summaries and 
listings of protocol deviations. 
 
Data will be reviewed after locking the database and subjects will be assigned to relevant 
Analysis populations. Suggested population assignments will be sent to GSK for approval 
before proceeding with the final analysis.  
 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
1 3  
 
5.  
C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S  A N D  D A T A  
H A N D LI N G C O N V E N TI O N S   
5. 1.  
St u d y Tr e at m e nt & S u b -gr o u p Di s pl a y D e s cri pt or s   
 
Tr e at m e nt Gr o u p De scri pti o n s  
D at a Di s pl a y s f or R e p orti n g  
D e s cri pti o n  
Or d er i n T L F  
G S K 2 7 9 8 7 4 5 3. 2 m g  O D  
1  
5. 2.  
B a s eli n e D efi niti o n s   
 
I n ge neral, baseli ne is defi ne d as t he last n o n -missi n g pre -d ose ass ess me nt  i ncl u di n g 
sc he d ule d a n d u ns c he d ul e d visits, u nless state d ot her wise.  
 
T he f oll o wi n g s p ecific s ce nari os will be c o nsi dere d f or baseli ne d efi niti o n  of all 
o p ht hal mic ex a mi nati o n s i ncl u di n g b ut n ot restrict e d t o S D -O C T,
: 
 
 If Da y -1 val ue is n ot a vaila ble a n d  a val ue fr o m a n y u nsc h e d ule d visit wit hi n 7 2 
h o u rs pri or t o Da y -1 or Da y 1 pre -d ose is a vaila ble, t he n it will be c o nsi dere d as 
baseli ne.  
 If m ulti ple val ues are a vaila ble, f or e x a m ple, o n Da y -1 as w ell as a n y 
u nsc he d ule d visit bef ore Da y 1 d osi n g , t h e n latest assess me nt will be c o nsi dere d 
as baseli ne. 
 
A missi n g baseli ne ass ess me nt will n ot be i m p ute d.  
 
5. 3.  
M ulti c e ntr e St u di e s   
I n t his m ultice ntre st u d y, u nless s pecifie d ot her wise i n s pecific dis pla ys, t h e data will be 
prese nte d i n a n a g gre gate d ma n ner d ue t o s mall sa m ple siz e . 
5. 4.  
St u d y E y e a n d F ell o w E y e   
T he ce ntr al s u bfiel d data a nal ys e d a n d pr o vi de d b y a Ce ntral Rea di n g Ce nt er will be use d 
f or t he a n al ys es. T he C R F data will n ot be use d f or re p orti n g. T h is data is c a pt ure d as t w o 
rec or ds p er s u bject p er visit o ne f or t he ri g ht e ye a n d a n ot her f or t he left e ye i n dicate d b y 
t he Lateralit y varia ble. T he i de ntificati o n of t he St u d y E ye will be ma de b y t he 
Ra n d o mize d  Lateralit y  v aria ble w hic h s p ecifie s w het her  t he st u d y e ye is t he ri g ht or left 
e ye.  
5. 5.  
Ot h er C o n si d er ati o n s f or D at a A n al y s e s a n d D at a H a n dli n g 
C o n v e nti o n s   
 
Ot her c o nsi derati o ns f or data a nal yses a n d data ha n dli n g c o n ve nti o ns are o utli ne d i n t he 
a p pe n dices:  
 
C CI


 
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Section 
Component 
11.1 
Appendix 1: Exclusions from Per Protocol Population 
11.2 
Appendix 2: Schedule of Activities 
11.3 
Appendix 3: Assessment Windows 
11.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
11.5 
Appendix 5: Data Display Standards & Handling Conventions 
11.6 
Appendix 6: Derived and Transformed Data 
11.7 
Appendix 7: Reporting Standards for Missing Data 
11.8 
Appendix 8: Values of Potential Clinical Importance 
11.9 
Appendix 9: Abbreviations & Trademarks 
11.10 
Appendix 10: List of Data Displays 
11.11 
Appendix 11: Example Mock Shells for Data Displays 


 
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6. 
STUDY POPULATION ANALYSES  
6.1. 
Overview of Planned Study Population Analyses  
 
The study population analyses will be based on the Enrolled set, unless otherwise 
specified. 
 
Study population analyses including summaries of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
exposure and treatment compliance. 
 
Details of the planned displays or mock shells are presented in Appendix 11: Example 
Mock Shells for Data Displays and accompanying shells document. 
 


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
1 6  
 
7.  
S A F E T Y A N A L Y S E S   
 
T he pri mar y statistical a n al ysis will be t o e val u ate t he safet y a n d t olera bilit y of 
G S K 2 7 9 8 7 4 5 f oll o wi n g 2 8 da ys of dail y oral a d mi nistrati o n t o a d ult s u bjects wit h D M E . 
Safet y e n d p oi nts i ncl u di n g a d v erse e ve nts , vital si g ns ( heart rate a n d bl o o d press ure), 
cli nical la b orat or y tests ,1 2 -lea d E C G a n d C S S R S  will be descri pti vel y s u m marise d a n d 
liste d. 
 
All Safet y a n d rel e va nt st u d y p o p ulati o n ta bles will be prese nte d usi n g t he m o difie d 
Safet y a nal ysis p o p ulati o n. O verall A d verse E v e nts, Oc ular A d verse E v e nts a n d Seri o us 
A d verse E v e nts wi ll be re peate d f or t he Safet y A nal ysis p o p ulati o n. S o me p o p ulati o n 
ta bles will be re peate d f or s u bjects w h o recei ve d treat me nt d osi n g fr o m site # 
( 6 
s u bjects). 
 
All safet y a n d rele va nt p o p ulati o n listi n gs will be prese nte d usi n g t he Safet y a n al ysis 
p o p ul ati o n. S o me safet y a n d p o p ulati o n listi n gs will be re peate d f or t he m o difie d safet y 
set as prese nt e d i n t he listi n g of o ut p uts i n A p pe n di x 1 0: List of Data Dis pla ys , a n d 
acc o m pa n yi n g s hells d oc u me nt . 
  
7. 1.  
A d v er s e E v e nt s A n al y s e s   
 
All ad verse e ve nts starti n g o n or after t h e first d os e of st u d y treat me nt will be i ncl u de d i n 
t he s u m maries. A d vers e e ve nts i ncl u di n g Seri o us  ( S A Es) a n d e v e nts relate d t o st u d y 
treat me nt will be s u m marise d descri pti vel y usi n g fre q ue n c y a n d p erce nta ges o verall a n d 
b y treat me nt p hases (i.e., pre -treat me nt a n d o n -tr eat me nt as defi ne d i n Secti o n  1 1. 4. 1 ).  
O n -treat me nt a d vers e e v e nts i ncl u de t h ose t hat occ urre d i n t he f oll o w -u p p hase.  
 
A d verse e ve nts will be c o de d usi n g t he sta n d ar d Me dical Dicti o nar y f or R e g ul at or y 
Affairs ( Me d D R A dicti o nar y) . A Sta n dar dise d M e d D R A Q uer y ( S M Q) will be use d t o 
i de ntif y all O c ular , N o n-oc ular,  a n d C O VI D -1 9 A Es . 
 
T he i nci de nce of A Es a n d S A Es ( Fatal a n d N o n -Fatal) of C O VI D -1 9, C O VI D -1 9 A Es 
lea di n g t o st u d y dr u g dis c o nti n uati o n, C O VI D-1 9 A Es lea di n g t o st u d y wit h dra wal, a n d 
C O VI D -1 9 A Es b y s e verit y, will be o btai ne d fr o m sta n dar d A E a n d S A E s u m maries , 
wit h o ut se parate o ut p uts d ue t o s mall sa m ple siz e . 
 
If >2 5 % p artici pa nts r e p ort ≥1 C O VI D -1 9 A E/ S A E, t he n s u m maries of o nset a n d 
d urati o n of t he first oc c urre nce of C O VI D -1 9 A Es/ S A Es, a n d of C O VI D -1 9 s y m pt o ms 
(fr o m t he C O VI D-1 9 e C R F pa ge) will be pr o d uce d , ot her wise n ot.  
 
 
A Es will be liste d b y s u bjects . T he details of t he pla n ne d dis pla ys are pr o vi de d  i n 
A p pe n di x 1 0: List of Data Dis pla ys , a n d acc o m pa n yi n g s hells d oc u me nt . 
 
P P D


 
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7.2. 
Adverse Events of Special Interest Analyses  
 
There are no other Adverse Events of Special Interest defined in the protocol of this 
study. 
 
