Conditions: Wound Healing
Keywords: diabetic foot ulcer pharmacodynamics pharmacokinetics ischemic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 65
Healthy volunteers: yes

Brief summary:
This is a randomized, placebo-controlled, single-blind (subjects and investigators will be blinded, GSK internal personnel will not be blinded), parallel-group, two part (Part A, Part B) trial in healthy volunteers and subjects with diabetic foot ulcers. Part A is designed to evaluate single applications of GSK1278863 in one cohort of healthy volunteers (intact skin) and approximately 3 cohorts of diabetic subjects. Part B is designed to evaluate first single, and then repeat applications of GSK1278863 in diabetics, both in the clinic and by subjects at home. Part B will include approximately 3 cohorts in which the concentration of drug applied will be determined by pharmacokinetic data from Part A and earlier cohorts in Part B.

Detailed description:

Arms:
arm 1: Healthy subjects in this arm will receive single applications of GSK1278863 or placebo (with 6:2 ratio) on intact skin in two escalating dosing periods each separated by 10 days. The first application will be with a single dose of 0.3 mg and second application will be single dose of 3 mg. arm 2: Subjects with diabetic foot ulcer (DFU) will receive a single application of GSK1278863 or placebo (with 6:2 ratio) in two dosing periods separated by 10 days. The first application will be made on intact skin and second application directly on DFU. Dose will be based on wound area and review from previous cohort data. arm 3: Subjects with DFU will receive single application of GSK1278863 or placebo directly on DFU. Dose will be based on wound area and review from previous cohort data. arm 4: Subjects with DFU will receive a single application of GSK1278863 or placebo (with 6:2 ratio) in two dosing periods separated by 10 days. The first application will be made on DFU and second application on intact skin. Dose will be based on wound area and review from previous cohort data. arm 5: Subjects with DFU will receive Standard of care (SOC) up to 15 days and then will be randomized to one of the three arms: GSK1278863 + SOC, or SOC only, or placebo + SOC with ratio of 12:2:2. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part A. subjects will first be given a single application of GSK1278863 or placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then repeat applications for 14 days, starting on Day 8. arm 6: Subjects with DFU will receive Standard of care (SOC) up to 15 days and then will be randomized to one of the three arms: GSK1278863 + SOC, or SOC only, or placebo + SOC with ratio of 12:2:2. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part A. subjects will first be given a single application of GSK1278863 or placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then repeat applications for 14 days, starting on Day 8. arm 7: Subjects with DFU will receive Standard of care (SOC) up to 15 days and then will be randomized to one of the three arms: GSK1278863 + SOC, or SOC only, or placebo + SOC with ratio of 12:2:2. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part A. subjects will first be given a single application of GSK1278863 or placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then repeat applications for 14 days, starting on Day 8.

Interventions: intervention 1: GSK1278863 intervention 2: Placebo
Intervention descriptions: intervention 1: White to off-white smooth ointment with unit dose strength of 0.05%w/w, 0.1%w/w, 0.5%w/w, 1.0%w/w for topical application as single or repeat doses. intervention 2: White to off-white smooth ointment for topical application as single or repeat doses.

Protocol document:
Prot_000.pdf: 
2011N130130_09
CONFIDENTIAL
The GlaxoSmithKline group of companies
PWH115760
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
Phase I Trial to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of Single Doses of 
Topical GSK1278863 in Healthy Volunteers and Diabetic 
Patients, and Repeat Doses of GSK1278863 in Diabetic Patients 
for the Treatment of Diabetic Foot Ulcer
Compound Number:
GSK1278863
Development Phase:
I
Effective Date:
31-JUL-2016
Protocol Amendment Number:  8
Author (s):
Clinical Pharmacology Science and Study Operations
Clinical Pharmacology Science and Study Operations
Discovery Medicine Heart Failure DPU, MPC
Discovery Medicine Heart Failure DPU, MPC
Clinical Statistics, MPC
Clinical Pharmacokinetics, Modeling and Simulations
Tahoma Research
Tahoma Research
University of Texas Southwestern Medical Center 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


2011N130130_09
CONFIDENTIAL
PWH115760
2
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2011N130130_00
2012-SEP-07
Original
2011N130130_01
2012-NOV-21
Amendment No.:01 
This amendment reflects changes to the patient eligibility criteria, stopping criteria and 
sampling time points per regulatory feedback.
2011N130130_02
2013-FEB-14
Amendment No.: 02 
This amendment reflects changes to DFU patient eligibility criteria number 7 and 
screening procedures in Part A as well as minor edits for clarity.
2011N130130_03
2013-JUN-06
Amendment No.: 03 
This amendment clarifies an eligibility criterion and DFU clinical assessments as well as 
minor edits for clarity.
2011N130130_04
2014-JAN-29
Amendment No.: 04 
This amendment reflects changes in the container type used to supply the bulk ointment.  
Minor edits are also included for clarity.
2011N130130_05
2014-JUN-02
Amendment No. 05
This amendment reflects modifications to the DFU inclusion and exclusion criteria, 
hemoglobin stopping criteria and a change in biopsy collection expectations.  Minor edits 
are also included for clarity.  
2011N130130_06
2014-JUN-09
Amendment No. 05
Amendment 5 was republished before distribution, with the DNG number of 
2011N130130_06, in order to correct an error.
2011N130130_07
2014-NOV-19
Amendment No. 06
Due to emerging data, specific areas of Part B of the protocol were redesigned to better 
meet the needs of the study.  To date Part A GSK1278863 systemic exposure is below 
analytical limits of quantification and therefore the stand alone single dose assessement in 
Part B is no longer required.  Eclusion criteria number 10 was adjusted to better  reflect 
the patient population.  Other minor edits were also included for clarity.  
2011N130130_08
2016-JAN-12
Amendment No. 07
This amendment contains modifications to inclusion/exclusion criteria.  Other changes 
include updates to Part B that occurred in stream based on emerging data, but did not 
require a protocol amendment.  Other minor edits for clarity.
2011N130130_09
2016-JUL-31
Amendment No. 08
This amendment provides the addition of lactating/nursing females to the exclusion 
criteria and includes the rationale for the modifications to the inclusion/exclusion criteria 
in amendment 7 per regulatory feedback.


2011N130130_09 
CONFIDENTIAL 
 
 
PWH115760 
 
3 
SPONSOR SIGNATORY 
 
 
 
 
 
Laura Demopoulos, MD 
 
 
Date 
SM Director, 
MPC Performance Unit 
31 July 2016
PPD
PPD


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SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax Number
GSK Address
Primary 
Medical 
Monitor
 
 MD 
709 Swedeland 
Rd. 
King of Prussia, 
PA 19406 
Secondary 
Medical 
Monitor
MD
709 Swedeland 
Rd. 
King of Prussia, 
PA 19406
Tertiary 
Medical 
Monitor
MD 
UM2523 
709 Swedeland 
Rd.
King of Prussia, 
PA 19406
Sponsor Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s):  IND 114,886
PPD
PPD
PPD
PPD
PPD


2011N130130_09
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5
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number PWH115760
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


2011N130130_09
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TABLE OF CONTENTS
PAGE
ABBREVIATIONS .........................................................................................................11
1.
INTRODUCTION....................................................................................................16
1.1.
Background ................................................................................................16
1.2.
Clinical Experience with GSK1278863........................................................18
1.3.
Rationale ....................................................................................................18
1.4.
Study Design Strategy ................................................................................19
1.4.1.
Dose Rationale ............................................................................20
1.4.1.1.
Single Dose Strategy..................................................20
1.4.1.2.
Single Dose Selection Rationale.................................22
1.4.1.3.
Repeat Dosing............................................................27
1.4.1.4.
Repeat Dose Rationale ..............................................28
1.5.
Summary of Risk Management...................................................................28
1.5.1.
Risks Relating to GSK1278863....................................................28
2.
OBJECTIVE(S) ......................................................................................................29
2.1.
Primary.......................................................................................................29
2.2.
Exploratory .................................................................................................30
2.2.1.
To evaluate the effect of single doses of GSK1278863 on...........30
2.2.2.
To evaluate the effect of repeat doses of GSK1278863 on..........30
3.
ENDPOINT(S)........................................................................................................30
3.1.
Primary.......................................................................................................30
3.2.
Exploratory .................................................................................................31
3.2.1.
After single doses of GSK1278863 (as data permit based 
on sampling feasibility).................................................................31
3.2.2.
After repeat doses of GSK1278863 (as data permit based 
on sampling feasibility).................................................................31
3.3.
Descriptions of Selected Endpoints.............................................................32
3.3.1.
Gene Expression Analysis ...........................................................32
3.3.2.
Biomarker Analysis ......................................................................32
3.3.2.1.
Cytokines and Growth Factors ...................................32
3.3.2.2.
Quantification of CD68+ Macrophages.......................32
3.3.2.3.
Cell Proliferation and Collagen Turnover ....................32
3.3.3.
Bacterial Load Determination.......................................................33
3.3.4.
Tissue Concentration of GSK1278863.........................................33
3.3.5.
Angiogenesis: Tissue Perfusion Assessment/Oxygen 
Availability....................................................................................33
3.3.6.
Physical Indicators of DFU Healing..............................................34
3.3.7.
Clinical Characteristics of the Wound...........................................34
4.
INVESTIGATIONAL PLAN.....................................................................................35
4.1.
Study Design/Schematic.............................................................................35
4.2.
Discussion of Design and Treatment Plan ..................................................36
4.2.1.
Part A – Single Doses in Healthy Volunteers and DFU 
Patients (Cohorts 1 through 4).....................................................36
4.2.1.1.
Screening (Part A)......................................................37
4.2.1.2.
Cohort 1 – Healthy Volunteers (Part A).......................37


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4.2.1.3.
Run-In Period (Part A)................................................38
4.2.1.4.
Cohort 2 (Part A) ........................................................38
4.2.1.5.
Cohorts 3 and 4 (Part A).............................................38
4.2.1.6.
Optional Cohorts (Part A) ...........................................38
4.2.1.7.
Follow-up Visits ..........................................................39
4.2.2.
Part B –Repeat Doses in Diabetic Foot Ulcer Subjects 
(Cohorts 5, 6 and 7).....................................................................39
4.2.2.1.
Screening (Part B)......................................................40
4.2.2.2.
Run-In Period (Part B)................................................40
4.2.2.3.
Treatment Period – (Part B)........................................40
4.2.2.4.
Follow-up Visits ..........................................................41
4.3.
Treatment Assignment................................................................................41
4.3.1.
Subject Numbering ......................................................................43
4.4.
Investigational Product and Other Study Treatment 
Dosage/Administration................................................................................44
4.5.
Dose Adjustment/Stopping Criteria .............................................................44
4.5.1.
Dose Adjustment/Stopping Safety Criteria ...................................44
4.5.1.1.
Hemoglobin Stopping Criteria.....................................44
4.5.1.2.
Liver Chemistry Stopping Criteria ...............................45
4.5.1.3.
QTc Withdrawal Criteria .............................................45
4.5.1.4.
Other Dose Adjustment/Stopping Safety 
Criteria........................................................................46
4.6.
Time and Events Table...............................................................................47
4.6.1.
Time and Events Table Part A .....................................................47
4.6.2.
Time and Events Table Part B .....................................................50
4.6.3.
Serial PK Time and Events Table Part B......................................53
5.
STUDY POPULATION...........................................................................................54
5.1.
Number of Subjects ....................................................................................54
5.2.
Eligibility Criteria – Healthy Volunteers (Part A Cohort 1)............................54
5.2.1.
Inclusion Criteria - Healthy Volunteers (Part A Cohort 1) .............54
5.2.2.
Exclusion Criteria – Healthy Volunteers (Part A Cohort 1) ...........55
5.3.
Eligibility Criteria – DFU Subjects ...............................................................56
5.3.1.
Inclusion Criteria – DFU Subjects ................................................56
5.3.2.
Exclusion Criteria – DFU Subjects ...............................................58
5.4.
Screen and Baseline Failures .....................................................................59
6.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................59
6.1.
Hypotheses and Treatment Comparisons...................................................59
6.2.
Sample Size Considerations.......................................................................59
6.2.1.
Sample Size Assumptions ...........................................................59
6.2.2.
Sample Size Re-estimation..........................................................59
6.3.
Data Analysis Considerations .....................................................................59
6.3.1.
Interim Analysis ...........................................................................60
6.3.2.
Final Analyses .............................................................................60
6.3.2.1.
Safety Analyses..........................................................60
6.3.2.2.
Pharmacokinetic Analyses..........................................60
6.3.3.
Pharmacodynamic Data Analyses ...............................................60
6.3.3.1.
Wound Healing Endpoints (Part B).............................60
6.3.3.2.
mRNA, Protein and Biomarker Data Analysis.............61
6.3.3.3.
Other Pharmacodynamic Endpoints ...........................61
6.3.3.4.
Pharmacokinetic/Pharmacodynamic Analyses ...........61


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8
6.3.3.5.
Pharmacodynamic/Biomarker Analyses .....................61
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................62
7.1.
Demographic/Medical History Assessments ...............................................62
7.2.
Safety .........................................................................................................62
7.2.1.
Physical Exams ...........................................................................62
7.2.2.
Vital Signs....................................................................................63
7.2.3.
Electrocardiogram (ECG).............................................................63
7.2.4.
Clinical Laboratory Assessments .................................................63
7.3.
DFU Assessments......................................................................................64
7.3.1.
Part A ..........................................................................................64
7.3.2.
Part B ..........................................................................................64
7.4.
Standard of Care Treatment .......................................................................64
7.4.1.
Wound Bed Preparation and Debridement...................................65
7.5.
Gene Expression ........................................................................................65
7.5.1.
RNA Expression Research of a Subset of RNA Species..............66
7.5.2.
Proteome Research.....................................................................66
7.6.
HIF Alpha....................................................................................................66
7.7.
Biomarkers (e.g., Cytokines, Bioburden and Gene Expression) 
Collection and Processing ..........................................................................66
7.7.1.
Wound Fluid Collection Directions ...............................................67
7.7.2.
Punch Biopsy Directions..............................................................67
7.7.3.
Macrophages...............................................................................68
7.7.4.
Sample Collection for Macrophage Immunostaining ....................68
7.8.
Angiogenesis: Tissue Perfusion Assessment/Oxygen Availability...............68
7.8.1.
Vascular Perfusion.......................................................................68
7.8.1.1.
Instructions for Assessing Vascular Perfusion 
with SensiLase ...........................................................69
7.8.2.
Oxygen Dynamics/Angiogenesis .................................................69
7.8.2.1.
Hyperspectral Imaging Instructions.............................69
7.9.
Physical Characteristics of the DFU............................................................69
7.9.1.
Location of the Study Ulcer..........................................................69
7.9.2.
Instructions for Assessment of Physical Characteristics of 
the DFU - Wound Measurement and Photography ......................70
7.9.2.1.
Photo Capture – Wound Images.................................70
7.9.2.2.
Wound Tracings .........................................................70
7.9.2.3.
Depth and Volume Measurements .............................70
7.9.2.4.
Ulcer Size Reduction..................................................70
7.10.
Clinical Characteristics of the DFU..............................................................71
7.10.1.
Ulcer Exudate ..............................................................................71
7.10.2.
Ulcer Assessments......................................................................72
7.10.3.
Irritation Symptom Assessment ...................................................72
7.11.
Cell Proliferation and Collagen Turnover (Heavy Water 
Assessment)...............................................................................................73
7.12.
Pharmacokinetics .......................................................................................73
7.12.1.
PK Blood Sample Collection ........................................................73
7.12.2.
PK Blood Sample Analysis ..........................................................74
7.12.3.
PK Sampling Windows.................................................................74
7.12.4.
Sample Analysis ..........................................................................74
7.12.5.
Microdialysis ................................................................................74
7.13.
Pregnancy ..................................................................................................74
7.13.1.
Time Period for Collecting Pregnancy Information .......................74


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7.13.2.
Action to be Taken if Pregnancy Occurs ......................................75
8.
LIFESTYLE AND/OR DIETARY RESTRICTIONS..................................................75
8.1.
Contraception Requirements ......................................................................75
8.1.1.
Female Subjects..........................................................................75
8.2.
Activity ........................................................................................................76
9.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........................76
9.1.
Prohibited Medications................................................................................76
9.2.
General Considerations ..............................................................................77
10. COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS ..................................77
10.1.
Subject Completion.....................................................................................77
10.2.
Subject Withdrawal Criteria.........................................................................77
10.3.
Subject Withdrawal Procedures..................................................................77
10.3.1.
Subject Withdrawal from Study....................................................77
10.3.2.
Subject Withdrawal from Study Treatment...................................78
10.4.
Treatment After the End of the Study..........................................................78
11. STUDY DRUG DOSAGE AND ADMINISTRATION................................................78
11.1.
In-House Dosing.........................................................................................78
11.1.1.
At-Home Dosing ..........................................................................79
11.2.
Blinding.......................................................................................................79
11.3.
Packaging and Labeling..............................................................................80
11.4.
Preparation/Handling/Storage/Accountability..............................................80
11.5.
Assessment of Compliance ........................................................................81
11.5.1.
Treatment of Study Treatment Overdose.....................................81
12. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) ..................81
12.1.
Definition of Adverse Events.......................................................................81
12.2.
Definition of Serious Adverse Events..........................................................82
12.3.
Cardiovascular Events................................................................................84
12.4.
Death Events..............................................................................................84
12.5.
Method of Detecting AEs and SAEs............................................................84
12.6.
Recording of AEs and SAEs .......................................................................84
12.7.
Evaluating AEs and SAEs...........................................................................85
12.7.1.
Assessment of Intensity...............................................................85
12.7.2.
Assessment of Causality..............................................................85
12.8.
Follow-up of AEs and SAEs........................................................................86
12.9.
Prompt Reporting of SAEs to GSK..............................................................86
12.10. Regulatory Reporting Requirements for SAEs ............................................87
13. LIVER CHEMISTRY FOLLOW-UP PROCEDURES...............................................87
14. STUDY CONDUCT CONSIDERATIONS ...............................................................89
14.1.
Posting of Information on Publicly Available Clinical Trial Registers............89
14.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................89
14.3.
Quality Control (Study Monitoring) ..............................................................90
14.4.
Quality Assurance.......................................................................................90
14.5.
Study and Site Closure ...............................................................................90
14.6.
Records Retention......................................................................................91


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14.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................91
14.8.
Data Management ......................................................................................92
15. REFERENCES.......................................................................................................93
16. APPENDICES........................................................................................................96
16.1.
Appendix 1: Liver Safety Algorithms ...........................................................96
16.2.
Appendix 2: Definitions ...............................................................................97
16.3.
Appendix 3: Protocol Amendment Changes................................................98


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ABBREVIATIONS
2-D
Two dimensional
C
Degrees Celsius
g
Microgram
ABI
Ankle Brachial Index
ACS
Acute coronary syndrome
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
ANCOVA
Analysis of co-variance
ANOVA
Analysis of variance
AST
Aspartate aminotransferase (SGOT)
ATP
Antiprothrombin antibody
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
AUC(0-)
Area under the concentration-time curve over the dosing interval
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to 
last time of quantifiable concentration within a subject across all 
treatments
BUN
Blood urea nitrogen
Cavg
Average concentration
CDC
Centers for Disease Control
Chem
Chemistry
CL
Systemic clearance of parent drug
cm2
Centimeters squared
Cmax
Maximum observed concentration 
CO2
Carbon dioxide
COX 2
Cyclooxygenase 2
COX 4
Cyclooxygenase 4
CPK
Creatine phosphokinase
CPSSO
Clinical Pharmacology Science and Study Operations
Css
Concentration at steady-state
CVA
Cerebrovascular accident
CYP2C8
Cytochrome P4502C8
DBF
Database freeze
Db/db Mice
Leptin activity deficient mice which are obese and diabetic
DFO
Desferoxime
DFU
Diabetic foot ulcer
DMOG
4-Amino-4-deoxy-N10-methylpteroylglutamyl-γ-glutamate
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EGLN 1, 2, 3
Egl nine homolog 1, 2, 3


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ELISA
Enzyme-linked immunosorbent assay
EPCs
Endothelial progenitor cells
EPO
Erythropoietin
F
Bioavailability
FDA
Food and Drug Administration
FGF
Fibroblast growth factors
Flux
Rate of drug transfer per unit of surface
FSH
Follicle Stimulating Hormone
FTIH
First time in humans
g/dL
Grams per deciliter
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilence
GGT
Gamma glutamyltransferase
GI
Gastrointestinal
GLP
Good Laboratory Practice
GLUT1
Glucose transporter 1
GLUT3
Glucose transporter 3
GSK
GlaxoSmithKline
2H2O
Deuterated or heavy water
h/hr
Hour(s)
Hb
Hemoglobin
HbA1c
Glycosylated hemoglobin
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
Hema
Hematology
Hep B
Hepatitis B
Hep C
Hepatitis C
HIF
Hypoxia-inducible factor
HIF
Hypoxia-inducible factor alpha
HIS
Hyperspectral imaging
HIV
Human Immunodeficiency Virus
HK1,2
Hexokinase-1, 2
HMOX1
heme oxygenase (decycling) 1
HO-1
Heme oxygenase 1
HPLC
High-performance liquid chromatography
HRT
Hormone replacement therapy
hsCRP
High sensitivity C-reactive protein
HIS
Hyperspectral imaging
HVT
Healthy volunteers
IB
Investigator’s Brochure
ID
Identification
IC50
Half maximal inhibitory concentration
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IDSL
Integrated Data Standards Library
IL
Interleukin (6,1b,8 and 10)


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IgM
Immunoglobin M
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
IU
International Unit
IUD
Intrauterine device
IUS
Intrauterine system
IVRS
Interactive voice response system
L
Liter
LDH
Lactate dehydrogenase
LSLV
Last subject last visit
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MI
Myocardial infarction
MIU/ml
Milli-international units per milliliter
mL
Milliliter
mm3
Millimeters cubed
mmHg
Millimeters of mecury
MMP1, 2, 9
Matrix metalloproteinase-1, 2 9
mRNA
Messenger RNA
MRSA
Methicillin-resistant Staphylococcus aureus
MSDS
Material Safety Data Sheet
Msec
Milliseconds
NCBP
Non-childbearing potential
ng.h/mL
Nanogram hours per milliliter
ng/mL
Nanograms per milliliter
NO
Nitric oxide
NOAEL
No observed adverse effect level
NOS
Nitric oxide synthase
PD
Pharmacodynamic
PDGF
Platelet-derived growth factor
PF4
Platelet factor 4
pg/mL
Picograms per milliliter
PHD
Prolyl hydroxylase
PK
Pharmacokinetic
pmol/L
Picomoles per liter
PO
Per os (by mouth)
PV
Pulse volume
PVR
Pulse volume recording
QT
QT interval
QTc
QT interval corrected for heart rate
RAP
Reporting and Analysis Plan


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RBC
Red blood cells
RD
Repeat dose
RNA
Ribonucleic acid
rtPCR
Reverse transcription polymerase chain reaction
SAE
Serious adverse event(s)
SAS
Statistical Analysis Software
SD
Single dose
SD
Standard deviation
SE
Standard error
SDF-1
Stromal cell-derived factor-1 alpha
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SoC
Standard of Care
SOP
Standard Operating Procedure
SPM
Study Procedures Manual
SPP
Skin perfusion pressure
t½
Terminal phase half-life
T-cell
T lymphocytes
TcPO2
Transcutaneous PO2
TE
Tris EDTA buffer solution
TGF
Stromal cell-derived factor-1
TGF1,2
Stromal cell-derived factor-1 beta 1 and beta 2
TIA
Transient Ischemic Attack
TIMP
Tissue inhibitors of metalloproteinase
Tlag
Lag time before observation of drug concentrations in sampled matrix
Tmax
Time of occurrence of Cmax
TNF
Tumor necrosis factor
TNF9
Tumor necrosis factor
TSP-1
Thrombospondin-1
ULN
Upper limit of normal
US
United States
VEGF
Vascular endothelial growth factor
ULN
Upper limit of normal
w/w
Weight for weight
WBC
White blood cells
Τ
Dosing interval


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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
ARANZ Medical Silhouette
Chiron RIBA
OCT
SensiLase System
WinNonlin


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1.
INTRODUCTION
Diabetes is a leading cause of non-traumatic amputation.  The estimated incidence of 
diabetes in the US exceeds 1.5 million new cases annually, with an overall prevalence of 
23.6 million people or 7.8% of the nation’s population [CDC, 2008].  One of the most 
common complications of diabetes in the lower extremity is diabetic foot ulcers (DFUs).  
There are over 850,000 diagnoses made in the US each year and an estimated 15% of 
patients with diabetes will develop a lower extremity ulcer during the course of their 
disease.  In addition, 7% to 20% of patients with foot ulcers will subsequently require an 
amputation.  Despite standardized protocols for wound care, chronic foot ulcers are the 
most common reason for hospitalization in the diabetic population. [Boulton, 2005; 
Reiber, 1999].  Furthermore, attempts to develop new pharmacologic therapies, mostly 
cytokine-based, have been largely unsuccessful.  In addition to the associated physical 
symptoms and economic burden to the health care system, a diabetic foot ulcer can have 
detrimental effects on patient quality of life, impacting almost every life aspect including 
psychological, physical, social, and economic functioning [Goodridge, 2006].  DFUs are 
a medical, economic, and social problem today that is expected to increase exponentially 
over time.
Even in the absence of diabetes, wound healing is a complex, multi-stage process 
involving interactions among epidermal and dermal cells, gene signaling, and the 
extracellular matrix, as well as influences on angiogenesis and signaling between a 
multitude of local as well as plasma derived proteins.  Effective healing requires a rapid, 
but transient inflammatory response which produces mediators including cytokines and 
growth factors, leading to the proliferation of dermal fibroblasts and keratinocytes.  These 
cells migrate, differentiate and generate an extracellular matrix to form an initial barrier.  
Differentiation of dermal precursor cells, coupled with an angiogenic response, induces 
re-epithelialization and wound healing [Yamaguchi, 2010].
In diabetics, these healing processes are disrupted.  Functional impairments include 
reductions in the proliferation of fibroblasts, endothelial cells, and keratinocytes; 
decreased macrophage function, decreased or impaired growth factor production 
[Galkowska, 2006], reduced collagen synthesis and granulation tissue, reduced 
angiogenesis, delayed re-epithelialization and impaired endothelial progenitor cell (EPC) 
homing [Falanga, 2005; Galiano, 2004; Mace, 2007; Gallagher, 2007].  An intervention 
that targets one or more of these pathways could convey significant improvements to 
wound healing in diabetic patients and thus represent a valuable therapeutic approach for 
the treatment of diabetic ulcers.
1.1.
Background
Closer interrogation of the wound healing pathways impaired in the diabetic patient 
reveals a significant overlap with those induced during hypoxic stress and commonly 
attributed to the hypoxia-inducible factor (HIF). [Li, 2007; Thangarajah, 2009; Ceradini, 
2004; Gallagher, 2007].  The transcriptional regulator, HIF, is a pivotal molecular switch 
that governs the adaptation to hypoxic insults.  HIF regulates an array of target genes 
which induce erythropoiesis (erythropoietin/EPO), vasoregulation (NOS2, 
hemeoxygenase I), angiogenesis (VEGF, SDF-1), and a switch to glycolytic 


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metabolism, as well as cellular/tissue preconditioning, cell survival and effects on
inflammatory mediators [Li, 2007; Thangarajah, 2009; Ceradini, 2004; Semenza, 2004; 
Lukashev, 2006; Gallagher, 2007].
While the precise mechanisms that underpin impaired wound healing in the diabetic are 
unknown, a recent investigation has revealed a link between elevated glucose levels and 
diminished HIF response due to decreased binding of HIF to the co-activator p300 
[Thangarajah, 2009].  The relationship between decreased HIF activity and impaired 
would healing is further demonstrated by the diminished angiogenic response and 
delayed burn wound healing in HIF heterozygote mice as compared to wild type 
littermates [Zhang, 2010].  Evidence also suggests that HIF is induced in wounds rapidly, 
and both local hypoxia and inflammatory cytokines such as TNFmay contribute to such 
increases [Albina, 2001]. Interestingly, the expression of HIF is impaired in diabetic 
animal models with chronic ischemia and with age.  For example, Liu et al. demonstrated 
that 6 month old db/db mice have much lower HIF levels than 2 month old mice, and this 
deficiency is closely associated with an impaired ability in these older mice to heal a 
cutaneous wound [Liu, 2008].  Furthermore, HIF appears critical to migration of human 
dermal fibroblasts through regulation of heat shock protein-90alpha which promotes cell 
motility [Li, 2007].  Notably, HIF may play a regulatory role in T-cell function, serving 
to limit the secretion of inflammatory cytokines, and in adenosine receptor regulation, 
which is important to inflammatory signaling and supports tissue protection [Lukashev, 
2006; Sitkovsky, 2004; Eltzschig, 2004].
Active HIF may also play a role in improving energy metabolism during ischemic 
conditions.  Increased activation of HIF is linked to a shift toward glucose utilization, by 
evidence of increased enzyme expression found in the glycolytic pathways (GLUT 1, 
GLUT 3, LDH HK1, 2) as well as mitochondrial adaptations (e.g., increased expression 
of COX4-2) that may maximize metabolic efficiency [Fukuda, 2007; Chang, 2007].  
Notably, in genetic mouse (PHD1 knockout) studies, muscle tissue is protected in the 
midst of glycolytic shifts, suggesting the preservation of ATP generation may provide 
protective benefit during ischemic or low blood flow conditions such as in diabetic foot 
ulcers. [Aragonés, 2008; Liu, 2008]
Several therapeutic modalities have been explored in animal models to evaluate whether 
enhancement of HIF signaling improves the wound healing process.  Intramuscular gene 
delivery of stabilized HIF DNA constructs in diabetic mice has been shown to increase 
circulating angiogenic cell number and accelerate healing [Liu, 2008].  Similar studies 
using viral delivery of stabilized HIF also demonstrate improved wound healing in 
diabetic mice [Botusan, 2008].  In addition to HIF over-expression studies, several 
investigators have evaluated the potential for a therapeutic role of prolyl hydroxylase 
(PHD) inhibition in these models.  HIF prolyl hydroxylases play an important role linking 
oxygen sensing to HIF activity and provide a vital link to transmit hypoxia signals to 
HIF-mediated transcriptional machinery.  Under normoxic conditions, HIFsubunits 
degraded by proteosomes lead to a decrease in target gene transcription.  The degradation 
of HIFsubunits is dependent on the hydroxylation of two conserved proline residues in 
the subunits and subsequent interaction with von Hippel-Lindau tumor suppressor 
protein.  This hydroxylation step is carried out by oxygen-requiring PHD enzymes (egl 
nine homologous proteins, e.g., EGLN 1, 2 and 3). During inhibition of proline 


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hydroxylation, HIFescapes degradation allowing translocation to the nucleus and 
subsequent transcription of target genes.
Experimental evidence strongly suggests that PHD inhibitors can mimic many key 
aspects of hypoxia by stabilizing HIF, and these agents are thought to have therapeutic 
potential for a variety of ischemic diseases, including wound healing. [Bruick, 2001; 
Myllyharju, 2009; Myllyharju, 2008; Chowdhury, 2008].  Chang et al. demonstrated that 
desferoxime (DFO) can overcome the negative feedback due to age-related increases in 
PHD expression and enhance wound healing [Chang, 2007].  In this study, mobilization 
of angiogenic EPCs and skin flap healing were enhanced with DFO treatment.  
Furthermore, local administration of another PHD inhibitor, DMOG, was shown to 
enhance HIF responses and accelerate healing in db/db mice [Botusan, 2008].  
Recruitment of circulating angiogenic precursor cells to wounded areas seems to be an 
important component of enhanced healing induced by DMOG.
Taken together, these data suggest that the HIF pathway is intimately associated with the 
wound healing process, and that this response is impaired in the diabetic setting.  
Targeting the inhibition of HIF-prolyl hydroxylase to increase active HIF levels would 
permit sustained or augmented production of HIF target genes and therefore be expected 
to have a positive impact on wound healing.
1.2.
Clinical Experience with GSK1278863
This study will be the first experience with GSK1278863 administered as a topical agent. 
All previous clinical experience with the compound has been through oral administration, 
and the information related to oral administration may be found in the investigator 
brochure [GSK1278863 Investigator’s Brochure GlaxoSmithKline Document Number 
RM2008/00267/07].
No human data are available to confirm which of the wound healing processes (e.g., 
inflammation, angiogenesis, cellular metabolism, or collagen production) is most affected 
by treatment with GSK1278863.  An important objective for this first experience in 
humans will be to understand the kinetics of topical delivery of GSK1278863 and to 
correlate the clinical outcome with the kinetics and biologic effects of this investigational 
wound care product.  This correlation will aid in establishing the appropriate use of 
GSK1278863 in the management of diabetic foot ulcers.  This clinical-biologic model 
may also represent a useful tool for future evaluation of wound care products.
1.3.
Rationale
The purpose of this study is to evaluate the safety/tolerability and pharmacokinetics of 
GSK1278863, and to describe the effects of GSK1278863 treatment on the clinical 
characteristics of DFUs as well as the components of the wound healing process (i.e., 
inflammation, bacterial load, angiogenesis, collagen formation and gene/protein 
expression for healing related pathways).  These assessments are aimed at determining if 
one or more of these components are linked to therapeutic activity.


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The delivery of the molecule to the site of action is expected to be optimized by local 
topical application, to elevate target tissue (i.e., skin) exposure while limiting systemic 
exposure, which could ultimately impart safety limitations due to the potent effect of the 
molecule on erythropoiesis.
While a number of pathways may be relevant to wound healing, the general hypothesis is 
that inhibition of HIF-prolyl hydroxylase by GSK1278863 will increase local 
concentrations of HIF and increase transcription of numerous target genes, notably those 
related to the angiogenesis, cellular metabolism, cell mobilization and reduction in pro-
inflammatory cells (macrophage) or proinflammatory cytokines.  Activation of these 
targets will improve cellular profiles for initial re-epithelialization, wound vascularization 
and perfusion and, ultimately, would closure.
1.4.
Study Design Strategy
This first-time-in-human study of the topical formulation of GSK1278863 is designed as 
an initial exploration of the safety, tolerability, pharmacokinetic and pharmacodynamic 
effects.  The study will be performed in a cohort of healthy volunteers and then in 
diabetics, including application both to healthy, intact skin, as well as to diabetic foot 
ulcers directly.  This study proposes to move rapidly into diabetic patients with foot 
ulcers, as no equivalent model for this disorder exists to understand kinetics and 
tolerability of the compound.  However, to provide some limited understanding of 
tolerability and kinetics, the study has been designed to gain initial information related to 
these parameters in healthy individuals with at least two doses of medication prior to 
entry into the diabetic cohorts.  Furthermore, the first diabetic cohort will have the 
compound applied to intact skin to gauge tolerability in this patient population and to 
compare PK with that of healthy individuals.  Subsequently, the same cohort of diabetic 
subjects will also receive equivalent dose(s) applied directly to the foot ulcer.  A 
treatment period of two weeks was selected for the repeat dosing segment of the study to 
permit initial assessment of healing rate and biomarker analyses that are important to 
inform decisions related to progression of the compound for the indication (Figure 1).


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Figure 1
Study Design/Schematic
1.4.1.
Dose Rationale
1.4.1.1.
Single Dose Strategy
As one of the main goals of this study is to determine the systemic exposure to 
GSK1278863 following topical administration, this study will follow a dose escalation 
paradigm.  For the purposes of this study, ‘dose’ will be defined as the total mass of 
GSK1278863 applied, either to intact skin or DFU.  The dose of GSK1278863 applied 
will be escalated based on safety/tolerability and the pharmacokinetic data from the 
preceding dose using petrolatum ointment formulations containing 0.05, 0.1, 0.5 and 1% 
GSK1278863.
Healthy volunteers and patients with DFUs will be recruited for this study, and drug will 
be applied to both intact skin (from healthy and DFU subjects) and to the DFU directly.  
There will be approximately six subjects on active drug and approximately two on 
placebo (6:2) for each single dose cohort.  Dose escalation will proceed through the 
planned dose levels within each part of the study once preliminary safety/tolerability and 
PK data have been reviewed for at least 4 subjects/patients at the previous dose level.  
Blood samples will be drawn from pre-dose to approximately 72 hours post-dose in order 
to fully characterize the systemic pharmacokinetics.  The initial sampling scheme can be 
found in the Time and Events table in Section 4.6.1, and may be changed if deemed 
necessary upon evaluating emergent pharmacokinetic data.