7.3. 
Clinical Laboratory Analyses  
 
Laboratory evaluations will be summarised descriptively and listed. The details of the 
planned displays are in Appendix 10: List of Data Displays, and accompanying shells 
document. 
 
7.4. 
Other Safety Analyses  
 
Other non-laboratory safety test results including CSSRS, ECGs and vital signs will be 
summarised descriptively and listed. The details of the planned displays are presented in 
Appendix 10: List of Data Displays, and accompanying shells document. 
 
 


 
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8. 
PHARMACOKINETIC ANALYSES  
8.1. 
Pharmacokinetic Analyses  
 
Intensive PK sampling in a subset (n  5) of subjects will be undertaken on Day 7 and 
Day 28 with all subjects providing a trough PK (Ctrough) sample on these 2 days. The Day 
7 PK data will be used to ascertain the systemic exposure of the parent drug at the 3.2mg 
OD is consistent with the predicted exposure (see Table 1 of Protocol).  
 
The plasma concentrations of GSK2798745 and its major metabolite M1 obtained on day 
7 and day 28 will be analysed using non-compartmental methods described below.  At 
end of study, all plasma samples (intensive PK Day 7 and Day 28) and trough samples 
will be analysed using a non-linear mixed effects analysis and is described in the 
pharmaco-statistical Section 8.1.3. The Population PK analyses using AUC and Cmax will 
be reported in a separate PK document, outside of the Clinical Study Report (CSR). 
 
8.1.1. 
Pharmacokinetic Analysis For Intensive PK Sampling  
 
Refer to Appendix 5: Data Display Standards & Handling Conventions Derived 
Pharmacokinetic Parameters. 
 
All non-compartmental pharmacokinetic derivation for the subjects with intensive PK 
sampling will be conducted by GSK under auspices of Clinical Pharmacology Modelling 
& Simulation (CPMS). Pharmacokinetic parameters will be calculated by standard non-
compartmental analysis according to current working practices and using the currently 
supported version of WinNonlin Professional. All calculations of non-compartmental 
parameters will be based on actual sampling times. Pharmacokinetic parameters listed 
will be determined from the concentration-time data, as data permits. Pharmacokinetic 
parameters for both parent drug and metabolite M1 will be undertaken. 
From the plasma concentration-time data [intensive sampling group], the following 
pharmacokinetic parameters will be determined for each subject for parent 
(GSK2798745) and metabolite (M1), if data permits:  
 
Parameter 
Parameter Description 
Cmax 
Maximum observed plasma concentration  
Ctrough 
Trough concentration 
 tmax 
Time to Cmax  
AUC0-τ 
Area under the curve over the dosing interval  
 
As the trial was terminated, only trough concentrations (Ctrough) for pharmacokinetic 
analysis will be provided. 
 
 
 
 
 


 
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8.1.2. 
Population of Interest  
 
The pharmacokinetic analyses (Non-Compartmental) will be based on the PK population, 
unless otherwise specified. 
 
8.1.3. 
Statistical Analyses / Methods  
 
Statistics and programming will prepare summaries of derived PK parameters provided 
by the CPMS team, if data permits. 
 
PK concentration data will be loge-transformed and summarised using geometric mean, 
95% CI for the geometric mean, SD of loge-transformed data, %CVb, and median, min, 
max of back-transformed data. 
  
Details of the planned displays are provided in Appendix 10: List of Data Displays, and 
accompanying shells document.  
 
The following PK modelling will be performed by GSK CPMS, if data permits. 
8.1.3.1. 
Pharmaco-Statistical Methodology Specification  
Endpoint / Variables 
 All GSK2798745 plasma concentrations at Day 7 and Day 28 including trough samples 
Model Summary 
 Based on the historical population PK model for GSK2798745, a maximum a 
posteriori  probability (MAP) Bayesian estimator based on the limited number of subjects 
and samples will be applied to derive population PK parameters and associated inter-subject 
variability taking into account demographic and physiological status of this population. These 
parameters will then be used in simulations to derive the Cmax and AUC over dosing interval 
at steady state for each subject. 
 Internal validation of the population PK model with this population will be undertaken using 
standard tools such as visual predictive checks and in accordance with the regulatory 
guidance https://www.fda.gov/media/128793/download . 
 The PK metrics for GSK2798745 (Cmax, Ctrough, AUC over dosing interval) will be used to 
assess any relationship with relevant PD parameter.  
 


 
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9. 
PHARMACODYNAMIC ANALYSES  
 
9.1. 
Primary Pharmacodynamic Analyses  
 
The coprimary endpoint of change from baseline in SD-OCT will be analysed using a 
Bayesian Analysis model.  
 
9.1.1. 
Endpoint / Variables  
 
Change from baseline in center subfield retinal thickness and center point in the study eye 
as measured by SD-OCT at 28 days. 
 
9.1.2. 
Summary Measure  
 
Mean change from baseline in SD-OCT at day 28. 
 
9.1.3. 
Population of Interest  
 
The primary pharmacodynamics analyses will be based on the Pharmacodynamic 
population, unless otherwise specified. 
 
9.1.4. 
Strategy for Intercurrent (Post-Randomization) Events  
 
The intercurrent events identified are: 
 
 Permanent Discontinuation of the Study Treatment due to any reason  
 
Lack of Compliance to Study Treatment 
 
9.1.4.1. 
Permanent Discontinuation of the Study Treatment due to any reason  
 
For the intercurrent event of treatment discontinuation prior to Day 28, a Principal 
Stratum Strategy will be used for the Primary Estimand, where we are interested to 
evaluate the treatment effect on subjects who did not permanently discontinue the 
treatment before 28 days to establish the proof of mechanism of the drug in this Phase 1b 
study.  
Thus, this Principal Stratum of interest will only include subjects who completed the 
study treatment until Day 28 and provided evaluable data at baseline and on Day 28.  
 
A supplementary analysis using a Hypothetical Strategy will be performed, where we are 
interested in a hypothetical situation that the treatment discontinuation would not occur. 
Data from all subjects whether completed treatment until Day 28 or not will be analysed 
using the same Bayesian Repeated Measures (BRM) analysis as done for the primary 
analysis.  
 


 
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9.1.4.2. 
Lack of Compliance to Study Treatment  
 
For the intercurrent event of lack of treatment compliance, a Principal Stratum Strategy 
will be used, where we are interested in subjects who have a high compliance to 
treatment (defined as ≥ 92% of treatment compliance). This principal stratum will include 
subjects who complete Day 28 with ≥ 92% of treatment compliance. 
 
For all other intercurrent events a Treatment Policy Strategy will be considered for the 
Study eye. 
 
9.1.5. 
Statistical Analyses / Methods  
 
Details of the planned displays are provided in Appendix 10: List of Data Displays, and 
accompanying shells document. 
 
9.1.5.1. 
Statistical Methodology Specification  
 
 
Endpoint / Variables 
Change from baseline in subfield retinal thickness in the study eye as measured by SD-OCT 
at 28 days.  
Center Subfield retinal thickness is obtained from data provided by Merit CRO. The 
variables required from the external data (non-CRF collected data) are: 
 
Thickness Sector (thscr_c),  
 
laterality (lateral), ). Laterality is to be matched with Study or Fellow Eye. 
 
Criteria of Center subfield thickness reliable (CTRSFTHR = ‘Y). 
The values of THSCR_C must be multiplied by 1000 for reporting. 
Bayesian Analysis Model Specification for the Primary Estimand using Principal Stratum 
Strategy (28 day Completers Analysis) 
 
The mean change from baseline in OCT at Day 28 is assumed to have a  t-distribution with 
(n-1) degrees of freedom. 
 
The variability will be calculated from the observed data. 
 
Evidence of an effect on 28-day OCT will be evaluated based on the posterior probabilities. 
 
Model Checking & Diagnostics 
 Not applicable. 
 
Model Results Presentation 
 Mean change from baseline, its 90% (equal-tailed) credible interval will be reported. 
 The posterior probabilities that the CFB > 0 μm, CFB > 70 μm decrease and CFB < 95 μm 
decrease will be reported for Day 28 completers. 
 


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
2 2  
 
A d diti o n al a n aly s es  
 Ex pl or atory A nalys es:  
9. 2.  
E x pl or at or y P h ar m a c o d y n a mi c A n al y s e s   
 
C CI
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
2 3  
 
C CI


 
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10. 
REFERENCES  
 
GlaxoSmithKline Document Number TMF-14377129 : Study Protocol Amendment 05 of 
212669, Phase I, Open-Label, Multi-Center Study to Evaluate Safety, Pharmacokinetics 
and Pharmacodynamics of GSK2798745 after 28 Day Repeat Oral Administration to 
Adults with Diabetic Macular Edema . 
 


 
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11. 
APPENDICES  
 
11.1. 
Appendix 1: Exclusions from Per Protocol Population  
 
Per protocol population is not defined in this protocol. Important protocol deviations and 
exclusions from any other analysis population will be listed. 


 
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11.2. 
Appendix 2: Schedule of Activities  
 
For a more detailed Schedule of Activities (SoA), please refer to the Section 1.3. 
Schedule of Activities of the protocol.  
Procedure / 
Study Day: 
Visit 1 
Screening 
Visit 2 
Baseline 
Treatment Period 
Early 
Withdrawal 
(WD) 
Follow-
up 
Day 56 
Week 8 
Day 1 
Week 0 
Visit 3 
Day 7 
Week 1 
Visit 4 
Day 14 
Week 2 
Visit 5 
Day 28 
Week 4 
Visit Window 
-1 to -14 
-3 to -1 
1 
6 – 8 
13 – 16 
27 – 30 
 
54 - 58 
Informed 
Consent 
X 
 
 
 
 
 
 
 
Outpatient 
Visit 
X 
X 
 
X 
X 
X 
X 
X 
Demography 
X 
 
 
 
 
 
 
 
Medical 
History 
(include 
substance 
usage & 
medication 
history) 
X 
X 
 
 
 
 
 
 
Complete 
Physical 
Examination 
X 
 
 
 
 
 
X 
X 
Brief 
Physical 
Exam 
 
X 
 
 
X 
X 
 
 
12-Lead ECG 
X 
X 
 
X1 
X 
X1 
X 
X 
Fecal Occult 
Blood Test 
(FOBT) 
X 
 
 
 
 
 
 
 
Columbia 
Suicidality 
Severity 
Rating Scale 
(CSSRS) 
X 
 
 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
X 
Clinical 
Chemistry, 
Hematology 
& UA 
(including 
Cardiac 
Troponin, 
CPK) 
X 
X 
 
X 
X 
X 
X 
X 
HbA1c 
X 
 
 
 
 
 
 
 
FSH / 
Estradiol 
X 
 
 
 
 
 
 
 
Inclusion / 
Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
Dispense 
Study 
Medication 
 
X 
 
 
 
 
 
 
Compliance 
Check for 
Study 
Medication 
 
 
 
X 
X 
X 
X 
 
First Day of 
Study 
Treatment 
 
 
X 
 
 
 
 
 


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
2 7  
 
 
 
D osi n g i n 
Cli nic  
 
 
 
X  
X  
X  
 
 
P K –  Tr o u g h 
Sa m pli n g  
 
 
 
X  
 
X  
 
 
P K –  
I nte nsi ve 
Sa m pli n g  
 
 
 
X  
 
X  
 
 
S pectral 
D o mai n 
O ptical 
C o here nce 
T o m o gra p h y 
( S D-O C T)  
X  
X  
 
 
X  
X  
X  
X  
Ge neral 
O p ht hal mic 
E xa m  
X  
X  
 
 
 
X  
X  
X  
A E - S A E 
Ass ess me nt  
X  
X  
X  
X  
X  
X  
X  
X  
C o nc o mita nt 
Me dicati o n  
X  
X  
X  
X  
X  
X  
X  
X  
C CI
C CI


 
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11.3. 
Appendix 3: Assessment Windows  
11.3.1. 
Definitions of Assessment Windows for Analyses  
 
There will not be multiple assessments for any of the endpoints and therefore assessment 
windows will not be used for reporting.  
Unscheduled visits will be listed and included in the summary of worst case post-baseline 
assessments only.  
Otherwise, only nominal time as per the protocol SoA will be used for all analysis.  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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11.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events  
11.4.1. 
Study Phases  
 
Assessments and Adverse Events (AEs) will be classified according to the time of 
occurrence relative to taking the first dose of the study treatment. 
 
Study Phase 
Definition 
Pre-Treatment  
Date < Study Treatment Start Date  
On-Treatment 
Date ≥ Study Treatment Start Date (including follow-up period) 
NOTE: Pre-treatment AEs will be listed only. 
 
11.4.1.1. 
Study Phases for Concomitant Medication  
 
Study Phase 
Definition 
Prior 
 If medication end date is not missing and is before study treatment start date. 
Concomitant 
Any medication or vaccine (including over-the-counter or prescription medicines, some 
vitamins, and/or herbal supplements), approved by the Investigator, in consultation 
with the GSK Medical Monitor, that the participant is receiving on or after the start of 
study treatment.  
NOTE: Please refer to 12: Reporting Standards for Missing Data for handling of missing and partial dates for  
  concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 


 
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11.5. 
Appendix 5: Data Display Standards & Handling 
Conventions  
11.5.1. 
Reporting Process  
 
Software 
 
SAS 9.4 software will be used. 
Reporting Area 
SASAppU8_ADC 
Server 
 \\usadc-nas01a\cp_ops\BIOS\GlaxoSmithKline\GSK212669 
Analysis Datasets  
 
Source dataset of SD-OCT from the Reading Center will be used for analysis 
 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1). 
Generation of RTF Files 
 
RTF files will be generated for final analysis results 
 
11.5.2. 
Reporting Standards  
 
General 
Reporting will follow IQVIA SOP CS_WI_BS014 Revision 15 standards. 
 
Table specifications are created for each table output to describe the mapping of derived data to the 
tables. Specifications are considered optional for listings and figures – but the table specification template 
options (CS_TP_BS023 or CS_TP_BS024) will be used when creating specifications for listings and 
tables. Table, figures and listings displays will be used according to CS_TP_BS023 shell standards. 
Where displays are deemed similar to GSK Standards Library (IDSL) by STL, GSK displays will be used 
instead.  
Formats 
 
IQVIA SOP CS_WI_BS014 for decimal places (DP’s) will be adopted for reporting of data based on 
the raw data collected, unless otherwise stated. 
 
Numeric data will be reported at the precision collected on the eCRF. 
 
The reported precision from non eCRF sources will follow the IQVIA SOP CS_TP_BS023 but may 
be adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
 
Reporting for tables, figures and formal statistical analyses: 
 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
 
The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate. 
 
Reporting for Data Listings:  
 
Planned and actual time relative to study drug dosing will be shown in listings. Unscheduled or 
unplanned readings will be presented within the subject’s listings.  
Unscheduled Visits 
 
Unscheduled visits will not be included in summary tables and/or figures. But will be included in the 
summary of worst-case post-baseline results. 
 
All unscheduled visits will be included in listings. 


 
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Descriptive Summary Statistics 
Continuous Data 
N, n, mean, sd, median, min, max 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
 
Refer to IQVIA SOP CS_TP_BS023  
 
11.5.3. 
Reporting Standards for Pharmacokinetic  
 
Reporting standards for PK data will be based on current CPMS NCA and POP PK 
guidance documents.  
 


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
3 2  
 
1 1. 6.  
A p p e n di x 6: D eri v e d a n d Tr a n sf or m e d D at a   
1 1. 6. 1.  
G e n er al   
 
M ulti pl e Me a s ur e m e nts at O n e A n al y si s Ti m e P oi nt  
 
Not A p plica bl e  
St u d y D a y  
 
Calc ul ate d as  t h e nu m b er of days fr o m First D os e D ate: 
 
R ef D at e = Missin g              → St u dy D ay = Missin g  
 
R ef D at e < First D os e D at e → St u dy D ay = R ef D at e –  First D os e D at e  
 
R ef D at a ≥ First D os e D at e → St u dy D ay = R ef D at e –  ( First D os e D at e) + 1     
 
1 1. 6. 2.  
St u d y P o p ul ati o n   
 
Tre at m e nt C o m pli a n ce  
 
Tr e at m e nt c o mpli anc e will b e c alc ul at e d b ase d o n th e f or m ul a:   
Tr e at m e nt C o m pli a n ce = N u m b er of Act u al D o s e s / ( Pl a n n e d Tre at m e nt D ur ati o n i n D a y s * 
Fr e q u e n c y)  
 
Fr e q u e ncy is 2 f or BI D an d 1 for d aily . Tr e at m e nt c o m pli a nce c o uld b e gre at er t ha n 1 0 0 % if t h er e are 
ev e nts of ov er d ose. C u m ul ative c o m pli a nc e (si nce D ay 1) at e ac h visit will b e c alc ul at e d . 
 