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The decision to proceed to the next dose level of GSK1278863 will be made by the GSK 
Study Team and the Investigator based on safety (including plasma hemoglobin (Hb) 
levels), tolerability and preliminary pharmacokinetic and/or pharmacodynamic data 
obtained in at least 4 subjects for single dosing (SD) (Part A) and 12 subjects for repeat 
dosing (RD) (Part B) at the prior dose level.  The actual doses to be administered may be 
adjusted based on safety, tolerability and preliminary pharmacokinetic and/or 
pharmacodynamic data at previous dose levels; these dose adjustments may involve 
either an increase or a decrease in the planned dose.  Pharmacokinetic data will be 
evaluated as appropriate throughout the study to continue dose escalation, or to adjust or 
discontinue dose escalation as necessary.  The chosen doses will be appropriate to 
prevent the projected Cmax and AUC(0-t) from exceeding 1400ng/mL and 
14,800ng.h/mL, respectively (NOAEL exposures from the three-month monkey safety 
assessment study).  Notably, the systemic activity of the compound has robust effects on 
erythropoiesis.  Therefore, doses will be selected to minimize systemic exposure of the 
compound to limit elevations in hemoglobin.  Hence, the exposures will be held to a 
much lower than NOAEL threshold by selecting maximal dose levels which are predicted 
to limit systemic exposure at or below levels equivalent to a 15mg oral dose (Cmax 
286ng/mL; AUC 650ng.h/mL).  (Note: modeling efforts predict that average exposures of 
the currently targeted highest dose (3mg of the 1% formulation; Cmax 55.3ng/mL; AUC 
334ng.h/mL) will be at or below the 10mg oral dose exposures (Cmax 135ng/mL; AUC 
319ng.h/mL).  The 15mg oral dose has been demonstrated to maintain average rates of 
hemoglobin elevation to <1g/dL over a 2 week period.
The first cohort of subjects will be healthy volunteers.  The starting dose in this cohort 
will be 0.1% GSK1278863 petrolatum ointment at 25mg/cm2 to a 12cm2 section of intact 
skin (300mg total mass of the formulation) on the foot, which will deliver 300g 
GSK1278863.  The site of application will be covered with an occlusive dressing.  The 
dosing vehicle will be removed from the skin by washing at 22.5 hours (Note:  For 
practical reasons, a dosing period of approximately 22.5 hours will be followed for both
the single and repeat dosing parts of this study.  This allows for subject hygiene and 
dehydration of the skin prior to reapplication when necessary and will allow consistency 
between the SD and RD portion of this protocol).  The second dose will be 10-fold 
greater, or a 3000g GSK1278863 dose achieved by using 300mg of the 1% petrolatum 
ointment formulation.  This will be applied to a different 12cm2 section of intact skin on 
the lower limb in the same cohort of healthy volunteers following at least a 10 day 
washout period.  Including a cohort of healthy volunteers allows for determination of the 
irritation potential of the formulation on intact skin before introducing the study drug to 
patients.  Additionally, this will provide a baseline of GSK1278863 absorption kinetics in 
healthy skin.  As petrolatum formulations have been on the market with numerous drugs, 
a low potential for irritation is expected in humans.
Diabetics with DFU no larger than 16cm2 will be the second cohort of the study and 
diabetic patients will be used for the remainder of the dose escalation cohorts.  Therefore, 
the largest anticipated amount of petrolatum ointment to be applied to a study wound is 
300mg.  In general, doses will be escalated by applying the same amount of ointment 
(25mg/cm2) using a higher percentage ointment.  However, if the need arises based on 
emergent data, doses may be escalated by increasing the amount of ointment applied per 
cm2 skin/wound diameter (i.e., greater than 25mg/cm2).


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The first dose applied to the intact skin of DFU patients will be determined based on 
estimates from the systemic exposure observed in the healthy volunteer cohort and the 
known exposure-response with respect to a hemoglobin response (safety limitation).  The 
first dose in patients will be applied on an area of intact skin (equal in size to their study 
wound) on the lower limb opposing the side with the study wound.  A within subject 
comparison will be made after an appropriate washout period, by applying the same dose 
to the diabetic subject’s wound.  This will allow for pharmacokinetic comparisons 
between:  1) healthy volunteer and diabetics following administration to intact skin; and 
2) intact skin and DFU applications in diabetics.
There will be at least two additional cohorts of diabetic patients. The dose in the second 
cohort of diabetics will be applied to their DFU only for one dosing session.  The final 
single dose to the last diabetic cohort will be applied first to their DFU and following a 
sufficient washout (as determined from PK data), the same drug amount applied to the 
opposite leg on intact skin (matching the area of their DFU).  The decision to include a 
within subject comparison between intact and wounded skin at a higher dose level will 
allow a test for linearity of pharmacokinetics from the lower dose that included intact and 
wounded skin.  If more than three diabetic cohorts are required in the single dose phase 
of the study, only the last cohort will include a dosing session on intact skin.
1.4.1.2.
Single Dose Selection Rationale
The starting doses and concentrations were chosen after performing theoretical 
simulations.  The simulations assumed that, following application of GSK1278863 to a 
DFU, the absorption kinetics would be similar to a zero order infusion.  The reason for
this assumption is that dermal vasculature will be exposed in these wounds and therefore 
the drug will have direct access to dermal vasculature.  The resultant systemic exposure 
predictions from these simulations are considered the worst case scenario with 90% of 
applied drug being available for systemic absorption (Table 1).  Therefore, 10% of the 
drug is considered remaining at the site of application or within the applied formulation.
As skin is the site of action, it is assumed that drug will be in the proper vicinity of PHD 
enzymes and therefore, at concentrations adequate for PHD inhibition.  Skin 
concentrations are predicted to exceed the in vitro derived IC50s (~5-31ng/mL).  As the 
equivalent drug concentration in the ointment formulations range from 0.5 – 10 mg/mL 
and if similar penetration is attained as was attained from ex vivo human cadaver skin 
studies (0.21% total absorption from a 0.2% ointment formulation dose), approximately 
0.3-6g of GSK1278863 should penetrate the closest layers of skin.  By assuming the 
wound volume is half a sphere and the compound needs to penetrate 1cm of skin beyond 
the wound, 10% of the lowest dose (150g) applied to a 12cm2 wound would result in a 
concentration of ~9.3ng/mL.  The highest dose prediction resulted in skin concentrations 
of 186ng/mL. Therefore, local concentrations are expected to be as high as or higher than 
the IC50s of the three prolyl hydroxylase enzymes even at the lowest dose level.  
Evidence of positive pharmacology via this topical route has been observed in mice with 
increases in HIF target genes 8 hours after topical administration of petrolatum 
formulations containing 0.05 -2% GSK1278863.


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To gain insight into the potential systemic exposure from topical administration, a 
comparison of exposures following administration of similar dose levels via the two 
routes of administration was performed on data sets available from animal studies.  For 
intact skin, there is evidence of drug penetration from preclinical studies in the mouse 
and rabbit.  A mouse study using topically administered GSK1278863 resulted in 
systemic exposures at 8 hours post dose for all drug concentrations studied (equivalent to 
~0.02, 0.2, 1 and 4mg GSK1278863 applied).  Additionally, there were equivalent 
exposures following application of drug to both wounded and non-wounded skin.  
Similarly, in the rabbit dermal irritation study, 0.5mL of the 2% formulation (equivalent 
to ~10mg of GSK1278863) resulted in similar systemic concentrations following 
administration to both intact and abraded skin.  When comparing the Days 1 and 14 
exposures (AUC) from this study (topical) to Day 5 exposures (4mg/kg/day which 
approximates 8-10mg/day) from an orally dosed study in pregnant rabbits, day 5 oral 
toxicokinetic exposure was   approximately 10-fold and 100-fold the systemic exposure 
on Day 14 and Day 1, respectively, following topical administration .  The change in ratio 
is accounted for by skin accumulation of the drug by day 14 compared to day one.  There 
were somewhat lower Cmax ratios of approximately 60:1 and 5:1 on Days 1 and 14, 
respectively, when comparing oral to topical administration.
In an ex vivo human trunk skin flux study, 0.21% of the total dose of GSK1278863 
administered from a 0.2% ointment formulation was absorbed and the flux was found to 
be variable across the 24 hour study.  The mean flux ranged from 0.0002 to 
0.0017g/cm2/h at 1 and 21 hours post dose, respectively.  Given the preclinical skin 
penetration data from animal and human skin studies, the predicted systemic exposures 
following application to intact skin in this study should be quite minimal.
Using the fastest flux and the following systemic exposures were predicted.
Equation 1.
                        
Css = plasma concentration at steady-state
F = presumed bioavailability via the topical route
Flux = rate of drug transfer per unit area of surface
Area = treatment area
CL =systemic clearance
Bioavailability was presumed to be 1% (5-fold greater than ex vivo skin absorption) and 
CL was assumed to be observed human oral CL/F corrected by an oral F of 34%.  This 
was the largest bioavailability observed in a preclinical species (monkey).
Additionally, simulations of human oral PK from an existing population PK model were 
performed to predict exposures from 0.15, 0.3, 1.5 and 3mg oral doses.  These exposures 


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were divided by 100 and 60 for AUC and Cmax predictions, respectively, based on Day 1 
rabbit PO:topical ratios.  The predicted exposures from the above mentioned methods 
following topical application to intact skin are reported in Table 1 and depicted 
graphically in Figure 2.  The intact and wounded skin predicted mean Cmax exposures at 
the presently assumed highest dose, even with the most conservative assumptions, are 
approximately 400- and 5-fold lower, respectively, than the Cmax exposure anticipated to 
raise Hb.  The respective intact and wounded predicted mean AUC exposures are 
approximately 700- and 2-fold lower than the threshold AUC for Hb elevation.


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Table 1
Human Exposure Predictions Following Topical Application
Cohort Type
Ointment 
Strength 
(%)
Ointment 
Amount 
Applied (mg 
for 12cm2
area)
Amount 
GSK1278863
Applied (mg)
Predicted SD 
Exposure 
(concentration 
(ng/mL))1, 2
Predicted SD Exposure 
(AUC (ng*hr/mL))3,4
Diabetic 
Patients (intact 
skin)
0.05
300
0.15
Css: 0.007
0.02-0.10
Cmax: 0.01-0.12
Cavg: 0.001-0.007
Healthy 
Volunteers or 
Diabetic 
Patients (intact 
skin)
0.1
300
0.3
Css: 0.013
0.04-0.23
Cmax: 0.03-0.19
Cavg: 0.003-0.02
Healthy 
Volunteers or 
Diabetic 
Patients (intact 
skin)
0.5
300
1.5
Css: 0.067
0.2-1.03
Cmax: 0.13-0.98
Cavg: 0.01-0.06
Healthy 
Volunteers or 
Diabetic 
Patients (intact 
skin)
1.0
300
3.0
Css: 0.13
0.49-1.93
Cmax: 0.22-1.9
Cavg: 0.03-0.13
Diabetic 
Patients 
(wound)
0.05
300
0.15
Cmax: 0.4-10.1
Cavg: 0.14-2.54
3.39-61.0
Diabetic 
Patients 
(wound)
0.1
300
0.3
Cmax: 1.08-17.3
Cavg: 0.28-6.73
6.62-162
Diabetic 
Patients 
(wound)
0.5
300
1.5
Cmax: 5.47-142
Cavg: 1.56-24.9
37.4-837
Diabetic 
Patients 
(wound)
1.0
300
3.0
Cmax: 7.49-210
Cavg: 3.12-67.5
74.9-1620
1.
Intact skin Css: from human skin flux predictions; Intact skin Cmax and Cavg: from oral dose simulations and 
applied rabbit po:topical exposure ratios
2.
Wounded Skin Cmax and Cavg: from zero order infusion simulations
3.
Intact skin AUC: from oral dose simulations and applied rabbit po:topical exposure ratios
4.
Wounded Skin AUC: from zero order infusion simulations


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Figure 2
Graphical Representation of Systemic Exposure Predictions 
Following Topical Administration
Intact Skin


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Wounded Skin
1.4.1.3.
Repeat Dosing
Preliminary safety/tolerability and pharmacokinetic data from single dose applications to 
DFU subjects will be reviewed prior to the application of repeat doses to investigate the 
cumulative irritation potential and repeat dose pharmacokinetics of GSK1278863.  
Similarly, data from each repeat dose cohort will be reviewed prior to dose escalation.  
There will be approximately 12 subjects on active drug in addition to standard of care 
(SoC), approximately two on standard of care only, and approximately two on placebo 
(vehicle) for each repeat dose cohort.  Doses will be identified based on 
pharmacokinetics, systemic exposure level, and its relevance to known effects on Hb, 
safety and tolerability.  The same percent (strength) ointmentwill be applied daily for two 
weeks.  The DFU subjects will have samples drawn for PK analysis at the beginning, 
midway through the treatment and at the end of the repeat dosing segment.  The samples 
will be collected out to the appropriate time following the last dose on day 14.  
Additionally, one trough sample will be taken at pre-dose on day 11. The PK sampling 


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scheme can be found in the Time and Events tables in Section 4.6.2 and Section 4.6.3 and 
may be changed if deemed necessary upon determining real time pharmacokinetics data.
For practical reasons, a dosing period of approximately 24 hours could not be maintained 
and therefore a dosing period of ~22.5 hours will be followed for repeat dosing parts of 
this study.  This allows for subject hygiene and dehydration of the skin prior to 
reapplication of the next dose.  The amount of ointment applied to the DFUs may change 
based on wound size following initial dosing to maintain consistency of amount 
applied/cm2 of wound size, which would also result in a change of the total mass of drug 
applied .  If deemed appropriate, intermittent dosing, i.e., a dosing interval greater than 24 
hours, may be implemented.
1.4.1.4.
Repeat Dose Rationale
Predicting systemic exposures following repeat topical dosing to DFU involves several 
uncertainties.  First, if there is a pharmacologic effect that improves wound healing, the 
DFU may decrease in size, and therefore less drug will be applied, and theoretically, 
there will be less penetration via the direct vascular route.  Additionally, in rabbits, an 
approximate 15-fold increase in exposure from Day 1 to Day 14 due to accumulation 
from repeat daily application has been observed.  There may be a depot effect 
contributing to this increase in systemic exposure over time.  It is therefore expected that 
the systemic pharmacokinetics of GSK1278863 will not remain constant during the 
repeat dosing phase of this study due to:  a) the changing wound characteristics; and b) 
this possible depot effect.  The emergent pharmacokinetic data from the first repeat dose 
cohort of this study will allow for better predictions for the subsequent repeat dosing 
cohorts.
1.5.
Summary of Risk Management
1.5.1.
Risks Relating to GSK1278863
There has been no previous experience in man with topical administration of 
GSK1278863.  The rationale for utilizing topical GSK1278863 therapy for DFU 
treatment is based on maximizing local concentrations of the active compound while 
limiting systemic exposure to reduce systemic liabilities.  In the current study, a stepwise 
progression for the compound is utilized both for order of the subjects exposed and for 
dose level.  Initial exposures will first take place in healthy subjects to gain initial 
tolerability and kinetic information prior to entry in the diabetic population.  Further, 
initial application of the compound to diabetics will take place on intact skin prior to 
application to the wound.  Dose levels will begin at low levels and be escalated only after 
adequate tolerability and kinetic understanding is obtained.  Maximal dose levels that are 
selected in the escalation process will be those which are predicted to limit systemic 
exposure to levels at or below levels equivalent to a 15mg oral dose.  The 15mg oral dose 
has been demonstrated to maintain average rates of hemoglobin elevation to <1g/dL over 
a 2 week period when compared to oral route of administration.  In nonclinical studies 
using the petrolatum formulation to support topical administration to date, no new or 
unique safety concerns have been identified.  Concentrations of GSK1278863 up to 2% 
w/w in petrolatum were not associated with dermal irritation or sensitization following 
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In non-clinical studies, oral and intravenous administration of GSK1278863 was 
associated with gastrointestinal side effects (abnormal feces & emesis) and stomach 
erosions with bleeding.  Thrombosis with ischemia secondary to polycythemia (excessive 
erythropoiesis) has also been observed.
All previous clinical studies in humans have utilized oral administration of GSK1278863.  
In these studies GSK1278863 has been generally well tolerated with no clinically 
significant safety-related findings attributable to the investigational product following 
doses up to 300mg single dose and up to 100mg once daily for 2 weeks in healthy 
subjects and 100mg once daily for 4 weeks in patients with anemia of chronic kidney 
disease, other than potential for robust erythropoietic responses.
Based on what is currently known of the possible roles for HIF-regulated pathways in 
mediating hypoxia associated pathophysiology, pulmonary artery hypertension and neo-
vascularization (e.g., retinal, joint synovium) have been identified as areas of theoretical 
concern based on the mechanism of action of GSK1278863.  No findings relevant to 
these theoretical concerns have been noted in animal or clinical studies conducted to date.
To minimize risks to participants, eligibility criteria, safety monitoring, and stopping 
criteria have been incorporated into the study design.  Hematologic parameters will be 
closely monitored throughout the dosing period with guidance provided regarding 
discontinuation of dosing.  Further, where appropriate, specific eligibility criteria or 
monitoring instructions relevant to theoretical concerns have been included in the study 
protocol.  For example, subjects who are at high risk for thrombotic events or 
malignancy, or who have underlying retinal vascular disorders, significant pulmonary 
disease or inflammatory conditions such as rheumatoid arthritis are not eligible to 
participate.  Stopping criteria and guidance for further evaluation are also provided (e.g., 
gastrointestinal, visual and pulmonary adverse events).
Please refer to the Investigator’s Brochure for GSK1278863 for additional pre-clinical 
and clinical details and Guidance for Investigator [GSK1278863 Investigator’s Brochure 
GlaxoSmithKline Document Number RM2008/00267/07].
2.
OBJECTIVE(S)
2.1.
Primary

To evaluate the safety and tolerability of the topical application of GSK1278863 in 
healthy volunteers and patients with diabetic foot ulcer following single dose (SD) 
and repeat dose (RD) administration.