Pl a n n e d Tr eat m ent D ur ati on is d efi n e d a s 28 d ays, wit h p ot enti al 8 -w e ek  o pt -i n tr e at m e nt peri o d. 
E xt e nt of E x p o s ure  
 
Nu m b er of days of exp os ure to st u dy dr u g will b e c alc ulat e d b as e d o n t h e f or m ul a:   
D ur ati o n of E x p o s ure i n D a ys = Tr e at m e nt St o p D at e –  (Tr e at m e nt St art Dat e) + 1  
 
S u bj ect s w h o w er e r an d o miz ed b ut di d n ot r ep ort a tr eat m ent st art d at e will b e cat e g oris e d as h avi n g 
z er o d ays of ex p os ur e.  
 
T h e c u m ul ativ e dos e will be bas e d o n t h e f or m ul a:  
C u m ul ati v e D o s e = S u m of ( N u m b er of Da y s x T ot al D aily D o s e)  
 
If t h er e ar e a ny tre at m ent br e aks d uri n g t he st u dy, ex p osur e d at a will b e a dj uste d acc or di ngly. 
 
1 1. 6. 3.  
P h ar m a c o d y n a mi c   
 
S D -O C T  
C h a n g e fr o m b a s eli ne c al c ulati o n  
C h a n ge fr o m Bas eli ne = Post -D os e Visit Val u e –  Bas elin e  Val u e  
 
Ot her o p ht hal m ol o g y assess me nts will be s u m marise d o nl y des cri pti vel y usi n g si milar 
c ha n ge fr o m baseli ne assess me nts.  
C CI


 
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11.7. 
Appendix 7: Reporting Standards for Missing Data  
11.7.1. 
Safety  
 
ULN of Laboratory Results 
Fold Upper Limit of Normal calculation 
Fold ULN = Laboratory value / the Upper Limit of the Normal range. 
 
LLN of Laboratory Results 
Fold Lower Limit of Normal calculation 
Fold LLN = Laboratory value / the Lower Limit of the Normal range. 
 
11.7.2. 
Premature Withdrawals  
 
Element 
Reporting Detail 
General 
 
Subject’s completion is defined as the completion of 28-day treatment period and 
provide an evaluable assessment of SD-OCT at 28 day 
 
Unscheduled assessments will only be included in listings 
 
 
11.7.3. 
Handling of Missing Data  
 
Element 
Reporting Detail 
General 
 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such 
o In this analysis dataset, a missing assessment at any scheduled visit will be 
considered unevaluable, will not be imputed and will not be included in data 
analysis. Only observed (OC) cases will be included for all primary, secondary 
and exploratory endpoints. 
Outliers 
 
Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
 
11.7.3.1. 
Handling of Missing and Partial Dates  
 
Element 
Reporting Detail 
General 
 
Partial dates will be displayed as captured in subject listing displays.  
 
Where necessary, display macros may impute dates as temporary variables for 
sorting data in listings only.  
 


 
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11.8. 
Appendix 8: Values of Potential Clinical Importance  
11.8.1. 
Laboratory Values  
 
Haematology  
Laboratory Parameter  
  
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit   
Ratio of 1 
Male 
 
0.54 
Female 
 
0.54 
∆ from BL 
↓0.075 
 
Hemoglobin   
g/L  
Male 
 
180 
Female 
 
180 
∆ from BL 
↓25 
 
Lymphocytes   
x109/ L 
 
0.8 
 
Neutrophil Count   
x109/ L 
 
1.5 
 
Platelet Count   
x109/ L 
 
100 
550 
While Blood Cell Count (WBC)  
x109/ L 
 
3 
20 
 
Clinical Chemistry  
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin   
mmol/L 
 
30 
Calcium  
mmol/L 
 
2 
2.75 
Creatinine  
mmol/L 
∆ from BL 
 
↑ 44.2 
Glucose  
mmol/L 
 
3 
9 
Magnesium  
mmol/L 
 
0.5 
1.23 
Phosphorus  
mmol/L 
 
0.8 
1.6 
Potassium  
mmol/L 
 
3 
5.5 
Sodium  
mmol/L 
 
130 
150 
Total CO2  
mmol/L 
 
18 
32 
 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT/SGPT  
U/L  
High 
≥ 2x ULN  
AST/SGOT  
U/L  
High 
≥ 2x ULN  
AlkPhos  
U/L  
High 
≥ 2x ULN  
T. Bilirubin  
µmol/L  
High 
≥ 1.5x ULN  
T. Bilirubin + ALT  
µmol/L  
  
U/L  
High 
≥ 1.5x ULN T. Bilirubin  
+  
2x ULN ALT  
D. Bilirubin  
µmol/L  
High 
≥ 1.5x ULN  


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
3 5  
 
1 1. 8. 2.  
Vit al Si g n s   
 
Vit al Si g n P ar a m et er  
( A b s ol ut e) 
U nit s  
Cli ni c al C o n c er n Ra n g e  
L o w er  
U p p er  
Syst olic Bl oo d Pr ess ur e  
m m H g  
9 0  
1 8 0 
Di ast olic Bl oo d Pr ess ur e  
m m H g  
4 0  
1 2 0 
He art Rat e  
b p m 
5 0  
1 2 0 
 
1 1. 8. 3.  
E C G   
 
E C G P ara m et er   
U nit s  
Cli ni c al C o n cer n R a n g e   
L o w er   
U p p er   
A b s ol ut e   
A bs ol ut e Q Tc 
I nt erv al  
ms ec   
> 4 5 0 [1]  
  
A bs ol ut e P R 
I nt erv al  
ms ec   
< 1 1 0 [1]  
> 2 2 0 [1]  
A bs ol ut e Q R S 
I nt erv al  
ms ec   
< 7 5 [1]  
> 1 1 0 [1]  
C h a n g e fr o m B a s eli n e   
I ncr e ase fr o m 
B as eli ne Q Tc   
ms ec   
> 6 0 [1]  
  
N O T E S:    
1 .  
R e pr es e nt st a n d ar d E C G v al u es of P CI f or H V st u di es   
 
1 1. 8. 4 O p ht h al mi c E x a mi n ati o n V al u e s of P ot e nti al Cli ni c al I m p ort a n c e   
 
O p ht h al mi c  P ar a m et er  
P ot e nti al cli ni cal c o n c er n  
S D -O C T  
If a p atie nt h as a ce ntr al s u bfiel d c ha n g e of > 1 2 0 μ m (t his corr es p o nds 
a p pr oxi m at ely wit h > 1 5 lett er ch a n g e [ C urr e nt O pi ni o n i n O pht h al mol o gy 
2 0 1 0, 2 1:1 7 2 – 17 7]), as ass ess e d by S D -O C T, t h e n t his assess me nt will b e 
c at e g oriz e d as cli nic ally si g nific a nt.  
I O P 
If a p atie nt h as a n I O P ass ess m e nt w hic h i ndic at es hy p o - or hy p ert o ni a as 
f oll o ws:  
C h a n g e fr o m b aseli ne of > = 5 m m H G   
I O P > = 2 5 m m H G  
I O P < 8 m m H G  
I ncr e ase of > = 5 m m H G fr o m pr evi o us visit > = 5 m m H g diff erenc e 
b et w e e n t h e t w o ey es at th e sa m e visit   
t h e n t his ass ess m ent will b e cat e g oriz e d as cli nic ally si g nific a nt.   
P u pil: p upill ary def ect  
A ny  p ost -b as eli n e fi n di n g of “ Pr es e nt” Aff ere nt p a pillary d ef ect ( A P D) i n eit her 
ey e if A P D  w as n ot pr es e nt i n t h at ey e at t h e b as eli n e ex a m.  
M otility  
P ost -b aseli n e c h an g es i n ey e m otility in eith er eye if m otility w as n or m al i n 
t h at ey e at t h e b as eli n e ex a m. 
C CI


 
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Ophthalmic Parameter 
Potential clinical concern 
Confrontation visual field 
New post-baseline defects in the confrontation visual field. 
Exam of upper and 
lower eyelids 
Any serious change from baseline by clinical judgment of the investigator 
captured as an AE. 
Meibomian gland 
dysfunction 
Post-baseline 2-step worsening or 2+ worse per eye. PCIs include: 
1) 
A subject that goes from absent to “obvious inspissation/mild 
injection, not trichiasis or lid thickening” or “inspissation, debris, obvious 
injection, lid thickening, may have trichiasis” 
2) 
A subject that goes from “mild inspissation/debris without injection or 
thickening” to “inspissation, debris, obvious injection, lid thickening, may have 
trichiasis” 
Conjunctival injection or 
chemosis 
2-step worsening and 2+ or worse per eye change from baseline in dilation of 
conjunctival vessels, cilliary injection, subconjunctival hemorrhage, diffuse 
edema, subconj. fluid or prolapse of conj. over lower lid. 
Tear Exam 
Any serious change from baseline by clinical judgment of the investigator 
captured as an AE. 
Cornea Epithelium 
 
2+ worsening change from baseline for edema (i.e., a change from 
none to mild patchy microcystic changes),  
 
 
Any new opacity or whorl-like pattern 
Corneal Stroma 
Any serious change from baseline by clinical judgment of the investigator 
captured as an AE. 
Corneal endothelium 
Any serious change from baseline by clinical judgment of the investigator 
captured as an AE. 
Anterior chamber cells 
 Post-baseline finding of Grade 2+ or worse per eye 
Anterior chamber 
hypopyon 
Any post-baseline finding of Present per eye 
Anterior chamber flare 
Any post-baseline finding of Grade 2+ or worse per eye 
Lens Opacity 
2+ or worse increase in any opacity as compared to baseline per eye (this 
can include cortical, nuclear, subcapsular).  Any change to “cannot evaluate” 
will be flagged as PCI. 
 
The increase will be calculated by using the following codes: 
1 - <1.0 = no Nuclear/Cortical/any subcapsular opacity, or less than Std. #1 
2 - 1.0 = Nuclear/Cortical/any subcapsular opacity similar to Std. #1 
3 - 1.5 = Nuclear/Cortical/any subcapsular opacity between Std. #1 and Std. 
#2 
4 - 2.0 = Nuclear/Cortical/any subcapsular opacity similar to Std. #2 
5 - 2.5 = Nuclear/Cortical/any subcapsular opacity between Std. #2 and Std. 
#3 
6 - 3.0 = Nuclear/Cortical/any subcapsular opacity similar to Std. #3 
7 - >3.0 = Nuclear/Cortical/any subcapsular opacity greater than Std. #3 
8 - 8.0 = cannot evaluate 
 
Iris 
None 
Vitreous  
Any serious change from baseline by clinical judgement of the investigator 
captured as an AE.  
Optic nerve head 
Any serious change from baseline by clinical judgement of the investigator 
captured as an AE. 
Posterior pole 
Any serious change from baseline by clinical judgement of the investigator 
captured as an AE. 


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
3 7  
 
1 1. 9.  
A p p e n di x 9 : A b br e vi ati o n s & Tr a d e m ar k s   
1 1. 9. 1.  
A b br e vi ati o n s   
 
A b br e vi ati o n  
D e s cri pti o n  
A E  
A dv ers e Ev e nt  
A L T  
Al a ni n e a mi n otra nsfer as e ( S G P T)  
A N O V A  
A n alysis of V ari anc e  
A S T  
As p art at e a mi n otr a nsf er as e ( S G O T)  
A U C  
Ar e a u n der c o nce ntr atio n-ti m e c urv e 
A U C( 0 -) 
Ar e a u n der t h e c o nce ntr ati on -ti m e c urv e over t he d osi ng i nt erv al 
B MI  
B o dy m ass in d ex  
B P  
Bl o o d pr ess ur e  
B P M  
B e at P er Mi n ut e  
B R M  
B ay esi an R e pe ate d M eas ures  
CI  
C o nfi d enc e I nt erval  
C Lr  
R e n al cl ear a nc e  
C L  
Syst e mic cl e ar anc e of par ent dr ug  
C L/ F  
A p p are nt cle ar a nce foll o wi n g or al dosi n g  
C m ax  
M axi m u m o bs erv e d c o nce ntr ati o n  
C O 2  
C ar b o n Oioxi d e  
C P K  
Cr e ati n e p h osp hoki n ase  
C P M S  
Cli nic al P h ar mac oki netics M o d eli n g & Si mul atio n  
C P S R  
Cli nic al  P h ar mac ol ogy Stu dy R e p ort  
C P S S O  
Cli nic al P h ar mac ol ogy Sci enc e & St u dy O per ati ons  
e C R F  
El ectr o nic C ase R e port F or m  
C S M E  
Cli nic ally Si g nific a nt Mac ul ar E d e m a ( 
)  
C S S R S  
S uici d ality Sev erity R ati ng Sc al e  
C tr o u gh 
Pr e -d os e Tr ou gh C o nce ntr ati o n m e asur e d at e n d of d osi n g i nterv al  
C V  
C o effici e nt of vari ati on  
D A  
Disc Ar e a  
D B P  
Di ast olic bl o o d pr essur e  
D M  
Di a b et es M ellit us  
D M E  
Di a b etic M ac ular E d e m a  
D M P K  
Dr u g M et a b olis m a nd P har m ac oki n etics  
D N A  
D e oxyri b o nucl eic aci d  
D R  
Di a b etic R etin o pat hy  
E C G  
El ectr oc ar di ogr a m  
E V A  
El ectr o nic Visu al Acuity  
F D A  
F o o d a n d Dr u g A d mi nistr atio n  
G L P  
G o o d L ab or atory Pr actic e  
G S K  
Gl ax o S mit h Kli ne  
C CI
C CI
C CI
C CI
C CI


 
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Abbreviation 
Description 
HbA1c 
Glycated Hemoglobin 
HBsAg 
Hepatitis B surface antigen 
h/hr 
Hour(s) 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDSL 
Integrated Data Standards Library 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IU 
International Unit 
IV 
Intravenous 
Kg 
Kilogram 
L 
Liter 
LDL 
Low-density lipoprotein 
LE 
Left Eye 
LFTs 
Liver function tests 
ln 
Naperian (natural) logarithm 
LLQ 
Lower limit of quantification 
Lp-PLA2 
Lipoprotein associated phospholipase A2 
µg 
Microgram 
µL 
Microliter 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligrams 
mL 
Milliliter 
msec 
Milliseconds 
MMRM 
Mixed Models Repeated Measures 
NCA 
Non-Compartmental Analysis 
NQ 
Non-quantifiable concentration measured as below LLQ 
NVD 
New Vessels on Disc 
NVE 
New Vessels – Elsewhere 
SD-OCT 
Optical coherence tomography 
PA 
Preliminary Analysis 
PC 
Phosphatidyl choline 
PD 
Pharmacodynamic 
PDR 
Proliferative Diabetic Retinopathy 
PGx 
Pharmacogenetics 
pH 
Power of Hydrogen 
PK 
Pharmacokinetic 
PoC 
Proof of Concept 
Pop 
Population 
QC 
Quality control 
RAGE 
Receptor for advanced glycation end products 
RBC 
Red blood cells 


 
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Abbreviation 
Description 
RE 
Right Eye 
RNA 
Ribonucleic acid 
SAC 
Final Statistical Analysis Complete 
SAE 
Serious adverse event(s) 
SAP 
Statistical and Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Standard deviation 
SD-OCT 
Spectral domain optical coherence tomography 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOP 
Standard Operating Procedure 
SPM 
Study Procedures Manual 
STL 
Study Lead Statistician 
t1/2 
Apparent Terminal Elimination Half-Life 
tlast 
Time of last observed quantifiable concentration 
ULN 
Upper limit of normal 
UK 
United Kingdom 
US 
United States 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White blood cells 
11.9.2. 
Trademarks  
 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
MONOLIX  
 
 
NONMEM  
 
 
RStudio 
 
 
SAS 
 
 
WinNonlin Professional 
 
 


 
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11.10. 
Appendix 10: List of Data Displays  
 
Data displays include a combination of displays from standardized GSK IDSL library 
(with a corresponding reference number as GSK_XXX), IQVIA specific displays 
(referenced as IQVIA_Tx or IQVIA_Lx) and custom, non-standard displays. 
 
A separate document provided the TFL templates is provided with this SAP. These 
templates describe the presentations for this study and therefore the format and content of 
the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
 
11.10.1. 
Data Display Numbering  
 
The following numbering will be applied for SAP generated displays: 
 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.8 
None 
Safety 
3.1 to 3.22 
None 
Pharmacokinetic 
4.1 
None 
Pharmacodynamic  
6.1 to 6.7 
6.1 to 6.3 
Section 
Listings 
ICH Listings 
1 to 13 
Other Listings 
14 to 34 
 
11.10.2. 
Mock Example Shell Referencing  
 
Nonstandard specifications will be referenced as indicated and example mock-up displays 
provided in Appendix 11: Example Mock Shells for Data Displays, and accompanying 
shells document. 
 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
Pharmacodynamic  
PD_Fn 
PD_Tn 
PD_Ln 
NOTES:  
 
Non-Standard displays are indicated in the ‘GSK Statistical Display Standard / Example Shell’ or ‘Programming 
Notes’ column as ‘[Non-Standard] + Reference.’ 
 