To determine the pharmacokinetics of single and repeat doses of GSK1278863 and 
its metabolites following SD and RD administration.


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2.2.
Exploratory
2.2.1.
To evaluate the effect of single doses of GSK1278863 on

Gene expression for HIF targets and genes associated with wound healing in the 
DFU.

Local levels of biomarkers (e.g., inflammatory panel for cytokines, proteases).

Bioburden in the wound (e.g., rtPCR for bacterial load).

Physical characteristics of the wound (e.g., rate of healing, wound volume).

Clinical characteristics of the wound (e.g., exudate, granulation tissue, color).
2.2.2.
To evaluate the effect of repeat doses of GSK1278863 on

Gene expression  for HIF targets and genes associated with wound healing in the 
DFU.

Local levels of biomarkers (e.g., inflammatory panel for cytokines, proteases, 
inflammatory cell counts, collagen turnover).

Bioburden in the wound (e.g., rtPCR for bacterial load).

Biomarkers of angiogenesis via blood flow and oxygen availability [e.g., skin 
perfusion pressure (SPP) and pulse volume (PV), hyperspectral imaging].

Tissue concentrations of GSK1278863 after repeat dosing in selected subjects, as site 
capabilities to perform the assessment permit.

Circulating biomarkers for HIF activation (e.g., hemoglobin, hepcidin, EPO).

Physical characteristics of the wound (e.g., rate of healing, wound volume).

Clinical characteristics of the wound (e.g., exudate, granulation tissue, color)

The dose-response and/or exposure-response relationships of repeat doses of 
GSK1278863 using PK/PD modeling for selected primary and exploratory endpoints 
(as data permit).
3.
ENDPOINT(S)
3.1.
Primary

Clinical safety and tolerability data including spontaneous AE reporting, ECGs, vital 
signs, nurse/physician observation and clinical laboratory values after single and/or 
repeat doses of GSK1278863.

Pharmacokinetic parameters of GSK1278863 and its metabolites:  SD: Cmax, tmax, 
terminal t½, tlag, AUC(0-), AUC(0-t), (AUC(0-) and RD: Cmax, tmax, terminal 
t½, AUC(0-t), (AUC(0-) and accumulation ratio), after single and/or repeat doses 
of GSK1278863, as data permit.


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3.2.
Exploratory
3.2.1.
After single doses of GSK1278863 (as data permit based on 
sampling feasibility)

Change from baseline in gene expression (mRNA) in the DFU tissue.

Change from baseline in biomarkers in the DFU (e.g., cytokine panel, protease 
panel).

Change from baseline on bioburden in the DFU (e.g., rtPCR for bacterial load).

Physical parameters of the wound (e.g., rate of healing, wound volume).

Clinical characteristics of the wound (e.g., exudate, granulation tissue, color).
3.2.2.
After repeat doses of GSK1278863 (as data permit based on 
sampling feasibility)

Change from baseline in gene expression (mRNA) in the DFU tissue.

Change from baseline in biomarkers of angiogenesis and blood flow and oxygen 
availability [e.g., skin perfusion pressure (SPP) and pulse volume (PV), 
hyperspectral imaging].

Change from baseline in biomarkers in the DFU (e.g., cytokine panel, protease 
panel, macrophage quantification)
a.
If the methodology can be validated at the site(s) cell proliferation and 
collagen turnover will be assessed.

Change from baseline on bioburden in the DFU (e.g., rtPCR for bacterial load).

Tissue concentrations of GSK1278863 in selected subjects as determined from 
micro-dialysis during RD, if feasible to conduct the assessment.

Change from baseline on circulating biomarkers of systemic HIF activation in 
the blood (e.g., hemoglobin, hepcidin, EPO).

Physical parameters of the wound following repeat doses of GSK1278863, for 
example: 
a.
Rate of wound healing (via planimetry).
b.
Change in wound volume (Silhouette software).
c.
Percentage of subjects with closure of the study DFU.
d.
Time to DFU closure.
e.
Time required to achieve a certain percent of wound closure.
f.
Incidence of DFU closure.

Clinical characteristics of the wound (e.g., exudate, granulation tissue, color).

Correlation between GSK1278863 dose and/or exposure and parameters of 
pharmacodynamic activity, safety, and tolerability, as data permit.


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3.3.
Descriptions of Selected Endpoints
Descriptions of selected endpoints related to wound healing are in the sections below.
3.3.1.
Gene Expression Analysis
Expression of genes important in a range of dynamic cellular processes (including 
inflammation, angiogenesis and extracellular matrix deposition) is expected to change as 
wound healing progresses.  Moreover, with active drug treatment, genes coding for direct 
downstream targets of HIF signaling (e.g., HMOX1, VEGF and NOS2) should be 
upregulated.  Genetic markers of bioburden may also change with active drug treatment.  
Gene expression will therefore be assessed by RT-PCR using tissue samples taken from 
the wound area.  Most of these genes will be probed for using a focused array covering 
approximately 600 genes.  TaqMan PCR will be employed to validate gene expression 
for a number of signature genes for each of the signaling pathways/cellular processes of 
interest and for any other genes of interest not captured in the focused array.
3.3.2.
Biomarker Analysis
The pattern of cytokines and growth factor levels as well as inflammatory cell levels are 
expected to show relationships with the healing process expressed by changes in ulcer 
characteristics.
3.3.2.1.
Cytokines and Growth Factors
Subjects receiving the active drug are expected to show a pattern of pro-inflammatory 
protein production that is lower than that in subjects receiving placebo.  Cytokine 
evaluation may include, but is not limited to:  IL-6, IL-1b, IL-8, IL-10, GM-CSF, TNF-, 
MMP-9, VEGF, HIF, TIMP, Fibrinogen, PDGF, and thrombospondin-1 (TSP-1), PF4 
and FGF with multiplexed ELISA assay.  Reductions in pro-inflammatory cytokines 
should correlate with reduction in wound dimensions.
3.3.2.2.
Quantification of CD68+ Macrophages
Cellular inflammatory response at the tissue level will be studied in tissue samples from 
the wound site.  Changes (decreases) in macrophage levels at week two are expected to 
coincide with improved clinical evidence for wound closure and with decreased 
inflammatory cytokines.  It is hypothesized that a decrease in the hyper-inflamed state of 
the wound would be reflected in decreases in macrophage count by the end of treatment.
Fluorescence immunohistochemistry will be employed to quantify the number of CD68+ 
macrophage in frozen tissue sections.  If methodology permits, macrophage subtype 
analysis may be performed by co-immunostaining sections for CD68 and CD206 (and 
potentially other markers) to identify and quantify the number of M2 macrophages.
3.3.2.3.
Cell Proliferation and Collagen Turnover
An assessment to determine the level of cell proliferation and collagen turnover will be 
conducted on a selected group of patients if the methodology can be validated within the 


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timeframe of the study.  Cell proliferation and collagen turnover are expected to increase 
at the wound site in patients receiving the active drug.  These processes will be assessed 
by systemic labeling of subjects with “heavy water” (2H2O or deuterated water, i.e., the 
stable isotope deuterium incorporated into water) and subsequent measurement of 
deuterium in tissue samples from the wound site.  If data confirm increased collagen 
turnover in patients receiving active drug, further analysis will be considered (e.g., 
collagen isoform identification to determine the form which contributes to the turnover).
3.3.3.
Bacterial Load Determination
Bacterial load in the wound fluid will be determined by DNA-DNA checkerboard 
hybridization assay using specific DNA probes generated against potential pathogenic 
microbial species (e.g., S. aureas, P. aeruginosa, C. rectus, P. mirabilis, MRSA).  
Changes in the bacterial loads (decreases) in the wounds are expected to reflect changes 
in the characteristics of the wound during the healing process.
3.3.4.
Tissue Concentration of GSK1278863
Assessment of tissue concentration of GSK1278863 will be assessed by skin 
microdialysis on a selected group of patients if the methodology can be validated within 
the timeframe of this study.  Local concentration of drug in the skin tissue is predicted to 
more closely associate with the pharmacodynamic endpoints being assessed in the study.  
Furthermore, critical insight toward available drug for inhibition of skin prolyl 
hydroxylase enzyme may be gained that will assist in refinement of the dosing regimen.
3.3.5.
Angiogenesis: Tissue Perfusion Assessment/Oxygen Availability
The ability of this therapeutic approach to impact blood flow within short term dosing 
will be explored using a laser Doppler SPP technique.  SPP will be evaluated with the 
SensiLase System, which provides quantitative evaluation of microcirculatory perfusion 
in the skin.  It is a non-invasive laser Doppler test combining SPP and pulse volume 
recording (PVR) to assess the capillary circulation and thereby assess wound healing 
potential.  The system measures skin perfusion using a laser Doppler sensor located 
beneath a pressure cuff at or near the wound.  It is hypothesised that angiogenic pathways 
will be activated by application of GSK1278863 and result in improved blood flow.  
Changes in flow are anticipated to coincide with changes in ulcer characteristics after two 
weeks of exposure.  A second exploratory technique for indirect evidence of 
angiogenesis, hyperspectral imaging (HSI), may be employed if the technique can be 
established/validated at the investigative centers.  Hyperspectral imaging uses a spectral 
separator to vary the wavelength of light admitted to a detector to assess both oxygen 
delivery (measured by oxyhemoglobin) and oxygen extraction (measured by 
deoxyhemoglobin) in tissues at or near the wounded tissue and would function as an 
indicator of a wound’s capacity to heal.  Higher levels of both molecules have shown 
correlation with a greater potential for healing (Khaodhia, 2007).


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3.3.6.
Physical Indicators of DFU Healing
Physical indicators of DFU healing will be assessed using planimetry (digital) as well as 
via acetate tracing methods.  Images and tracings will be assessed by blinded personnel 
both at run-in to determine eligibility, and during the indicated timings throughout the 
study for endpoint analysis (including wound diameter, area and wound volume 
(Silhouette software).  Changes in indicators of healing are expected to correlate with 
changes in assessments of angiogenesis, inflammation (cytokine levels), and macrophage 
number/type.
3.3.7.
Clinical Characteristics of the Wound
The clinical characteristics of the wound will be assessed (Section 7.10) and recorded on 
clinical case report forms designed to capture information which describe the wound 
(e.g., redness, swelling etc).


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4.
INVESTIGATIONAL PLAN
4.1.
Study Design/Schematic
Figure 3
Study Design/Schematic


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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 Time and Events Table are essential and required for study conduct.
4.2.
Discussion of Design and Treatment Plan
This is a randomized, placebo-controlled, single-blind (subjects and investigators will 
be blinded, GSK internal personnel will not be blinded), parallel-group, two part (Part 
A, Part B) trial in healthy volunteers and subjects with diabetic foot ulcers.  The study 
seeks to gain information related to safety/tolerability, pharmacokinetics and 
pharmacodynamics of the compound in this first administration to subjects via a 
topical formulation.
Part A is designed to evaluate single applications of GSK1278863.  Part A will 
include one cohort of healthy volunteers (intact skin) and approximately 3 cohorts of 
diabetic subjects.  Part B is designed to evaluate repeat applications of GSK1278863 
in diabetics, both in the clinic and by subjects at home.  Part B will include 
approximately 3 cohorts in which the concentration of drug applied will be 
determined by pharmacokinetic data from Part A and earlier cohorts in Part B.
For both parts of the protocol, additional cohorts may be added as necessary to obtain 
relevant safety, pharmacokinetic or pharmacodynamic data.  Based on emerging data, 
the number of cohorts and subjects may be reduced to avoid unnecessary exposure.
Furthermore, for both Parts A and B, there will be at least one week between cohorts 
for review of safety, tolerability and PK data by the GSK study team (unblinded) and 
the Investigator (blinded).  Pharmacodynamic data, where available, may be obtained 
for review.
Enrollment to each cohort may be staggered (i.e., cohorts do not have to be enrolled 
as one group).  
Diabetic subjects, in either Part A or B, will require a two week run-in period in 
which standard of care (Section 7.4) is given before treatment of the DFU with 
GSK1278863or placebo in order to ensure the wound does not show a greater than 
30% reduction in size.
4.2.1.
Part A – Single Doses in Healthy Volunteers and DFU Patients 
(Cohorts 1 through 4)
Part A will enroll approximately 4 cohorts, moving from healthy volunteers (Cohort 1) to 
Type I or II diabetic patients with diabetic foot ulcer (3 or more cohorts), and will 
administer single applications of ascending doses of GSK1278863 or placebo.  Each 
cohort in Part A will enroll enough subjects to complete approximately 6 on active drug 
and 2 on placebo (assumes ~10 subjects will be recruited per cohort to achieve 6:2 ratio).  
Diabetic subjects may participate in more than one cohort in Part A (requires a minimum 
of 14 days between cohorts to ensure a healing rate of less than 30%) and may also 
participate in Part B (requires a minimum of 14 days between cohorts to ensure a healing 
rate of less than 30%) provided the subject meets all selection criteria and this 


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participation will not result in blood withdrawal over the limit (Section 5.2.2).  
Participation in more than one cohort in Part A will not require the subject to be screened 
again. 
4.2.1.1.
Screening (Part A)
To determine subject eligibility for enrollment in the study, a screening visit will be 
performed within approximately 28 days of first dose administration.  For the 
purposes of subject eligibility for enrollment in the study, fasting screening 
assessments are defined as any assessments performed prior to the first dose of study 
drug in each part.  Ideally screening for diabetic patients would occur 14 days prior to 
Day 1 of the treatment of the DFU to accommodate the required run in period prior to 
wound treatment.
If a subject is not eligible for the study based on the Inclusion and Exclusion Criteria at 
the initial attempt, but becomes eligible at a later date during the enrollment period, the 
investigator should contact the GSK Medical Monitor to discuss the possibility of re-
screening the subject.
4.2.1.2.
Cohort 1 – Healthy Volunteers (Part A)
Cohort 1 will enroll healthy volunteers.  Subjects will be randomized to receive single 
applications of GSK1278863 or placebo on intact skin in two escalating dosing periods 
for evaluation of safety and tolerability, PK of GSK1278863 and PD.  The first 
application will be with a dose of 0.3mg (by utilization of 300mg of 0.1%).  A review of 
preliminary safety and tolerability data will be conducted by the GSK study team 
(unblinded) and the Investigator (blinded).  If GSK1278863 is well tolerated, subjects 
will receive a new dose as a single application to be determined based on data from the 
first application at least 10 days after the first application.
Subjects will come in to the clinic fasting early in the morning of Day 1 of each dosing 
period.  They will receive their application of GSK1278863 or placebo after safety labs 
are drawn, and ECGs and vitals have been collected.  Subjects may remain in the clinic 
post application for monitoring of safety and collection of blood for PK and PD 
sampling.  Subjects may also be discharged from the clinic once all Day 1 assessments 
have been completed, and return for subsequent assessments.  In this case, subjects will 
return to the clinic fasting early in the morning on Day 2, Day 3 and Day 4 for PK trough 
samples and safety assessments.  This will be repeated at least 10 days later with a new 
dose of GSK1278863 in the second dosing period.  Subjects will then return to the clinic 
7 to 10 days and 1 month after dosing for follow-up visits.  See Section 4.6.1 for detailed 
timing of assessments and sampling.
The duration of PK sampling may change dependent upon the kinetics observed.
The data obtained from this healthy cohort of subjects on intact skin will provide 
preliminary data on tolerability and initial PK following topical route of administration.  
These data will be used to select the dose for the first DFU cohort.


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4.2.1.3.
Run-In Period (Part A)
For two weeks prior to Day 1 of the DFU Treatment Period, subjects will receive 
standard-of-care.  For all diabetic subjects in Part A, each subject’s DFU will be 
measured at screening and Day 1; if, after 14 (1 day) days from screening, the subject’s 
DFU has reduced in size by greater than 30 %, the subject will not be randomized to 
receive investigational product.  If Screening and Day 1 are not 14 days (1 day) apart, 
an additional visit (Optional Baseline Run-In) will need to be scheduled prior to Day 1 to 
meet the Run-In requirement. Subjects that do not meet randomization eligibility will be 
discontinued from the study.
4.2.1.4.
Cohort 2 (Part A)
Cohort 2 will enroll DFU subjects who fulfill screening criteria.  Subjects will be 
randomized to receive a single application of GSK1278863 or placebo in two dosing 
periods.  The two dosing periods are intended to provide a ‘within patient’ comparison of 
PK between application to intact skin and to DFU.  The first application will be made on 
intact skin, followed by a 10-day washout period.  Blood for serial PK sampling will be 
collected out to 72 hours post-dose.  After review of safety, tolerability and PK data, 
these subjects will then receive an application of the same dose directly to the DFU.
Subjects will come in to the clinic fasting early in the morning of Day 1 of each dosing 
period and will follow the same schedule as Cohort 1, with the exception that the first 
application will be on intact skin, and the application in the second dosing period will be 
directly to the DFU.  See Section 4.6.1 for detailed timing of assessments and sampling.
4.2.1.5.
Cohorts 3 and 4 (Part A)
Cohorts 3 and 4 will enroll DFU subjects who fulfill screening criteria.  Subjects will be 
randomized to receive either GSK1278863 or placebo.  Each cohort will evaluate a new 
dose of GSK1278863, with applications made directly to the DFU.  If subjects are re-
enrolling from a previous cohort, they must complete the second Follow-up visit (Day 
28-32 post last dose) and therefore the 14 day Run-in period may begin 14 days prior to 
this visit.  If Cohort 4 is the final cohort, subjects will also receive application to intact 
skin.  
Subjects in Cohort 3 will come in to the clinic fasting early in the morning of Day 1 and 
will follow the assessments as outlined in Section 4.6.1.
Cohort 4, or the final cohort if optional cohorts are enrolled, will have 2 dosing periods 
(10 day washout between periods), with GSK1278863 applied directly to the DFU in 
dosing period one and followed by application to intact skin in the second dosing period.  
Subjects will follow the same schedule as for Cohorts 1 and 2.  See Section 4.6.1 for 
detailed timing of assessments and sampling.
4.2.1.6.
Optional Cohorts (Part A)
Additional cohorts may be added as necessary to obtain relevant data for determination of 
starting doses for the repeat (Part B) portion of the study.