11.10.3. 
Deliverables  
 
This section includes deliverables of the IQVIA Statistics and Programming Functions. 
 
Delivery  
Description 
PA 
Preliminary Analysis (also referred to as the End of Treatment Analysis) 
SAC  
Final Statistical Analysis Complete 


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
4 1  
 
1 1. 1 0. 4.  
St u d y P o p ul ati o n  T a bl e s   
 
St u d y P o p ul ati o n T a ble s  
N o.  
P o p ul ati o n  
G S K St a n d ar d   / 
E x a m pl e S h ell  
S h ell I D ( O ut p ut I D)  Titl e   
Pr o gra m mi n g N ot e s  
D eli v er a bl e [ Pri orit y] 
S u bj e ct Di s p o siti o n  
1. 1.                 
Scr e e n e d  
G S K _ E S 6    
G S K _ E S 6  
S u m m ary of Scr e eni n g Stat us 
a n d R e as ons f or Scr e e n 
F ail ur e  
I C H E3   
S A C [ 1]  
1. 2.                 
S af ety  
G S K _ E S 1  
G S K _ E S 1  
S u m m ary of S u bject 
Dis p ositi o n f or t h e S ubj ect 
C o ncl usi o n R ec or d  
I C H E3, Pr es e nt t h e d at a 
by 2 gr o u ps m S af ety, 
Sit e #
S A C [ 1]  
  
1. 3.                 
S af ety  
G S K _ S D 1  
G S K _ S D 1  
S u m m ary of Tr e at m e nt St at us 
a n d R e as ons f or 
Disc o nti n u ati o n of Stu dy 
Tr e at m e nt  
I C H E3, Pr es e nt t h e d at a 
by 2 gr o u ps m S af ety, 
Sit e #
S A C [ 1]  
 
 
 
Pr ot o c ol De vi ati o n  
 
P P D
P P D


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
4 2  
 
St u d y P o p ul ati o n T a ble s  
N o.  
P o p ul ati o n  
G S K St a n d ar d   / 
E x a m pl e S h ell  
S h ell I D ( O ut p ut I D)  Titl e   
Pr o gra m mi n g N ot e s  
D eli v er a bl e [ Pri orit y] 
1. 4.                 
E nr oll e d  
G S K _ D V 1  
G S K _ D V 1  
S u m m ary of I mp ort a nt 
Pr ot oc ol D evi ati o ns  
I C H E3. R e p ort o nly t h e 
pr ot oc ol d evi ati o ns w hic h 
ar e d efi n e d as i m p ort a nt.  
S A C [ 1]  
 
Pr es e nt t h e d at a by 3 
gr o u ps E nr oll e d, ms af ety 
a n d Sit e #
 
P o p ul ati o n A n al y s e d  
 
1. 5.                 
E nr oll e d  
G S K _ S P 1  
G S K _ S P 1  
S u m m ary of St u dy 
P o p ul atio ns  
  
S A C [ 1]  
 
De m o gra p hi c a n d Ba seli n e C h ar a ct eri sti c s  
 
1. 6.                 
S af ety  
G S K _ D M 1  
G S K _ D M 1  
S u m m ary of D e m ogr a p hic 
C h ar act eristics  
I C H E3, F D A A A, E u dr a C T 
S A C [ 1]  
 
Pr es e nt t h e d at a by 2 
gr o u ps m S af ety, Sit e #
 
1. 7.                 
m S af ety  
P O P _ T 1  
P O P _ T 1  
S u m m ary of Di a b et es Ty p e 
by P o p ulati o n  
Ty p e 1 a n d Ty p e 2  
S A C [ 1]  
 
1. 8.                 
m S af ety  
G S K _ V S 1  
DI A B _ T 1  
S u m m ary of Di a b et es 
D ur ati o n  
I n y e ars 
S A C [ 1]  
 
 
P P D
P P D


 
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11.10.5. 
Safety Tables  
 
Safety: Tables 
No. 
Population 
GSK Standard/ 
Example Shell 
Shell ID (Output ID) 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
3.1.    
Safety 
GSK_AE13 
GSK_AE_SUM 
Summary of Overall and Ocular Adverse 
Events  
Please display study eye 
and fellow-eye 
separately as by 
groups.    
SAC [1] 
3.2.    
mSafety 
GSK_AE13 
GSK_AE_SUM_mSAF 
Summary of Overall and Ocular Adverse 
Events  
SAC [1] 
3.3. 
mSafety 
IQVIA_T2 
AE007 
Incidence of Ocular and Non-Ocular 
Adverse Events by System Organ Class 
and Preferred Term 
SAC [1] 
3.4 
mSafety 
IQVIA_T2 
AE025 
Incidence of Serious Ocular and Non-
Ocular Adverse Events by System Organ 
Class and Preferred Term 
SAC [1] 
3.5 
mSafety 
IQVIA_T2 
AE013 
Incidence of Drug-Related Ocular and 
Non-Ocular Adverse Events by System 
Organ Class and Preferred Term 
SAC [1] 
3.6 
mSafety 
IQVIA_T2 
AE014 
Incidence of Serious Drug-Related 
Ocular and Non-Ocular Adverse Events 
by System Organ Class and Preferred 
Term 
SAC [1] 
3.7 
mSafety 
GSK_AE5A 
AE019 
Incidence of Ocular and Non-Ocular 
Adverse Events by System Organ Class 
and Preferred Term and Maximum 
Severity 
SAC [1] 


 
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Safety: Tables 
No. 
Population 
GSK Standard/ 
Example Shell 
Shell ID (Output ID) 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.8 
mSafety 
GSK_AE15 
AE030 
Summary of On-Treatment Common 
(>=x%) Non-serious Adverse Events by 
System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
SAC [1] 
COVID-19 related AEs 
3.9 
mSafety 
GSK_PAN1 
GSK_PAN1 
Summary of COVID-19 Assessments for 
Subjects with COVID-19 Adverse Events 
  
SAC [1] 
3.10 
mSafety 
GSK_PAN2 
GSK_PAN2 
Summary of COVID-19 Additional 
Assessments for Subjects with 
Suspected, Probable or Confirmed 
COVID-19 Case Diagnosis 
  
SAC [1] 
3.11 
mSafety 
IQVIA_PAN1 
IQVIA_PAN1 
Summary of time to onset and duration 
of first occurrence of COVID-19 Adverse 
Events 
Optional, only  if 
>25% participants 
reported ≥ 1 COVID-
19 AE/SAE 
SAC [1] 
Laboratory: Chemistry including LFT 
3.12 
mSafety 
GSK_LB1 
Chem001 
Summary of Chemistry including Liver 
Function Test Changes from Baseline 
Include LFT parameters 
SAC [1] 
3.13 
mSafety 
GSK_LB17 
Chem002 
Summary of Worst-Case Chemistry 
including Liver Function Test Results by 
PCI Criteria  
Include LFT 
parameters 
SAC [1] 
Post-Baseline Relative to Baseline 


 
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Safety: Tables 
No. 
Population 
GSK Standard/ 
Example Shell 
Shell ID (Output ID) 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Hematology 
3.14 
mSafety 
GSK_LB1 
Hem001 
Summary of Hematology Changes from 
Baseline 
  
SAC [1] 
3.15 
mSafety 
GSK_LB17 
Hem002 
Summary of Worst-Case Hematology 
Results by PCI Criteria 
  
SAC [1] 
Post-Baseline Relative to Baseline 
Laboratory: Urinalysis 
3.16 
mSafety 
GSK_UR1 
UR001 
Summary of Worst Case Urinalysis 
Results Post-Baseline Relative to 
Baseline 
  
SAC [1] 
ECG 
3.17 
mSafety 
IQVIA_T10 
EG001 
 Summary of ECG Values and Change 
from Baseline 
  
SAC [1] 
3.18 
mSafety 
IQVIA_T11 
EG002 
Summary of Shift from Baseline in ECG 
Findings  
  
SAC [1] 
Vital Signs 
3.19 
mSafety 
IQVIA_T10 
VS001 
Summary of Vital Signs Values and 
Change from Baseline Findings 
  
SAC [1] 
3.20 
mSafety 
IQVIA_T13 
VS002 
Summary of Subjects with Vital Sign 
Results outside PCI Ranges 
  
SAC [1] 


 
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Safety: Tables 
No. 
Population 
GSK Standard/ 
Example Shell 
Shell ID (Output ID) 
Title  
Programming Notes 
Deliverable 
[Priority] 
Columbia Suicidality Severity Rating Scale (CSSRS) 
 
3.21 
mSafety 
GSK_CSSRS1   
CSSR01 
Summary of Subjects with C-SSRS 
Suicidal Ideation or Behaviour during 
Treatment 
  
SAC [1] 
3.22 
mSafety 
GSK_CSSRS3 
CSSR02 
Shift Table of Changes in C-SSRS 
Categories from Pre-Treatment to On-
Treatment 
  
SAC [1] 
3.23 
mSafety 
IQVIA_T13 
EG003 
Summary of Subjects with ECG Results 
outside PIC Ranges 
 
SAC [1] 


 
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11.10.6. 
Safety Figures  
 
Not planned due to small sample size. 
 