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
If the data from Cohort 4 are considered sufficient to establish dosing for Part B, 
subjects from that cohort will be asked to return to the clinic for a SD 
administration of the compound to intact skin in order to make comparisons of 
systemic PK for linearity between low and high doses and a within-patient 
comparison of application of drug to intact skin versus DFU.

If however, the data are NOT sufficient to establish dosing for the repeat dose 
section of the protocol, another cohort will be recruited for application of an 
additional dose to their DFU.  This process will be repeated until sufficient data 
are collected to establish dosing for Part B. Once this is established, the last 
cohort will be asked to return for application of the compound to intact skin for 
the comparisons as described above.
Subjects of the cohort asked to return for application of the compound to intact skin will 
undergo PK sampling at time points established by the findings of the kinetics in the 
previous cohorts.
The timing of the final cohort, in which application to intact skin is assessed, may overlap 
with the first cohort of Part B, as long as all doses of GSK1278863 in previous cohorts 
are well tolerated and provide sufficient PK for Part B predictions.  Systemic exposures 
may or may not permit predictions for dose selection and therefore dose determination 
will be selected based on available safety and tolerability data.
GSK1278863 PK data from the cohorts of Part A will be used for the predictions of the 
expected systemic exposures in Part B (data permitting).  Preliminary safety, tolerability 
and PK data will be reviewed before initiating the randomized repeat-dosing period of 
Part B at approximately the same time as the final cohort in Part A.
4.2.1.7.
Follow-up Visits
Follow-up visits will occur 7 to 10 days and 28 to 32 days following completion of 
dosing.  Any subject withdrawing from the trial prematurely will also be asked to 
complete all follow-up procedures.
See Section 4.6 for details regarding all study procedures performed during the course 
of this trial.
4.2.2.
Part B –Repeat Doses in Diabetic Foot Ulcer Subjects (Cohorts 5, 
6 and 7)
Part B will include approximately 3 cohorts.  Enough subjects will be enrolled in each 
cohort to complete approximately 16 diabetic subjects with diabetic foot ulcer. All 
subjects will receive standard of care (SoC; Section 7.4) up to randomization, and then 
will be randomized to one of three arms, a) 12 active drug + SoC, b) 2 SoC, and c) 2 
placebo + SoC).  The randomized repeat application in Part B may start after dosing in 
Cohort 4 of GSK1278863 has been found to be safe and well tolerated.
Doses for the cohorts in Part B will be determined from safety, tolerability and PK data 
from Part A.  Each cohort will enroll a new group of subjects, randomized to either the 


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same dose, ascending dose or descending dose of GSK1278863.  All applications in Part 
B will be made directly to the subject’s DFU.  
For each cohort, subjects will undergo repeat applications of GSK1278863 or placebo, at 
the dose chosen for that cohort for 14 days.  The first day of the 14-day repeat application 
period will be conducted in the clinic.  Subjects will return to the clinic as indicated in 
Section 4.6.2, and applications between visits will be performed by the subject at home.
Blood for PK sampling will be collected on Days 1, 7, 14 and 15.  See Section 4.6.3 for 
specific time points for drawing samples.
There will be approximately one week between cohorts to allow for review of 
preliminary safety, tolerability and PK data before proceeding to the next cohort.  
Pharmacodynamic data, where available, may be obtained for review.
Subjects may not participate in more than one cohort in Part B.  Subjects may participate 
in Part A and then Part B which will require the subject to be screened again.
4.2.2.1.
Screening (Part B)
To determine subject eligibility for enrollment in the study, a screening visit will be 
performed within approximately 28 days of first dose administration.  For the purposes of 
subject eligibility for enrollment in the study, screening assessments are defined as any 
assessments performed prior to the first dose of study drug in each part.
If a subject is not eligible for the study based on the Inclusion and Exclusion Criteria at 
the initial attempt, but becomes eligible at a later date during the enrollment period, the 
investigator should contact the GSK Medical Monitor to discuss the possibility of re-
screening the subject.
4.2.2.2.
Run-In Period (Part B)
For two weeks prior to Day 1 of the Treatment Period, subjects will receive standard-of-
care as described in Section 7.4.  For all subjects in Part B, each subject’s DFU will be 
measured at screening and Day 1; if, after 14 days from screening, the subject’s DFU has 
reduced in size by greater than 30 %, the subject will not be randomized to receive 
investigational product and is considered a Run In Failure.  If Screening and Day 1 are 
not 14 days (1 day) apart, an additional visit (Optional Baseline Run In) will need to be 
scheduled prior to Day 1 to meet the Run In requirement. Subjects that do not meet 
randomization eligibility will be discontinued from the study.
4.2.2.3.
Treatment Period – (Part B)
Cohorts 5, 6 and 7 (numbering assumes no optional cohorts are enrolled in Part A) will 
each enroll sufficient subjects so that approximately 48 DFU patients who fulfill 
screening criteria complete all study visits.  Doses selected for these cohorts will be 
chosen based on preliminary safety data and PK results from Part A of this study.


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14-Day Dosing (Part B)
Subjects will be randomized to receive applications of GSK1278863 or placebo 
directly to the DFU on Day 1 for evaluation of safety and tolerability, PK of 
GSK1278863 and PD.  Applications of study drug will be done in clinic on Days 1, 4, 
7, and 14.  Subjects are responsible for study drug application on Days 2-3, 5- 6 and 
8-13. 
It should be noted that on days where serial PK sampling occurs it is permissible to 
allow subjects to check out of the clinic after the 8 hour PK time point has been 
collected as long as the subject can return for sample collection within the 10 to 12 
hour PK window.  If subjects elect to stay overnight, they should be encouraged to 
apply the study ointment and complete the diary entries themselves before being 
discharged in the morning.  Study staff can take this opportunity to provide additional 
instruction to subjects. 
Subjects will be given detailed instructions for application of GSK1278863 at home, 
and enough study drug for applications at home between clinic visits.  See Section 
11.1 for further instructions on at-home dosing.
Doses for subsequent cohorts may be adjusted based on PK results, and/or safety and 
tolerability data.
4.2.2.4.
Follow-up Visits
Follow-up visits will occur 7 to 10 days and 28 to 32 days following completion of 
dosing.  Any subject withdrawing from the trial prematurely will also be asked to 
complete all follow-up procedures.
See Section 4.6 for details regarding all study procedures performed during the course 
of this trial.
4.3.
Treatment Assignment
This will be a single-blind study.  Treatments will be blinded to subjects and the 
investigator site staff only.  GSK study staff is not blinded.
Subjects will be assigned to receive GSK1278863A or vehicle (placebo) in Part A 
and GSK1278863A or vehicle or SOC only (moist occlusion) in Part B in accordance 
with the randomization schedule generated by GSK Discovery Biometrics, prior to 
the start of the study, using validated internal software.
Subjects will be randomized into the study by means of an interactive voice response 
system (IVRS) to receive one of the treatment regimens listed in the below tables 
(Table 2 and Table 3).


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Table 2
Part A Doses
Cohort
Regimen
Dose (mg)
Treatment Area by 
Period
1
2
1
P
Placebo1
Intact
Intact
A
0.3mg
B
TBD2
2
P
Placebo
Intact
Wound
C
TBD
3
P
Placebo
Wound
N/A
D
TBD
4(or final)
P
Placebo
Wound
Intact
E
TBD
O (Optional)3
P
Placebo
Wound
N/A
F
TBD
1.
Placebo = vehicle
2.
Actual doses to be determined as preliminary PK data are reviewed and predicted exposures can be calculated.
3.
More than one optional cohort may be used.
Table 3
Part B Doses
Cohort1
Regimen
Dose (mg)
5
P
Placebo2
S
Standard of Care
F3
TBD
6
P
Placebo
S
Standard of Care
G
TBD
7
P
Placebo
S
Standard of Care
H
TBD
1.
Cohort numbering may be different based on the number of cohorts conducted in Part A
2.
Placebo = vehicle 
3.
Starting dose may be adjusted based upon evaluation of PK data from Part A
In Part A
For Cohorts 2 through 4, drug volume to be administered will be based on wound 
area.  See Section 11 for details.
An example of planned doses of GSK1278863 and regimen designation for Part A is 
in Table 4.


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Table 4
Example Treatment Options
Cohort
Regimen/
Dosing Period
Dose (mg)
Treatment Area
1 (HVT)
P1
Placebo1
Intact Skin
A
0.3 mg
Intact Skin
P1
Placebo
Intact Skin
B
TBD2
Intact Skin
2
P1
Placebo
Intact Skin
C1
TBD
Intact Skin
P2
Placebo
Wound
C2
TBD
Wound
3
P2
Placebo
Wound
D
TBD
Wound
4(or final)
P2
Placebo
Wound
E1
TBD
Wound
P1
Placebo
Intact Skin
E2
TBD
Intact Skin
O (Optional)3
P2
Placebo
Wound 
F
TBD
Wound
1.
Placebo = vehicle
2.
Actual doses to be determined as preliminary PK data are reviewed and predicted exposures can be calculated.
3.
More than one optional cohort may be used.
In Part B
Drug volume to be administered will be based on wound area, which may vary during the 
treatment period.  See Section 4.4 for details.  Actual doses will be chosen based on 
preliminary PK data (data permitting, See Section 4.2.1.6) from Part A.
4.3.1.
Subject Numbering
Subjects will be assigned a unique Subject Number at Screening for each cohort the 
subject opts to participate in.  When a subject is known to qualify for randomization, the 
subject number will remain consistent for the duration of the participation in each cohort.  
GSK will provide the site with a unique set of Subject Numbers in sequential order 
beginning with the lowest number.  Once a subject number is assigned to a subject, it 
cannot be re-assigned to any other subject during the study
If a subject is prematurely discontinued from the study and a replacement subject is to be 
recruited, a replacement treatment number will be used to assign the same treatment to 
the replacement subject.


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4.4.
Investigational Product and Other Study Treatment 
Dosage/Administration
Study Treatment
Product name:
GSK1278863
Placebo
Formulation description:
White to off-white smooth 
ointment
White to off-white smooth ointment
Dosage form:
Ointment
Ointment
Unit dose strength(s)/Dosage 
level(s):
0.05%w/w, 0.1%w/w, 0.5%w/w, 
1.0%w/w
Placebo
Route/Administration/Duration:
Topical
Topical
Dosing instructions:
See Section 11 for Dosage and 
Administration Instructions
See Section 11 for Dosage and 
Administration Instructions
Device:
Part A: Amber Bottle or White 
Tube
Part B: White Tube
Part A: Amber Bottle or White 
Tube
Part B: White Tube
Manufacturer/
source of procurement:
Part A: GlaxoSmithKline
Part B: DPT Laboratories, 
Ltd./GlaxoSmithKline
Part A: GlaxoSmithKline
Part B: DPT Laboratories, 
Ltd./GlaxoSmithKline
4.5.
Dose Adjustment/Stopping Criteria
This protocol allows some alteration from the outlined dosing schedule, but the predicted 
maximum exposure will not exceed systemic exposure to a 15mg oral dose.  Modeling 
currently predicts that the highest dose levels will achieve exposures at or below a 10mg 
oral dose.
The dosing schedule may also be adjusted to expand a dosing cohort to further evaluate 
safety and/or pharmacokinetic findings at a given dose level, or to add cohorts to evaluate 
up to sufficient additional dose levels.  The study procedures for these additional 
subject(s) or cohort(s) will be the same as that described for other study subjects.
These dose adjustments may involve either an increase or a decrease in the planned dose, 
but all doses will be selected so as not to exceed mean a systemic exposure equivalent to 
a 15mg oral dose.
4.5.1.
Dose Adjustment/Stopping Safety Criteria
An individual patient will be withdrawn from the study at the discretion of the 
Investigator and the study team.  In the event one or more patients are withdrawn, 
additional patients may be enrolled to ensure an adequate number of patients complete 
each cohort.
4.5.1.1.
Hemoglobin Stopping Criteria
A patient that experiences an absolute increase in hemoglobin of 1.5g/dL above their
baseline level at any time will be withdrawn from the study.


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Should hemoglobin values achieve the above set criteria, additional samples may be 
collected every 2-3 days and appropriate procedures (venesection or erythrocytapheresis) 
may be considered and implemented at the discretion of the investigator until the 
laboratory result returns to the patient’s normal range.
4.5.1.2.
Liver Chemistry Stopping Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance).  
Study treatment will be stopped for a subject if the following liver chemistry stopping 
criteria is met:

ALT 3xULN
Refer to Section 14, Liver Chemistry Follow-up Procedures, for details of the 
required assessments if a subject meets the above criteria.
4.5.1.3.
QTc Withdrawal Criteria
Healthy Volunteers (Part A, Cohort 1)
A subject that meets criteria below will be withdrawn from the study.  The QT correction 
formula used to determine discontinuation should be the same one used throughout the 
study.

QTc > 500msec
Withdrawal decisions are to be based on an average QTc value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief period, and 
then use the averaged QTc values of the 3 ECGs to determine whether the subject should 
be discontinued from the study.
DFU Patients (Part A Cohorts 2 through Final Cohort, Part B All Cohorts)
A subject who meets the criteria below will be withdrawn from the study.  The QT 
correction formula used to determine discontinuation should be the same one used 
throughout the study.

QTc > 530msec or uncorrected QT >600msec

If subject has underlying bundle branch block then the QTc withdrawal criteria 
depends on the baseline value:


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Baseline QTc 
value with 
underlying 
bundle branch 
block)
QTc withdrawal 
criteria
≤500msec
>530msec
≤530 msec
550msec
Withdrawal decisions are to be based on an average QTc value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief period, and 
then use the averaged QTc values of the 3 ECGs to determine whether the subject should 
be discontinued from the study.
4.5.1.4.
Other Dose Adjustment/Stopping Safety Criteria

Any other occurrence that raises significant safety concern in the mind of the 
investigator.

Any patient who has an increase from baseline in total wound area > 20% at any 
time will be withdrawn from treatment

Any patient who develops at any time after randomization 3 of the following 6 signs 
at the study wound site will be withdrawn from treatment:  local erythema, edema, 
pain, pus, local warmth, loss of function

Diagnosis of cancer, with the exception of squamous cell and basal cell carcinoma 
(unless in proximity of the wound treated with GSK1278863).
The GSK Medical Monitor must be notified within 24 hours of any subject’s withdrawal
as a result of safety concerns.


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4.6.
Time and Events Table
4.6.1.
Time and Events Table Part A
Study 
Population
Procedure
Screening1
(HVT: -28 to 
-1 days; 
DFU: -28 to  
-14 days 
prior to Day 
1)
Study Day (each dosing period)
Follow Up
Day 1
Day 
2
Day 
3
Day 
4
7-10
days 
post 
last 
dose
28-32 
days 
post 
last 
dose
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48h
72h
All Subjects
Check in
X
Informed Consent
X
Demographics
X
Full Physical Exam
X
Brief Physical Exam
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
X
12-lead ECG2
X
X
X
X
Vital signs3
X
X
X
X
X
Urine pregnancy(women)
X
X
X
HIV, Hep B and Hep C4
X
Hema/Chem Safety Labs5
X
X
X
X
Blood for HIFSamples 
(e.g., hepcidin, 
EPO,VEGF)6  
X
X
X6
X
Study treatment dosing
X
Pharmacokinetic 
Sampling7
X
X
X
X
X
X
X
X7
X
X
X


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Study 
Population
Procedure
Screening1
(HVT: -28 to 
-1 days; 
DFU: -28 to  
-14 days 
prior to Day 
1)
Study Day (each dosing period)
Follow Up
Day 1
Day 
2
Day 
3
Day 
4
7-10
days 
post 
last 
dose
28-32 
days 
post 
last 
dose
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48h
72h
Concomitant Medications
=============================================================
X
Adverse Event Review8
=============================================================
X
X
Subjects 
with DFUs9
Only
Gene Expression 
(mRNA) Tissue 
Samples10
X
X
X
Biomarker fluid samples 
(e.g., for cytokines, 
growth factors, and 
bioburden)
X
X
X
Physical Characteristics 
(e.g., photos and wound 
measurement post-
debridement, volume) 
X
X
X
X
Clinical Characteristics11
X
X
X
X
X
X
X
X
X
X
Vascular Perfusion 
Eligibility Assessments12
X


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1.
For subjects with DFUs to be eligible for the study or for entry into more than one cohort in Part A, rate of healing must be assessed in the 14 days prior to Day 1.
2.
Single ECGs will be taken at Screening,  pre-dose on Day 1, at 48h post-last-dose on Day 3 and at the 7-10 day Follow-up Visit.  ECGs should be taken while subject is supine for 
at least 5 minutes.  Additional ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
3.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Day 1 and at the 48h post-last-dose on Day 3, and at the 
Follow-up Visits.  Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
4.
HIV, Hep B and Hep C are only assessed in the Healthy Volunteer population.
5.
Blood samples for safety analyses will be collected fasting at Screening, on Day 1, at 48h post-last-dose on Day 3 and at the 7-10 day Follow-up Visit.  Refer to Section 7.2.4 for 
specific laboratory parameters to be tested.
6.
Blood samples HIFactivation on Day 1 will be collected at pre-dose, 8 and 10-12 hour window.  Refer to Section 7.6 for additional details on the collection and processing of 
these samples.
7.
Serial blood samples for the determination of the PK for GSK127886 and metabolites will be collected immediately pre-dose and 0.25, 0.5, 1, 2, 4, 8, 10-12 (once within the 10-12 
window for out-patients only)/12 (in-patient subjects only), 24, 48 and 72hrs post-dose.  Refer to Section 7.12 for details on the collection and processing of PK samples.  PK 
sampling times may be changed based on the observed GSK1278863 PK profile, but the total number of samples will not change.
8.
Adverse events are to be collected from first dose through the final Follow-up Visit.
9.
These assessments are to be performed only when IP is applied to the ulcer not to the patient’s intact skin unless for screening/eligibility purposes.  
10. Tissue sample collection at Pre-dose, Day 4 and the 7-10 Follow-up Visit is at the discretion of the PI or designee.  Wounds that have healed such that biopsies would be 
disruptive to the continued healing process are exempt.
11. Clinical characteristic assessments of the DFU begin with Section 7.10 and contain instructions for completing the assessments including the irritation/symptom scale as needed.  
The 12 hr assessment can be done once within the 10-12 window for out-patients and at 12 hrs for in-patient subjects. Assessments are recorded in the eCRF
12. See Item 7 in the Inclusion Criteria – DFU Subjects for acceptable perfusion parameters.  Only 1 test of the 4 (TcPO2, ABI/TcPO2, toe pressure, Doppler ultrasound) is required 
for eligibility. 