 
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11.10.7. 
Pharmacokinetic Tables  
 
Pharmacokinetic: Tables 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Shell ID (Output 
ID) 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
GSK2798745 and M1 Metabolite 
4.1.    
PK 
GSK_PK01 
PK001 
Summary of GSK2798745 and M1 metabolite 
Pharmacokinetic Concentration-Time Data 
  
SAC [1] 
 
 


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
4 9  
 
1 1. 1 0. 8.  
P h ar m a c o d y n a mi c T a bl e s   
 
P h ar m a c o d y n a mic: T a bl e s     
N o.  
P o p ul ati o n  
G S K 
St a n d ar d/ 
E x a m pl e S h ell  
S h ell I D 
( O ut p ut I D) 
Titl e   
Pr o gra m mi n g N ot e s  
D eli v er a bl e [ Pri orit y] 
S D -O C T  
6. 1.     
P D  
P D _ T 1  
P D 0 0 1  
S u m m ary of  C e nt er Su bfi el d R eti n al 
T hickn ess i n th e St u dy a n d Fell o w -Ey e as 
M e as ure d by S D -O C T, i ncl u din g c h a ng e 
fr o m b as elin e. 
Pr es e nt st u dy ey e a n d f ell o w ey e 
as s e p ar at e by gr o u ps    
P A, S A C [ 1]  
6. 2.     
P D  
P D _ T 2  
P D 0 0 2  
B ay esia n A n alysis of C h an g e fr o m 
B as eli ne i n C e nt er S u bfiel d Reti n al 
T hickn ess i n th e St u dy a n d Fell o w Ey e as 
M e as ure d by S D -O C T  at D ay 2 8  ( Day 2 8 
C o m pl et ers A n alysis)  
I ncl u d es o nly s u bj ects w h o h av e 
c o m pl et e d D ay 2 8 
P A, S A C [ 1]  
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
5 0  
 
P h ar m a c o d y n a mic: T a bl e s     
N o.  
P o p ul ati o n  
G S K 
St a n d ar d/ 
E x a m pl e S h ell  
S h ell I D 
( O ut p ut I D) 
Titl e   
Pr o gra m mi n g N ot e s  
D eli v er a bl e [ Pri orit y] 
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
5 1  
 
P h ar m a c o d y n a mic: T a bl e s     
N o.  
P o p ul ati o n  
G S K 
St a n d ar d/ 
E x a m pl e S h ell  
S h ell I D 
( O ut p ut I D) 
Titl e   
Pr o gra m mi n g N ot e s  
D eli v er a bl e [ Pri orit y] 
Ot h er E x pl orat ory E n d p oi nts  
 
 
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
5 2  
 
1 1. 1 0. 9.  
P h ar m a c o d y n a mi c Fi g ur e s   
 
P h ar m a c o d y n a mic: Fi g ur e s  
N o.  
P o p ul ati o n  
G S K 
St a n d ar d/ 
E x a m pl e S h ell  
S h ell I D ( O ut p ut 
I D) 
Titl e   
Pr o gra m mi n g N ot e s  
D eli v er a bl e [ Pri orit y]  
S D -O C T  
6. 1.     
P D  
S A F E _ F 2  
P D FI G 0 0 1  
I n divid u al Pl ot of C ha n g e fr o m 
B as eli ne i n C e nt er S u bfiel d Reti n al 
T hickn ess i n th e St u dy Ey e as 
M e as ure d by S D -O C T  
M ock s h ell pr ovi d e d is a n 
ex a m pl e fi g ur e, n ot st u dy 
s p ecific 
X -axis is visit, Y -axis is 
c h a n g e fr o m b as eli n e i n 
c e nt er s u bfi el d r eti n al 
t hick n ess. 
G e n er al c o m m e nt: F or m at t h e 
i nt erv als b as e d o n t h e i nt erv al 
of ti m e.  
P A, S A C [ 1]   
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
5 3  
 
P h ar m a c o d y n a mic: Fi g ur e s  
N o.  
P o p ul ati o n  
G S K 
St a n d ar d/ 
E x a m pl e S h ell  
S h ell I D ( O ut p ut 
I D) 
Titl e   
Pr o gra m mi n g N ot e s  
D eli v er a bl e [ Pri orit y]  
S D -O C T &
 
6. 3.     
P D  
S A F E _ F 2  
P D FI G 0 1 1  
C orr el ati o n Pl ot of C ha n g e fr o m 
B as eli ne i n O C T v ers us 
at D ay 
2 8 . 
M ock s h ell pr ovi d e d is a n 
ex a m pl e fi g ur e, n ot st u dy 
s p ecific.  
X -axis is C F B of 
at D ay 
2 8 , Y-axis is C F V of S D O C T 
at D ay 2 8. Als o pr es e nt 
Pe ars o n's C orr el ati o n 
c o effici e nt (r). 
S A C [ 1]  
 
 
 
C CI
C CI
C CI


 
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11.10.10. ICH Listings  
 
ICH: Listings 
No. 
Population 
GSK Standard / 
Example Shell 
Shell ID (Output 
ID) 
Title  
Programming Notes 
Deliverable [Priority] 
Subject Disposition 
1.         
Screened 
GSK_ES2  
GSK_ES2 
Listing of Reasons for Study 
Withdrawal 
ICH E3 
SAC [1] 
2.         
Safety 
GSK_SD2  
GSK_SD2 
Listing of Reasons for Study 
Treatment Discontinuation 
ICH E3 
SAC [1] 
Protocol Deviations 
 
3.         
Enrolled 
GSK_DV2  
GSK_DV2 
Listing of Important Protocol 
Deviations  
ICH E3 
SAC [1] 
 
4.         
Enrolled 
GSK_IE3  
GSK_IE3 
Listing of Subjects with 
Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
SAC [1] 
 
Populations Analysed 
 
5.         
Enrolled 
GSK_SP3  
GSK_SP3 
Listing of Subjects Excluded 
from Any Population 
ICH E3 
SAC [1] 
 
Demographic and Baseline Characteristics 
 
6.         
Safety 
GSK_DM2 
DEMO 
Listing of Demographic 
Characteristics 
ICH E3 
SAC [1] 
 
7.         
Safety 
GSK_DM9 
RACE 
Listing of Race 
ICH E3. Use Geographic 
ancestry data. 
SAC [1] 
 
Exposure and Treatment Compliance 
 


 
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ICH: Listings 
No. 
Population 
GSK Standard / 
Example Shell 
Shell ID (Output 
ID) 
Title  
Programming Notes 
Deliverable [Priority] 
8.         
Safety 
GSK_EX3  
Exposure 
Listing of Exposure 
ICH E3 
SAC [1] 
 
9.1         
Safety 
GSK_COMP2a 
Compliance 
Listing of Compliance 
ICH E3 
SAC [1] 
 
9.2 
Safety 
GSK_COMP2a 
Noncompl_Reason 
Listing of Reasons for Non-
Compliance 
ICH E3 
SAC [1] 
 
Adverse Events 
 
10.      
Safety 
GSK_AE8 
AEList1 
Listing of All Adverse Events  
ICH E3;  
PA, SAC [1] 
 
11.      
Safety 
GSK_AE8 
AEList3 
Listing of Adverse Events 
Leading to Permanent 
Discontinuation of Study 
Treatment or Withdrawal from 
Study 
ICH E3 
SAC [1] 
 
Serious Adverse Events 
 
12.      
Safety 
GSK_AE8 
AEList5 
Listing of Serious Adverse 
Events  
ICH E3 
SAC [1] 
 
All Laboratory 
 
13.      
Safety 
IQVIA_L1 / 
GSK_LB5 
LABList 
Listing of All Laboratory Data 
for Subjects including Any 
Value of Potential Clinical 
Importance 
ICH E3; include LFT and 
Urinalysis parameters 
SAC [1] 
 