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4.6.2.
Time and Events Table Part B
Procedures
Screening
Optional 
Baseline 
Run In 
Visit1
Day 1
Day
4
Day
7
Day 
14
Day
15
Follow-up
Visit Window 
(relative to Day 1)
-28 to -14 
days
Exams/samples 
pre-dose
7-10 days post 
last dose
28-32 days post 
last dose
Clinic Visit
X
X
X
X
X
X
X
X
X
Informed Consent
X
Demographics
X
Complete physical
X
Brief physical
X
X
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
X
12-lead ECG2
X
X
X
Vital signs3
X
X
X
X
X
X
Urine 
pregnancy(females)
X
X
X
Hema/Chem/ Safety 
Labs4
X
X
X
X
X
Vascular Perfusion 
Eligibility 
Assessments5
X
Blood samples for 
HIF, (e.g., EPO, 
Hepcidin, VEGF) 6
X
X
X
Standard of Care 
Treatment7
X
X
<-=========================================->
X
X
Study 
Treatment/Dosing
In the Clinic8
X
X
X
X


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Procedures
Screening
Optional 
Baseline 
Run In 
Visit1
Day 1
Day
4
Day
7
Day 
14
Day
15
Follow-up
PK serial blood 
sampling9
X
X
X
X
PK Trough Sample9
Tissue Biopsies 
(gene expression, 
macrophage and 
bioburden 
analysis)10
X
X
X
Wound Fluid 
(cytokine and 
bioburden 
analysis)11
X
X
X
X
SensiLase (Doppler 
blood flow) 
X
X
X
X
Physical 
Characteristics
(assessed pre-
dose)12
X
X
X
X
X
X
X
Clinical 
Characteristics13
X
X
X
X
X
X
X
Concomitant 
Medication Review
X
  <-=============================->
X
X
Adverse Event 
Assessment14
X
<-============================->
X
X
1.
Optional Baseline Run In visit:  This optional visit is for subjects that will exceed the 14 (1 day) Run-in window between screening and Day 1.
2.
Single ECGs will be taken at Screening and pre-dose on Day 1 and 24h post-last dose on Day15.  ECGs should be taken while subject is supine for at least 5 minutes.  Additional 
ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.


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3.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Days 1, 7, 15 (24h post-last dose), and at Follow-up Visits.  
Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
4.
Blood samples for safety will be collected fasting at Screening and pre-dose/equivalent time on Days 1, 7, 15 (24h post-last-dose), and at the 7-10 day Follow-up Visit.  Refer to 
Section 7.2.4 for specific laboratory parameters to be tested.
5.
See Item 7 in the Inclusion Criteria – DFU Subjects for acceptable perfusion parameters.  Only 1 test of the 4 (TcPO2, ABI, toe pressure, Doppler ultrasound) is required for 
eligibility.
6.
Blood samples for HIFactivation will be collected at pre-dose/equivalent time.  
7.
All subjects will be on SOC throughout the study (Section 7.4).
8.
In between clinic visits, subjects will perform applications of study drug at home.
9.
See separate Time and Events table for serial PK sampling details for Days 1, 7 and 14 and the associated 24 time point.  Refer to Section 7.12 for details on the collection and 
processing of PK samples.  PK sampling times may be changed based on the observed GSK1278863 PK profile.
10. Direct wound tissue biopsies will be collected at pre-dose/equivalent on Days 1, 7, and 15, however based on emerging data, time points may be added or deleted; wounds that 
have healed sufficiently may be exempt.  Refer to Section 7.7.2 for additional details on the collection and processing of tissue biopsies.
11. Wound fluid will be collected at pre-dose/equivalent on Days 1, 7, 15 and at the 7-10 day Follow-up Visit.  Refer to the Section 7.7.1 for additional details on the collection and 
processing of wound fluid samples.
12. Physical characteristics of the wound (i.e., photos of the wound and wound measurement assessments) will be assessed at Screening (Optional Baseline Run In Visit), at pre-
dose/equivalent time on Days 1, 4, 7, 15 and at the 7-10 day Follow-up Visit.
13. Clinical characteristic assessments of the DFU begin with Section 7.10 and contain instructions for completing the assessments including the irritation/symptom scale as needed.  
Assessments are recorded in the eCRF.
14. Adverse events are to be collected from first dose through the final Follow-up visit.


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4.6.3.
Serial PK Time and Events Table Part B
VIST DAY
Part B Serial PK Sampling1,2 
Hours (h)
Pre-
dose
1h
2h
4h
8h
10h
11h
12h
24h
Day 1 
X
X
Day 7 
X
X
Day 14 OUT-PATIENTS
X
X
X
X
X
X3
X
Day 14 IN-PATIENTS
X
X
X
X
X
X
X
1.
Patients are permitted to either stay in clinic (in-patients) or be discharged and return for clinic visits (out-patients).  Refer to Section 7.12 for details on the collection and 
processing of PK samples.  
2.
PK sampling times may be changed based on observed GSK1278863 PK profile.
3.
Sample must be taken within the 10 to 12 hour time window.


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5.
STUDY POPULATION
5.1.
Number of Subjects
Enough subjects will be enrolled in Part A (Single Doses) such that approximately 32 
subjects (~8 healthy volunteers in Cohort 1, and ~24 DFU subjects in Cohorts 2, 3 and 4) 
complete dosing and critical assessments.  If optional cohort(s) are utilized, each cohort 
will enroll approximately 8 subjects (6 on active drug, 2 on placebo).
In Part B, enough subjects will be enrolled such that approximately 48 subjects in Part B 
(~16 DFU subjects per cohort) complete dosing and critical assessments (assumes 
approximately 3 cohorts).
Additional subjects/cohorts may be enrolled to allow for evaluation of additional dose 
levels, based on emerging data.  The IRB will be informed if any additional cohorts 
(including optional cohorts) are included in the study based on local site requirements.
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment sequence at the discretion of the 
GSK Medical Monitor in consultation with the Investigator.
5.2.
Eligibility Criteria – Healthy Volunteers (Part A Cohort 1)
5.2.1.
Inclusion Criteria - Healthy Volunteers (Part A Cohort 1)
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline 
Document Number RM2008/00267/07] Deviations from inclusion criteria are not 
allowed because they can potentially jeopardize the scientific integrity of the study, 
regulatory acceptability or subject safety.  Therefore, adherence to the criteria as 
specified in the protocol is required.
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. ALT, alkaline phosphatase and bilirubin 1.5xULN (isolated bilirubin >1.5xULN 
is acceptable if bilirubin is fractionated and direct bilirubin <35%).
2. Single QTc < 450msec.
3. Healthy as determined by a responsible and experienced physician, based on a 
medical evaluation including medical history, physical examination, laboratory 
tests and ECGs.  A subject with a clinical abnormality or laboratory parameters 
outside the reference range for the population being studied may be included only 
if the Investigator and the GSK Medical Monitor agree that the finding is unlikely 
to introduce additional risk factors and will not interfere with the study 
procedures.  Subjects with Hb values higher than ULN the normal range should 
always be excluded from enrollment.


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4. Male or female between 18 and 90 years of age inclusive, at the time of signing 
the informed consent.
5. A female subject is eligible to participate if she is of:
1.
Childbearing potential, and agrees to use one of the approved 
contraception methods as outlined in Section 8.1 from Screening until completion 
of the Follow-up Visit OR 
2.
Non-childbearing potential (NCBP) defined as pre-menopausal females 
with a documented tubal ligation or hysterectomy; or postmenopausal defined as 
12 months of spontaneous amenorrhea [in questionable cases a blood sample with 
simultaneous follicle stimulating hormone (FSH) > 40MlU/ml and estradiol < 
40pg/mL (<147pmol/L) is confirmatory].  Females on hormone replacement 
therapy (HRT) and whose menopausal status is in doubt will be required to use 
one of the contraception methods in Section 8.1 if they wish to continue their 
HRT during the study.  Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status prior to study enrollment.  For most forms 
of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the 
blood draw; this interval depends on the type and dosage of HRT (consult with 
GSK Medical Monitor).  Following confirmation of their post-menopausal status, 
they can resume use of HRT during the study without use of a contraceptive 
method.
5.2.2.
Exclusion Criteria – Healthy Volunteers (Part A Cohort 1)
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is required.
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody 
result within 3 months of screening 
2. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones).
3. History of malignancy within 5 years of Screening or those with a strong family 
history of cancer (e.g., familial cancer disorders), with the exception of squamous 
cell or basal cell carcinoma of the skin that has been definitively treated.  
4. A history of drug or alcohol abuse, or a history of regular alcohol consumption 
within 6 months of the study defined as an average weekly intake of >14 drinks 
for males or >7 drinks for females.  One drink is equivalent to 12g of alcohol: 12 
ounces (360mL) of beer, 5 ounces (150mL) of wine or 1.5 ounces (45mL) of 80 
proof distilled spirits.
5. A positive test for HIV antibody.


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6. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the 
current study: 30 days, 5 half-lives (whichever is longer).
7. Unable to refrain from the use of prescription or non-prescription drugs, including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days 
(or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) prior to the first dose of study medication, unless in the opinion of the 
Investigator and GSK Medical Monitor the medication will not interfere with the 
study procedures or compromise subject safety.
8. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or GSK 
Medical Monitor, contraindicates their participation.
9. Where participation in the study would result in donation of blood or blood 
products in excess of 500mL within a 56 day period
10. Pregnant females as determined by positive urine hCG test at screening or prior to 
dosing.
11. Unwillingness or inability to follow the procedures outlined in the protocol.
12. Subject is mentally or legally incapacitated.
5.3.
Eligibility Criteria – DFU Subjects
5.3.1.
Inclusion Criteria – DFU Subjects
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is required.
A DFU subject will be eligible for inclusion in this study only if all of the criteria listed 
are met. 
1. Diagnosed with Type I or Type II diabetes mellitus.
2. HbA1c ≤ 12%.
3. Single QTc ≤ 500msec, or ≤ 530msec in subjects with bundle branch block.  No 
QTc exclusion for subjects with a predominantly paced rhythm.
4. Lower extremity diabetic foot ulcer of 30-364 days’ duration.
5. DFU between 1cm² and 22cm² at screening.
6. Presence of at least one DFU that meets all of the following criteria:
a.
Ulcer has been diagnosed as a full-thickness, neuropathic DFU and is located 
at or distal to the malleolus (excluding ulcers between the toes but including 
those of the heel).


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b. There is a minimum 2cm margin between the qualifying study ulcer and any 
other ulcers on the specified foot.
c.
Ulcer size (area) ≥ 1cm2 and ≤ 16cm2 (post-debridement at time of 
randomization).
d. Wagner Grade 1.
e.
Depth ≤ 5mm with no capsule, tendon or bone exposed and no tunneling, 
undermining, or sinus tracts.
Note: If the subject has more than one qualifying DFU, the ulcer designated as the study 
ulcer will be at the discretion of the Investigator.  Non-study ulcers being treated during 
the course of the study will be treated with moist wound therapy Standard of Care (SoC) 
identified under this study).
7. Adequate vascular perfusion of the affected limb within 30 days of screening, as 
defined by at least one of the following:
a) TcPO2 > 35mmHg.
b) Ankle-Brachial Index (ABI) ≥ 0.6 and ≤ 1.2
c) Toe pressure (plethysmography) > 50mmHg.
d) Doppler ultrasound (biphasic or triphasic waveforms) consistent with 
adequate blood flow to the affected extremity, as determined by SoC.
8. ALT, alkaline phosphatase and bilirubin 1.5xULN (isolated bilirubin >1.5xULN 
is acceptable if bilirubin is fractionated and direct bilirubin <35%).
9. Male or female between 18 and 90 years of age inclusive, at the time of signing 
the informed consent.
10. A female subject is eligible to participate if she is of:
1. Childbearing potential, and agrees to use one of the approved contraception 
methods as outlined in Section 8.1 from Screening until completion of the 
Follow-up Visit OR,
2. Non-childbearing potential (NCBP) defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy; or postmenopausal defined as 12 
months of spontaneous amenorrhea [in questionable cases a blood sample with 
simultaneous follicle stimulating hormone (FSH) > 40MlU/ml and estradiol < 
40pg/mL (<147pmol/L) is confirmatory].  Females on hormone replacement 
therapy (HRT) and whose menopausal status is in doubt will be required to use 
one of the contraception methods in Section 8.1 if they wish to continue their 
HRT during the study.  Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status prior to study enrollment.  For most forms 
of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the 
blood draw; this interval depends on the type and dosage of HRT (consult with 
GSK Medical Monitor).  Following confirmation of their post-menopausal status, 
they can resume use of HRT during the study without use of a contraceptive 
method.


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5.3.2.
Exclusion Criteria – DFU Subjects
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is required.
Diabetic subjects that are being considered for this study will not be eligible for inclusion 
in this study if any of the following criteria apply.
1. Subjects with:

Ulcers accompanied by infected cellulitis, osteomyelitis, or clinical signs or 
symptoms of infection,

Gangrene on any part of affected limb,

Active Charcot’s foot on the study limb,

Planned vascular surgery, angioplasty or thrombolysis, 

Ulcers involving exposure of tendon, bone, or joint capsule (It is acceptable 
to have ulcers extending through the dermis and into subcutaneous tissue 
with presence of granulation tissue),

Ulcers due to non-diabetic etiology.
2. Any unstable vascular syndromes (such as TIA, CVA, unstable angina, acute MI 
or ACS event) within 3 months prior to randomization.
3. Malignancy within 2 years of screening, with the exception of squamous cell or 
basal cell carcinoma of the skin that has been definitively treated.
4. Other clinically significant cardiovascular, pulmonary, renal, endocrine, hepatic, 
neurological, psychiatric, immunological, gastrointestinal, hematological, or 
metabolic disease that is, in the opinion of the Investigator or the GSK Medical 
Monitor, not stabilized or may otherwise impact the results of the study.
5. Patients undergoing hemodialysis.
6. Use of prohibited medications as described in Section 9.1 of the protocol.
7. A history of drug or alcohol abuse in the past year, or a history of regular alcohol 
consumption within 6 months of the study defined as an average weekly intake of 
>14 drinks for males or >7 drinks for females.  One drink is equivalent to 12g of 
alcohol: 12 ounces (360mL) of beer, 5 ounces (150mL) of wine or 1.5 ounces 
(45mL) of 80 proof distilled spirits.
8. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the 
current study: 30 days, 5 half-lives (whichever is longer).
9. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or GSK 
Medical Monitor, contraindicates their participation.


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10. Where participation in the study would result in donation of blood or blood 
products in excess of 500mL within a 56 day period.
11. Pregnant females as determined by positive urine hCG test at screening or prior to 
dosing or lactating/nursing females.
12. Unwillingness or inability to follow the procedures outlined in the protocol.
13. Subject is mentally or legally incapacitated.
5.4.
Screen and Baseline Failures
Data for screen and baseline failures will be collected in source documentation at the site 
but will not be transmitted to GSK.
6.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
6.1.
Hypotheses and Treatment Comparisons
The primary objectives of this study are to investigate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of single (Part A) and repeated (Part B) doses 
of GSK1278863A.  No formal statistical hypotheses are to be tested.  Instead, point 
estimates and confidence intervals will be constructed, where appropriate.
6.2.
Sample Size Considerations
6.2.1.
Sample Size Assumptions
There is no formal calculation of power or sample size in this study.  Sample sizes are 
based on feasibility.  A sample size of six subjects per active single dose (Part A), and 
twelve subjects per active repeated dose (Part B) completing the study are feasible 
sample sizes to provide sufficient safety and PK data for this FTIH study.
The target sample size is set at 8 subjects per cohort in Part A, (6 on active treatment and 
2 on placebo), and 16 per cohort in Part B, (12 on active treatment , 2 on placebo and 2 
receiving standard of care.  The sample size for the placebo at each dose level is set at 
two to avoid subject bias in safety assessment.
6.2.2.
Sample Size Re-estimation
No sample size re-estimation will be performed.
6.3.
Data Analysis Considerations
Details of the statistical data analyses will be provided in the Reporting and Analysis Plan
(RAP) separately.  An outline of the statistical analyses is provided in the protocol.


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6.3.1.
Interim Analysis
There will be no formal interim analysis; however, all preliminary safety, tolerability, and 
available pharmacokinetic data will be reviewed internally at GSK prior to each dose 
escalation (GSK study staff are unblinded).
6.3.2.
Final Analyses
Final analyses will be performed after Data Base Freeze (DBF) is declared by Clinical 
Pharmacology Science and Study Operations (CPSSO)
6.3.2.1.
Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
6.3.2.2.
Pharmacokinetic Analyses
Listings will be generated and summary statistics (n, arithmetic mean, standard deviation, 
minimum, median, maximum, geometric mean, SD-log and 95% confidence intervals 
about the geometric mean) will be calculated for each derived plasma pharmacokinetic 
(PK) parameter by regimen and time. PK parameters are listed in Section 3.1.
For Part A, within group comparison (wound versus intact), comparisons of high dose 
versus low dose in DFU, and DFU versus HVT will be assessed used a mixed ANOVA 
model as data permit.
For Part B, dose proportionality will be assessed by using a power model as described 
below:
log(PK Parameter) = 0 + 1∙log(dose)
where 0 is the intercept and 1 is the slope. AUC and Cmax will be used for dose 
proportionality assessments.
If data permit, accumulation ratio will be assessed in Part B.
6.3.3.
Pharmacodynamic Data Analyses
6.3.3.1.
Wound Healing Endpoints (Part B)
Wound healing data will be summarized by regimen and time.
If data permit, rate of wound healing will be analyzed by analysis of covariance 
(ANCOVA) with dose group, visit, interaction of dose group and visit as fixed effects 
and the baseline assessments as covariates, appropriate variance-covariance structure may 
apply if data permit.  Point estimates and 95% confidence intervals will be constructed 
for the comparisons of interest (i.e., Active – Placebo) for each dose of GSK1278863A.  
If appropriate, loge-transformation will be applied.  In such cases, results will also be 
presented as ratios (Active : Placebo) with 95% confidence intervals.


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Time to complete DFU closure will be assessed by time to event method (log rank test) as 
data permit.
Other wound healing related endpoints will analyzed as appropriate to the data, as data 
permit.
Mean/SE plot and box plot will be created as appropriate to the data.
6.3.3.2.
mRNA, Protein and Biomarker Data Analysis
Biomarker data will be summarized by regimen and visit for Part A and Part B.
Biomarkers of HIF activation in Part A will be analyzed by 1) analysis of variance model 
(ANCOVA), 2) comparison of active dose vs. placebo, and 3) change from baseline 
within treatment group will be assessed, as data permit.
Biomarker data from Part B will be analyzed similarly.  In the ANCOVA model, 1) visit, 
2) interaction of dose and visit, and 3) comparison of active dose versus placebo at each 
visit time point will be assessed as data permit.
Mean/SE plots and box plots will be created as appropriate to the data.
6.3.3.3.
Other Pharmacodynamic Endpoints
Pharmacodynamic (PD) endpoints will be summarized and analyzed as described in 
Section 6.3.3.1, as appropriate to the data.
6.3.3.4.
Pharmacokinetic/Pharmacodynamic Analyses
If data permit, exploratory analyses will be performed to determine any potential 
relationships between systemic indices of exposure (Cmax and AUC) and various 
markers of efficacy and safety.  Where potential relationships are observed, various 
established hierarchies of linear and non-linear models may be tested and fitted to 
evaluate any relationship seen.
A goal of this study is to identify a drug exposure (or dose) relationship with the primary 
endpoint, rate of wound healing. If data allow, the observed trajectories of wound 
healing from Day 1 until the end of repeat dosing (two weeks) will be modeled and the 
relationship with drug exposure (or dose) will be determined.  This model will aid in 
designing the next long term study for this indication and will be implemented by 
performing simulations to chose doses, numbers of patients per dose, etc. In addition, 
any relationships/correlations between the wound healing rate and biomarkers will be 
identified and included in the model if deemed appropriate. 
6.3.3.5.
Pharmacodynamic/Biomarker Analyses
If data permit, the relationships between various biomarkers and wound healing
endpoints, as well as other PD endpoints, will be explored similarly to Section 6.3.3.4.


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7.
STUDY ASSESSMENTS AND PROCEDURES
This section lists the parameters of each planned study assessment.  The exact timing of 
each assessment is listed in the Time and Events Table (Section 4.6).  Detailed 
procedures for obtaining each assessment are provided in the sections below.  Whenever 
vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: 12-lead ECG, vital signs, blood draws.  
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 
and pharmacodynamic/biomarker/novel biomarker 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 approved and 
documented by GSK, but this will not constitute a protocol amendment.  The IRB will be 
informed of any safety issues that require alteration of the safety monitoring scheme.  No 
more than 500mL of blood will be collected over the duration of the study, including any 
extra assessments that may be required.
7.1.
Demographic/Medical History Assessments
The following demographic parameters will be captured: date of birth, gender, race and 
ethnicity.
Medical/medication/alcohol history will be assessed as related to the eligibility criteria 
listed in Section 5.2.  Cardiovascular medical history/risk factors will also be assessed at 
baseline.
7.2.
Safety
Planned timepoints for all safety assessments are listed in the Time and Events Tables 
(Section 4.6).  Additional time points for safety tests such as vital signs, physical exams 
and laboratory safety tests may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.2.1.
Physical Exams
The exam will be performed by a qualified licensed, medical professional (i.e., physician, 
physician assistant, or nurse practitioner) and include a thorough review of all body 
systems.

A complete physical examination will include assessments of the head, eyes, ears, 
nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and 
spleen), lymph nodes and extremities.  Height and weight will also be measured and 
recorded.

A brief physical examination will include assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).


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7.2.2.
Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure and pulse rate.  
The subject will be resting in a supine or semi-supine position for at least 5 minutes prior 
to the procedure.  
7.2.3.
Electrocardiogram (ECG)
Single 12-lead ECGs will be obtained at each timepoint during the study using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  The subject will be resting in a supine position for at least 5 minutes prior to 
the procedure.  Refer to Section 4.5.1.3 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.
7.2.4.
Clinical Laboratory Assessments
Hematology, clinical chemistry, and additional parameters to be tested in all subjects are 
listed in Table 5.
Table 5
List of Clinical Laboratory Assessments
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes
Reticulocyte Count
MCHC
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
Clinical Chemistry
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Chloride
ALT (SGPT)
Uric Acid
Glucose, fasting
Total CO2
GGT
Albumin
Sodium
Calcium
Alkaline phosphatase
Total Protein
CPK
HbA1C
hsCRP
Additional Lab Assessments for HIF activation
VEGF
Hepcidin
Iron
EPO
Ferritin
Iron Binding Saturation


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Other screening tests
HIV
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody -- if second generation Hepatitis C antibody positive, a hepatitis C antibody 
Chiron RIBA immunoblot assay (or other third generation immunoassay) should be reflexively performed on 
the same sample to confirm the result, as sample availability permits. 
FSH and estradiol (as needed in women of non-child bearing potential only)
Urine pregnancy test (females only, with the exception of subjects randomized to SoC)
7.3.
DFU Assessments
The following assessments will be performed in Part A and Part B of the study according 
to site designation, capability and feasibility.
7.3.1.
Part A
Blood samples for HIF, (e.g., VEGF, EPO).  All Cohorts
Biomarker Samples  (e.g., for cytokines and bioburden)  DFU subjects only
Gene Expression (mRNA) Tissue Samples DFU subjects only
Physical Indicators (e.g., photos and wound measurement)  DFU subjects only
Clinical Indicators  DFU subjects only
7.3.2.
Part B
Blood samples for HIF, (e.g., VEGF, EPO).
Biomarker Samples:  (e.g., for cytokines and bioburden)
Gene Expression (mRNA) and Macrophages (Immunohistochemistry)Tissue Samples
Heavy Water (Site involvement will depend on site feasibility – selected subjects (one cohort) 
based on emerging data) (Repeat Dosing only.)  Tissue samples via biopsy.
SensiLase (Dopplar blood flow)
Hyperspectral Imaging (oxygen dynamics) – if the technique can be established/validated. (Site 
involvement will depend on site feasibility – selected subjects (one cohort) based on emerging 
data) (Repeat Dosing only.)  
Physical Indicators (e.g., photos and wound measurement). Silhouette for volume (record in eCRF)  
Digital photos (core) and acetate tracings (after screening scan and upload and send to core).
Clinical Indicators
Irritation/symptom Scale
7.4.
Standard of Care Treatment
All subjects with DFU will receive Standard of Care treatment during this study.  This 
will include active treatment arms, Run-in, Washout and for those randomized to the SoC 
treatment arm in the Treatment Period.  Patients in this study will receive the same SoC-
wound care that they would receive were they not in the study.


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SoC consists of treatment plans that manage the wound environment through the phases 
of wound healing.  Debridement and moist wound care are the fundamentals of wound 
care.  A moist wound environment is promoted through the appropriate use of wound 
dressings and wound gels or ointments.  Appropriate dressing application manages 
wound exudates and prevents degradation of epithelial cells and biochemical wound 
healing components.
SoC treatment arm is as follows:

Cleanse wound with normal saline.

Perform sharp debridement "as needed".

Apply moist occlusion (0.9% sodium chloride gel plus a secondary dressing 
consisting of non-adherent foam and an outer gauze wrap) and offload using a 
removable cast or healing sandal, as appropriate.
7.4.1.
Wound Bed Preparation and Debridement
Wound bed preparation is defined as the management of the ulcer to accelerate 
endogenous healing to facilitate the effectiveness of other therapeutic measures.  The 
goal of wound bed preparation is to convert the molecular and cellular environment of a 
chronic wound to that of an acute wound.  Necrotic tissue, excessive bacterial burden, 
senescent cells, and cellular debris can all inhibit wound healing.  Surgical (sharp) 
debridement is the preferred method of debridement. 
Wound debridement procedures:
Assess pain level and determine appropriate method of pain control.

Cleanse wound with sterile saline.

Utilize sterile tissue scissors, forceps, surgical blade and/or other appropriate surgical 
instruments to remove devitalized tissue, as clinically indicated.

Following debridement, cleanse wound with sterile saline.

Achieve hemostasis through use of pressure, topical coagulants or electrocautery as 
indicated.

Apply appropriate wound dressing.
7.5.
Gene Expression
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with DFU or medically related conditions and/or the action of 
GSK1278863 will be identified by application of:

Measurement of the levels of a subset of RNA species on blood and wound tissue 
samples.

Proteome analysis of plasma and wound tissue samples.


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All samples will be retained for a maximum of 15 years after the last subject completes 
the trial.
7.5.1.
RNA Expression Research of a Subset of RNA Species
RNA expression studies will be conducted using quantitative RT-PCR, and/or alternative 
equivalent technologies, which can facilitate the simultaneous measurement of the 
relative abundances of hundreds of RNA species resulting in a RNA expression profile 
for each blood and wound tissue sample.  The RNAs assayed may be those involved with 
the pathogenesis or bioburden of DFUs, the absorption, distribution, metabolism, or 
excretion of GSK1278863 or in the subject’s response to GSK1278863.  In addition 
continuing research may identify other proteins or regulatory RNAs that may be involved 
in response to GSK1278863 or the pathogenesis of DFUs.  The RNAs that code for these 
proteins and/or regulatory RNAs may also be studied.  This will enable the evaluation of 
changes in RNA expression profiles that may correlate with biological response relating 
to DFUs, wounds, disorders related to the skin or the action of GSK127886.
7.5.2.
Proteome Research
Wound tissue proteome studies may be performed by 2-D gel separation, and/or peptide 
mass mapping, or an alternative equivalent procedure.  Proprietary algorithms and 
standard statistical techniques, such as ANOVA and ANCOVA, may be used to identify 
individual proteins exhibiting statistically acceptable changes in their levels between 
samples, and between groups of samples.  These differentially expressed proteins may be 
identified by mass spectrometry or equivalent technology.  This will enable the 
evaluation of changes in proteome profiles that may correlate with biological response 
relating to DFUs, wounds, other disorders of the skin and medically related conditions, or 
the action of GSK1278863.
The same samples may also be used to confirm findings by application of alternative 
technologies.
7.6.
HIF Alpha
Blood samples for evidence of HIF activity (i.e., EPO, Hepcidin, VEGF) will be collected 
for all subjects, according to the table in Section 4.6.  See the Study Procedures Manual 
(SPM) for processing, storage and shipping instructions.
7.7.
Biomarkers (e.g., Cytokines, Bioburden and Gene 
Expression) Collection and Processing
With the subject’s consent, wound biopsy tissue, wound fluid and blood sample(s) will be 
collected during this study to  be used for the purposes of measuring novel biomarkers to 
identify factors that may influence wound healing and tissue repair and/or medically 
related conditions, as well as the biological and clinical responses to GSK.1278863.  If 
relevant, this approach will be extended to include the identification of biomarkers 
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Samples will be collected at the timepoints indicated in Section 4.6.  The timing of the 
collections may be adjusted on the basis of emerging PK or PD data from this study or 
other new information in order to ensure optimal evaluation of the PD endpoints.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with wound healing and tissue repair or medically related conditions 
and/or the action of GSK1278863 may be assessed in accordance with the objectives and 
endpoints of the study.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial.
7.7.1.
Wound Fluid Collection Directions

All wound fluid samples are to be collected before wound debridement.  The 
periwound area is to be prepped with an alcohol swab while being careful not to 
touch the wound base or the interior of the wound with the swab.

The following wound fluid samples are to be collected at each visit using periopaper:

Three cytokines samples, placed in pre-labeled cryovials 

Two bacterial samples, placed in pre-labelled cryovials containing Tris EDTA 
(TE) buffer solution (150µL/tube)

Remove the periostrip from the sleeve by carefully holding only the orange section 
of the strip with a sterile forceps.

Place the white end of the periostrip at appropriate collection site.  Hold each 
periostrip in place for 30 seconds or until the entire white section of the periopstrip is 
visibly wet.

Immediately after collection, using the forceps, transfer the periopstrip to the pre-
labelled cryovial and then immediately drop the vial into liquid nitrogen to snap 
freeze samples.

After snap freezing, the vials are to be transferred to a pre-labelled freezer box and 
then moved immediately into a -80C freezer.  Samples will be shipped to laboratory 
within 8 months of collection.  Shipping instructions are in the SPM.
7.7.2.
Punch Biopsy Directions

Whenever feasible, tissue biopsies should be done at the time of debridement.

Prior to obtaining biopsies, the wound is to be cleansed with saline solution.  

Obtain 3 tissue samples in the locations shown in Figure 4 by holding a punch biopsy 
instrument vertically over the wound then rotating down in a circular motion (using 
first two fingers).   Once the instrument has penetrated the wound bed down to the 
hub, it can be removed.  Using a needle held in the non-dominate hand, stretch the 
cylindrical tissue specimen away from the wound bed and use scissors held in the 
dominate hand to cut the specimen free.  The use of forceps is discouraged because 
these instruments cause crush artifact that can render the sample unusable.


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Figure 4
Sample locations within the DFU

Place tissue samples in pre-labelled collection tubes for processing and storage.

Obtain hemostasis as needed by method of choice of application of pressure, 
lumicain, or silver nitrate.  Dress wound with appropriate dressing.

Study wounds that have healed sufficiently will be exempt from further biopsies.  
This determination is at the discretion of the Principal Investigator or designee.
7.7.3.
Macrophages
Macrophage analysis will be performed by immunostaining of sections of tissue prepared 
from biopsy samples.  Tissue sections will be prepared for immunohistochemical analysis 
according to standard procedures, and immunostained with anti-CD68 antibody to detect 
macrophage.  If methodology permits, CD68 immunostaining may be combined with 
markers of particular macrophage subtypes (for e.g., CD206 for M2 macrophage).  This 
will enable the evaluation of changes in immune cell infiltration and function that may 
correlate with biological response relating to DFUs, wounds, diseases of the skin and 
medically related conditions or the action of GSK1278863.
7.7.4.
Sample Collection for Macrophage Immunostaining
Upon collection, the biopsy will be placed in a pre-labelled cryovial and snap frozen in 
liquid nitrogen.  The cryovials will be transferred to a pre-labelled freezer box and then 
moved immediately into a -80C freezer.  Samples will be shipped to laboratory within 8 
months of collection.  Shipping instructions are in the SPM.
7.8.
Angiogenesis: Tissue Perfusion Assessment/Oxygen 
Availability
7.8.1.
Vascular Perfusion
Assessments of vascular perfusion will be made according to the schedule in Section 4.6.  
Skin Perfusion Pressure (SPP) will be evaluated with the SensiLase System, which 
provides quantitative evaluation of microcirculatory perfusion in the skin.  It measures 
skin perfusion (capillary perfusion pressure, or microcirculation) using a laser Doppler 


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sensor located beneath a pressure cuff (much like a blood pressure cuff).  During the test 
the cuff is automatically inflated to the point the sensor determines that skin perfusion has 
stopped; the pressure is then released at a controlled rate while the cuff pressure and skin 
perfusion are measured.  A laser detects the movement of blood upon release of the cuff; 
the pressure measured, in mmHG, is recorded at this instance giving the SPP reading.  
Subjects will have a plastic guide placed next to their wound and then a blood pressure 
cuff will be placed over the guide.  The cuff will then be inflated and deflated while the 
reading is automatically captured.  Software displays a graph of pressure and perfusion 
during cuff deflation and indicates the pressure at which skin perfusion is found to return.
7.8.1.1.
Instructions for Assessing Vascular Perfusion with SensiLase
The subject is placed in a supine position.  The laser wand is placed in the guide and the 
guide is placed adjacent to the wound, as close to the peri-wound area as possible while 
remaining on completely epithelialized tissue.  A disposable cuff liner is placed on the 
cuff and the cuff is then placed snugly but not overly tight around the laser guide.  One or 
two readings are to be taken:  The first reading is to be taken at 12:00, with 12:00 being 
the most proximal edge of the wound.  The next reading is also to be taken at the 
proximal side of the wound but within the angiosome tissue block, if position one is not 
within the angiosome tissue block.  All relevant angiosomes necessary for appropriate 
interpretation of blood flow should also be captured. Angiosomes are designated 
locations found in the instruction manual for SensiLase.
7.8.2.
Oxygen Dynamics/Angiogenesis
Oxygen dynamics and angiogenesis may be assessed by hyperspectral imaging as site 
feasibility allows and if the technique can be established/validated.
7.8.2.1.
Hyperspectral Imaging Instructions
The hyperspectral imaging system illuminates the patient’s tissue with light. Light that is 
reflected from the tissue is captured by a digital camera, and from a series of color 
images, spectral and statistical analyses are performed using computer software, to 
determine the chemistry of the tissue being imaged.  A light and camera are placed 
several feet from the patient (None of this equipment ever touches the patient) and the 
image is captured in the system for analysis.  The outcome of this study is for the 
resulting chemically encoded images to aid surgeons and clinicians assess and navigate 
the patient’s condition and to make clinical decisions regarding treatment.
7.9.
Physical Characteristics of the DFU
7.9.1.
Location of the Study Ulcer
The location of the study ulcer will be recorded as foot (left or right), surface (plantar, 
dorsal, medial aspect of heel, medial aspect of great toe, posterior or lateral), and area 
[forefoot, midfoot, hindfoot (including the calcaneus), first through fifth metatarals or 
proximal to the foot on the ankle].  If more than one ulcer is located in the same 
proximity, be certain to clearly identify the specific study ulcer. 