 
 


 
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11.10.11. Non-ICH Listings  
 
Non-ICH: Listings 
No. 
Population 
GSK Standard GSK 
Statistical Display 
Standard / Example 
Shell 
Shell ID (Output ID) 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition  
14 
Screened 
GSK_ES7 
SCRFail 
Listing of Reasons for 
Screen Failure 
Journal Guidelines 
SAC [1] 
Prior and Concomitant Medications 
15 
Safety 
GSK_CM3 
PM1 
Listing of Diabetes 
Information 
Listing-Other; Including 
Diabetes type, length of 
duration (in years)  
SAC [1] 
16 
Safety 
GSK_CM3 
MH1 
Listing of Medical 
History 
  
SAC [1] 
17 
Safety 
GSK_CM3 
PM2 
Listing of Prior 
Medication by Generic 
Term 
For prior, including a column 
of relative time to first dosing 
day (Day 1) (in months, if 
month is missing, use 
December); DME 
medication4  
SAC [1] 
Listing-Other 
18 
Safety 
GSK_CM3 
CM1 
Listing of Concomitant 
Medication by Generic 
Term 
  
SAC [1] 
19 
Safety 
NA 
LASERLIST 
Listing of Laser History 
  
SAC [1] 
Adverse Events 
20 
Safety 
GSK_PAN7 
COVList 
Listing of All Subjects 
with Visits or 
Assessments 
  
SAC [1] 


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
5 7  
 
N o n -I C H: Li sti n g s 
N o.  
P o p ul ati o n  
G S K St a n d ar d G S K 
St ati sti c al Di s pl ay 
St a n d ar d / E x a m pl e 
S h ell  
S h ell I D ( O ut p ut I D)  
Titl e   
Pr o gra m mi n g N ot e s  
D eli v er a bl e 
[ Pri orit y] 
I m p acte d by C O VI D-
1 9  
He p at o bili ar y ( Li v er)  
2 1  
S af ety  
I Q VI A _ L 2 
L F T List  
Listi ng of F ol d U L N f or 
L F Ts  
  
S A C [ 1]  
O p ht h al m ol o gi c al A s s es s me nt s  
2 2  
P D  
S A F E _ T 2  
O P T 0 0 1  
Listi ng of G e n er al 
O p ht h al mic 
Ex a mi nati o ns D at a 
i ncl udi n g 
A b n or m aliti es of 
P ot e nti al Cli nic al 
I m p ort a nc e 
I ncl u d e all s u bj ects i n t h e 
listi n g e x cl u di n g S D -O C T 
a n d
a n d fl a g a ny 
v al u es of p ot e nti al cli nic al 
i m p ort a nc e 
S A C [ 1]  
2 3  
P D  
S A F E _ T 3  
O P T 0 0 2  
Listi ng of A bs ol ute a n d 
C h a n g e fr o m b aseli ne 
i n S D-O C T Nu m eric 
E n d p oi nts f or b ot h 
ey es i nclu di ng 
A b n or m aliti es of 
P ot e nti al Cli nic al 
I m p ort a nc e   
I ncl u d e all s u bj ects i n t h e 
listi n g a n d fl a g a ny v al u es of 
p ot e nti al cli nic al i m p ort a nc e  
S A C [ 1] 
2 4  
P D  
S A F E _ T 4  
O P T 0 0 3  
Listi ng of S D -O C T 
N o n -n u m eric 
E n d p oi nts f or b ot h 
ey es i nclu di ng 
I ncl u d e all s u bj ects i n t h e 
listi n g a n d fl a g a ny v al u es of 
p ot e nti al cli nic al i m p ort a nc e  
S A C [ 1]  
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
5 8  
 
N o n -I C H: Li sti n g s 
N o.  
P o p ul ati o n  
G S K St a n d ar d G S K 
St ati sti c al Di s pl ay 
St a n d ar d / E x a m pl e 
S h ell  
S h ell I D ( O ut p ut I D)  
Titl e   
Pr o gra m mi n g N ot e s  
D eli v er a bl e 
[ Pri orit y] 
A b n or m aliti es of 
P ot e nti al Cli nic al 
I m p ort a nc e   
2 5  
P D  
S A F E _ T 3  
O P T 0 0 4  
Listi ng of A bs ol ute a n d 
C h a n g e fr o m B as eli n e 
i n 
N u m eric 
E n d p oi nts f or St u dy 
a n d F ell o w Ey es 
i ncl udi n g 
A b n or m aliti es of 
P ot e nti al Cli nic al 
I m p ort a nc e   
I ncl u d e all s u bj ects i n t h e 
listi n g a n d fl a g a ny v al u es of 
p ot e nti al cli nic al i m p ort a nc e  
S A C  [ 1] 
2 6  
P D  
S A F E _ T 4  
O P T 0 0 5  
Listi ng of 
N o n -
n u m eric E n d p oi nts f or 
b ot h ey es incl ud e d 
A b n or mliti es of 
P ot e nti al Cli nic al 
I m p ort a nc e 
I ncl u d e all s u bj ects i n t h e 
listi n g a n d fl a g a ny v al u es of 
p ot e nti al cli nic al i m p ort a nc e  
S A C [ 1]  
2 7  
P D  
S A F E _ T 3  
O P T 0 0 6  
Listi ng of A bs ol ute a n d 
C h a n g e fr o m b aseli ne 
i n 
a n d
E n d p oi nts f or b ot h 
ey es i nclu di ng 
A b n or m aliti es of 
P ot e nti al Cli nic al 
I m p ort a nc e   
I ncl u d e all s u bj ects i n t h e 
listi n g a n d fl a g a ny v al u es of 
p ot e nti al cli nic al i m p ort a nc e  
S A C [ 1]  
C CI
C CI
C CI
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 2 6 6 9  
 
5 9  
 
N o n -I C H: Li sti n g s 
N o.  
P o p ul ati o n  
G S K St a n d ar d G S K 
St ati sti c al Di s pl ay 
St a n d ar d / E x a m pl e 
S h ell  
S h ell I D ( O ut p ut I D)  
Titl e   
Pr o gra m mi n g N ot e s  
D eli v er a bl e 
[ Pri orit y] 
2 8  
P D  
S A F E _ T 4  
O P T 0 0 7  
Listi ng of 
an d 
N o n -n u m eric 
E n d p oi nts f or b ot h 
ey es i nclu di ng 
A b n or m aliti es of 
P ot e nti al Cli nic al 
I m p ort a nc e   
  
S A C [ 1]  
E C G  
2 9  
S af ety  
I Q VI A _ L 3 
E C G LI S T 0 1  
Listi ng of I ndivi d u al 1 2 -
l e a d E C G R es ults 
i ncl udi n g A ny V al ue of 
P ot e nti al Cli nic al 
I m p ort a nc e 
  
S A C [ 1]  
3 0  
S af ety  
G S K _ E G 5  
E C G LI S T 0 2  
Listi ng of All E C G 
Fi n di n gs f or S ubj ects 
wit h a n A b n or m al 
Fi n di n g  
  
  
Vit al Si g n s  
3 1  
S af ety  
I Q VI A _ L 5 
V S LI S T 0 1  
Listi ng of I ndivi d u al 
Vit al Si g ns R es ults 
i ncl udi n g A ny V al ue of 
P ot e nti al Cli nic al 
I m p ort a nc e 
  
S A C [ 1]  
C CI
C CI


 
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Non-ICH: Listings 
No. 
Population 
GSK Standard GSK 
Statistical Display 
Standard / Example 
Shell 
Shell ID (Output ID) 
Title  
Programming Notes 
Deliverable 
[Priority] 
Columbia Suicidality Severity Rating Scale (CSSRS) 
32 
Safety 
GSK_CSSRS4 
CSSRLIST01 
Listing of  C-SSRS 
Suicidal Ideation and 
Behaviour Data 
  
SAC [1] 
PK Endpoints 
33 
PK 
GSK_PK07 
PKLIST001 
Listing of GSK279845 
and M1 Metabolite 
Plasma 
Pharmacokinetic 
Concentration-Time 
Data [intensive & 
Ctrough samples] 
  
SAC [1] 
34 
PK 
GSK_PK13 
PKLIST002 
Listing of Derived 
GSK279845 and M1 
Metabolite Plasma 
Pharmacokinetic 
Paramaters [intensive 
& Ctrough samples] 
  
SAC [1] 
 
 


 
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11.11. 
Appendix 11: Example Mock Shells for Data Displays   
 
Please refer to the mock shells document.