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7.9.2.
Instructions for Assessment of Physical Characteristics of the 
DFU - Wound Measurement and Photography
7.9.2.1.
Photo Capture – Wound Images
Photographic documentation of the wound should be obtained after debridement.  
Randomization and weekly imaging of the wound should occur after cleansing and before 
treatment with study drug.
Photographic documentation should be sent electronically to the core lab as soon as
possible, preferably on the same day the picture was taken.
Photographs of wounds will be stored locally at each site and uploaded to the wound core 
lab.  Refer to the SPM for details.
7.9.2.2.
Wound Tracings
Tracings of the wound should be obtained after debridement. To ensure the subject meets 
the randomization eligibility of the change in ulcer size between screening (or optional 
Baseline Run In visit, if different from day of screening) and randomization on Day 1, 
percent reduction of wound size must be calculated by the Investigator or designee using 
the method for measuring wound area provided in the SPM.  The core lab may be 
consulted for assistance with area measurements or percent reduction determinations if 
necessary.
All wound tracings are to be scanned and sent to the core lab along with wound 
photographs (Section 7.9.2.1).  
Original copies of the wound tracing are to be retained as source documents in the 
subjects’ study files.  Original tracings may be sent to the wound core lab when a quality 
scan cannot be obtained.  Refer to the SPM for additional details.
7.9.2.3.
Depth and Volume Measurements
The ARANZ Medical Silhouette system will be used for wound depth and volume 
measurement.  All photographic parameters, including lighting, distance, and exposure, 
should comply with the ARANZ Silhouette Digital Camera Instruction Manual 
specifications.  The volume measurement will be obtained directly from the camera and 
the measurement recorded on the case report form.  Sites that do not have access to the 
ARANZ Medical Silhouette system will not be required to collect these exploratory data. 
7.9.2.4.
Ulcer Size Reduction
Percent change in study ulcer area will be determined by the site after the subject has 
completed the two-week Run-in period in order to determine if the subject qualifies for 
randomization.  At the end of the Run-in period, the subject ulcer size reduction cannot 
exceed 30% in order for the subject to receive treatment.  This assessment will be 
determined as an objective measurement, using the ulcer tracings collected at study visits.


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7.10.
Clinical Characteristics of the DFU
At each study visit, the investigator will assess the characteristics of the ulcer being 
treated.  The investigator will assess, using the chart below (Table 6), the wound edge, 
base color, periwound condition, periwound color, degree of edema, amount of exudate 
(drainage), type of exudate and percent of granulation tissue present.  The investigator 
will also assess whether the wound is healed or not healed.
Table 6
Ulcer Characteristics Chart
7.10.1.
Ulcer Exudate
Using the categories below as guidance, the Investigator will determine the amount and 
type of study ulcer exudate.  The Investigator must take into account the amount of 
exudate absorbed into the study ulcer dressing.  The following categories will be used to 
quantify the amount of ulcer exudate:


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
No exudate

Minimal amount: Light (scant) or small amount

Moderate amount
Heavy/large/copious amounts
The following categories will be used to describe the type of exudate:
Not applicable: no exudate present
Serous: clear or light yellow watery plasma
Serosanguineous: pink to light-red watery plasma
Sanguineous: red with fresh bleeding
Purulent: thick and opaque exudate, of creamy yellow, green, white, or tan color
7.10.2.
Ulcer Assessments
The presence/absence of the following signs of infection at the study ulcer site will be 
documented at each visit:
Purulence
Malodor
Pain
Increased warmth
Erythema*
Tenderness
Induration
Swelling*
No symptoms present

If Erythema or Swelling is selected, please complete the more detailed irritation 
assessments in Section 7.10.3. 
7.10.3.
Irritation Symptom Assessment
An irritation symptom assessment may be completed in both Part A and Part B of the 
study if ulcer assessments suggest that erythema and/or swelling are present. 
Irritation Symptom Scale
Skin Irritation Scale:
Is infection present: Y / N


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Erythema:
Score _____
Very slight erythema (barely perceptible) =1
Well-defined erythema = 2
Moderate to severe erythema = 3
Severe erythema[Severe erythema (beet redness) to slight eschar formation]= 4
Swelling/Edema:
Score_____
Very slight edema (barely perceptible) =1
Slight edema (edges are well defined by definite raising) = 2
Moderate (rasing approximately 1 millimeter) = 3
Severe edema (raising more than 1 millimeter and extending beyond the area of 
exposure = 4
7.11.
Cell Proliferation and Collagen Turnover (Heavy Water 
Assessment)
Cell proliferation and collagen turnover will be assessed by incorporation of 2H2O (also 
called deuterated water or heavy water) into DNA and proteins in tissue biopsy samples.
Cell proliferation and collagen turnover is expected to increase at the wound site in 
patients receiving GSK1278863.
Complete instructions for heavy water assessment are not available at the time of this 
published protocol; if heavy water assessment is to be performed, based on feasibility 
(including site feasibility) and emerging data, an amendment will be issued prior to 
implementation.
7.12.
Pharmacokinetics
7.12.1.
PK Blood Sample Collection
Except for subjects randomized to Standard of Care, blood samples for pharmacokinetic 
analysis of GSK1278863 and metabolites will be collected into 2mL K3 EDTA tubes at 
the time points indicated in Section 4.6, Time and Events Tables. The actual date and 
time of each blood sample collection will be recorded. The timing of PK samples may be 
altered and/or PK samples may be obtained at additional time points to ensure thorough 
PK monitoring. Sample collection, processing, storage and shipping procedures are 
provided in the Study Procedures Manual (SPM).


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7.12.2.
PK Blood Sample Analysis
Plasma analysis will be performed under the management of Bioanalytical Science and 
Toxicokinetics, DMPK, GlaxoSmithKline. Concentrations of GSK1278863 and 
metabolites will be determined in plasma samples using the currently approved analytical 
methodology. Raw data will be stored in the archives at the site of bio-analysis. Once 
the plasma has been analyzed for GSK1278863 and metabolites any remaining plasma 
may be analyzed qualitatively for other circulating metabolites and the results reported 
under a separate DMPK protocol.
7.12.3.
PK Sampling Windows
Best effort should be made to draw pharmacokinetic blood samples at exactly the 
scheduled time point.  However, samples will be considered drawn per protocol if 
obtained within the following windows following each dose:

Within 2 minute of target time, for samples from 0:30 to 1:30 post-dose

Within 15 minutes of target time, for samples from 2:00 to 6:00 post-dose

Within 30 minutes of target time, for samples after 6:00 post-dose

Within 3 hours of target time for the 48 hour post-dose PK sample
7.12.4.
Sample Analysis
Plasma analysis will be performed under the management of Worldwide Bioanalysis, 
DMPK, GlaxoSmithKline.  Concentrations of GSK1278863 will be determined in plasma 
samples using the currently approved analytical methodology.  Raw data will be stored in 
the GLP Archives, GlaxoSmithKline.  Once the plasma has been analyzed for 
GSK1278863 any remaining plasma may be analyzed qualitatively for other circulating 
metabolites and the results reported under a separate DMPK protocol.  
7.12.5.
Microdialysis
Tissue samples may also be analyzed by micro-dialysis for concentrations of 
GSK1278863 (Part B repeat dosing).  Microdialysis, if performed, will be conducted at 
one site only in selected subjects (one cohort), based on emerging data.
Instructions for microdialysis are not available at the time of this published protocol; if 
Microdialysis is to be performed, based on feasibility and emerging data, anamendment 
will be issued prior to implementation.
7.13.
Pregnancy
7.13.1.
Time Period for Collecting Pregnancy Information
Information on all pregnancies in female subjects will be collected after the start of 
dosing and through follow-up. 


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7.13.2.
Action to be Taken if Pregnancy Occurs
The investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study.  The investigator will record pregnancy 
information on the appropriate form and submit it to GSK within 2 weeks of learning of a 
subject's pregnancy.  The subject will also be followed to determine the outcome of the 
pregnancy.  Information on the status of the mother and child will be forwarded to GSK.  
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.  Any premature termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE.
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK as 
described in Section 12.9.  While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating will discontinue study 
medication and be withdrawn from the study and complete all withdrawal procedures.
8.
LIFESTYLE AND/OR DIETARY RESTRICTIONS
8.1.
Contraception Requirements
8.1.1.
Female Subjects
For female subjects who can become pregnant and for those on HRT and for whom 
menopausal status is not confirmed, at least one of these contraceptive methods, 
classified as highly effective, is required.
Abstinence
Abstinence from penile-vaginal intercourse must be consistent with the preferred and 
usual lifestyle of the subject.  Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Contraceptive Methods with a Failure Rate of < 1%

Oral contraceptive, either combined or progestogen alone

Injectable progestogen

Implants of etonogestrel or levonorgestrel

Estrogenic vaginal ring

Percutaneous contraceptive patches


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
Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure 
rate as stated in the product label

Male partner sterilization (vasectomy with documentation of azoospermia) prior 
to the female subject's entry into the study, and this male is the sole partner for 
that subject.  For this definition, “documented” refers to the outcome of the 
investigator's/designee’s medical examination of the subject or review of the 
subject's medical history for study eligibility, as obtained via a verbal interview 
with the subject or from the subject’s medical records.

Male condom combined with a female diaphragm, either with or without a 
vaginal spermicide (foam, gel, cream or suppository).
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible 
for ensuring subjects understand how to properly use these methods of 
contraception.
8.2.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests.  Subjects may participate in light recreational activities 
during studies (e.g., watch television, read).
9.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
9.1.
Prohibited Medications
The healthy volunteer subjects must abstain from taking prescription or non-prescription 
drugs (including vitamins and dietary or herbal supplements), with the exception of those 
listed in Section 9.2, within 7 days (or 14 days if the drug is a potential enzyme inducer) 
or 5 half-lives (whichever is longer) prior to the first dose of study medication until 
completion of the follow-up visit, unless in the opinion of the Investigator and sponsor 
the medication will not interfere with the study.
Diabetic subjects must abstain from taking potent CYP2C8 inhibitors and inducers such 
as gemfibrozil and rifampin/rifampicin.  This is because the primary route of metabolism 
of GSK1278863 involves CYP2C8.  Data from a study (PHI113634) to assess the 
interaction potential between GSK1278863 and a CYP2C8 inhibitor (gemfibrozil) 
showed a clinically significant increase in GSK1278863 exposure following 
co-administration.  Therefore, inhibitors of CYP2C8 are prohibited from 7 days prior to 
the first dose of investigational product until 7 days after the last dose of investigational 
product and inducers of CYP2C8 are prohibited from 14 days prior to the first dose of 
investigational product until 7 days after the last dose of investigational product.


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9.2.
General Considerations
Occasional use of acetaminophen, defined as doses of 2 grams/day up to 48 hours prior 
to the first dose of study drug and until completion of follow-up procedures may be 
acceptable, at the discretion of the Principal Investigator or his/her designee.
Patients may not receive any erythropoietin stimulating agent for 3 months prior to 
screening, until after final study assessments during the Follow-Up Visit.
Patients may not receive systemic medication known to affect healing (e.g. 
corticosteroids (inhaled are permitted), methotrexate, TNF agents etc).
Women receiving HRT are permitted to continue therapy while on study.  See Section 
5.2.1 or Section 5.3.1.
All concomitant medications taken during the study will be recorded in the CRF. The 
minimum requirement is that drug name, dose administered and the dates of 
administration be recorded.
If the study ulcer is considered infected after the subject is enrolled the ulcer infection 
must be recorded as an Adverse Event.  Subjects can remain in the study, however if 
infection occurs during washouts etc, the subjects must clear the infection prior to 
continuing. 
10.
COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS
10.1.
Subject Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
10.2.
Subject Withdrawal Criteria
Refer to Section 4.5 for dose adjustment/stopping criteria based on safety/PK/PD criteria.
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral or 
administrative reasons.
10.3.
Subject Withdrawal Procedures
10.3.1.
Subject Withdrawal from Study
Subjects may withdraw from the study at any time and for any reason.  They are not 
obliged to state the reason for withdrawal.  However, the reasons for withdrawal, or 
failure to provide a reason, must be documented by the physician on the eCRF.  Every 
effort should be made by the physician to follow up subjects who withdraw from the 
study, by adhering to follow-up procedures specified in Section 4.6.


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10.3.2.
Subject Withdrawal from Study Treatment
If a subject does not receive all doses of randomized study drug planned for that subject,
the subject will be considered to have prematurely discontinued study drug.  Every effort 
should be made by the physician to follow up subjects who withdraw from the study, by 
adhering to follow-up procedures specified in Section 4.6.
Decisions regarding replacement of subjects prematurely discontinued from study drug 
will be made by the Investigator and GSK Medical Monitor on a case-by-case basis.
10.4.
Treatment After the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition, whether or not GSK is providing specific 
post-study treatment.
11.
STUDY DRUG DOSAGE AND ADMINISTRATION
11.1.
In-House Dosing
Subjects will receive investigational product directly from the Investigator or appropriate 
designee.
The dose of investigational product will be confirmed by a member of the study site staff 
other than the person administering the investigational product and prior to 
investigational product administration.
Instructions to sites:
1) Determine wound size in cm2
2) Using proper ointment strength, determine amount (mg) of ointment to dispense 
for direct application to wound, for example:
3) Weigh ointment and transfer into dosing syringe
4) Weigh dosing syringe with ointment and record weight
5) Dispense ointment directly onto wound via syringe
6) After ointment is applied record the weight of empty dosing syringe to determine 
the precise amount of drug delivered
The amount of ointment (per wound size) applied may change as data is collected in 
order to adjust for exposure and/or safety.


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11.1.1.
At-Home Dosing
Pharmacists should dispense study drug for at-home dosing and label the container “Take 
as directed”.  A dosing card will be given to the subject, depending on the group they are 
randomized to, for instruction on at-home dosing.  The dosing card will include detailed 
contact information for contacting study staff 24 hours per day.  The patient’s wound size 
will be determined and the amount of ointment for daily administration will be recorded 
on the dosing card.  As above: 
A conversion of ointment amount to ribbon length measured with the placard will be 
provided by GSK.
Compliance with study medication will be checked every time the subject returns for a 
study visit.  The ointment tubes will be weighed prior to dispensing and during office 
visits to assess a daily averaged administered amount.
Patient instructions for dosing at home:  
1. Site will provide a pre-marked placard to the patient indicating the amount of 
ointment to be applied. 
2. Subjects will be directed to apply the ointment using the placard and to continue 
with their prescribed SoC. 
3. Subjects will be instructed to avoid contact with the ointment other than at the 
wound site and to maintain aseptic techniques.
4. They will be instructed to return to the site with the tube(s) at each visit. 
5. The sites will weigh the tube(s) to estimate the amount of ointment use by the 
patient. 
11.2.
Blinding
This will be a single-blind study, in that GSK study team members and the pharmacist at 
the site will be unblinded, but other site staff and subjects are blinded. 
Because the GSK study team will be assessing data on a real-time basis while the study is 
ongoing, the team will be unblinded during the trial to allow accurate correlation of 
safety and tolerability information with PK and PD values.  For this reason, this study is 
characterized as a single-blind study.
The investigator or treating physician may unblind a subject’s treatment assignment only 
in the case of an emergency, when knowledge of the study treatment is important for the 
appropriate clinical management or welfare of the subject.  Whenever possible, the 
Investigator must first discuss options with the GSK Medical Monitor or appropriate 
GSK study personnel before unblinding the subject’s treatment assignment.  If this is 
impractical, the investigator must notify GSK as soon as possible, but without revealing 
the treatment assignment of the unblinded subject, unless that information is important 


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for the safety of subjects currently in the study.  The date and reason for the unblinding 
must be recorded in the appropriate data collection tool.
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician.  The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the eCRF.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE.  If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to clinical investigators in 
accordance with local regulations and/or GSK policy.
11.3.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
11.4.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK1278863 is 
provided in the SPM.
Study drug must be dispensed or administered according to procedures described herein.  
Only subjects enrolled in the study may receive study drug.  Only authorized site staff 
may supply or administer study drug.  All study drug must be stored in a secure area with 
access limited to the investigator and authorized site staff.  Study drug is to be stored at 
15-25C and protected from light.  Maintenance of a temperature log (manual or 
automated) is required.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance.  
The investigator or the head of the medical institution (where applicable), or designated 
site staff (e.g., storage manager, where applicable) must maintain study treatment 
accountability records throughout the course of the study.  The responsible person(s) will 
document the amount of study treatment received from and returned to GSK and the 
amount supplied and/or administered to and/or returned by subjects.  The required 
accountability unit for this study will be tube, including tube weight.  Discrepancies are 
to be reconciled or resolved.  Procedures for final disposition of unused study treatment 
are listed in the SPM.
Investigational product is not expected to pose significant occupational safety risk to site 
staff under normal conditions of use and administration.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists.  Notify the 
monitor of any unintentional occupational exposure.  A Material Safety Data Sheet 
(MSDS)/equivalent document describing occupational hazards and recommended 
handling precautions either will be provided to the investigator, where this is required by 
local laws, or is available upon request from GSK.


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11.5.
Assessment of Compliance
When the individual dose for a subject is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff.
When subjects are dosed at the study site, they will receive study treatment directly from 
the investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.
Instructions for checking drug compliance after at-home dosing are in the SPM.
11.5.1.
Treatment of Study Treatment Overdose
GSK does not recommend specific treatment for an overdose.  The investigator will use 
clinical judgment to treat any overdose.
12.
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE 
EVENTS (SAE)
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the start of Study Treatment and until the follow-up contact.
SAEs will be collected over the same time period as stated above for AEs.  However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product will 
be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact.  All SAEs will be recorded and reported to GSK within 
24 hours, as indicated in Section 12.9.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
subject has been discharged from the study, and he/she considers the event reasonably 
related to the study treatment or study participation, the investigator would promptly 
notify GSK.
12.1.
Definition of Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
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 medicinal product.


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Events meeting the definition of an AE include:

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be 
clinically significant in the medical and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae.).
Events that do not meet the definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied, or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
subject’s condition, or otherwise meets the definition of an SAE.  For 
example, periodic treatment responsive hyperglycemia in patients with diabetes, 
ulcer: non-purulent exudates, transient inflammation near wound, some pain and 
local swelling with debridement.

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition 
that leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
12.2.
Definition of Serious Adverse Events
If an event is not an AE per Section 12.1, 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, etc).
An SAE is any untoward medical occurrence that, at any dose:
a) Results in death
b) Is life-threatening


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NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c) Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d) Results in disability/incapacity, or
NOTE:  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 or prevent everyday life functions but do not constitute a substantial 
disruption.
e) Is a congenital anomaly/birth defect
f)
Medical or scientific judgment should be exercised in deciding whether reporting 
is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These should also be 
considered serious.  Examples of such events are invasive or malignant cancers, 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse.
g) Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or 

ALT 3xULN and INR** > 1.5. 
* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick.  If fractionation is unavailable 
and ALT 3xULN and total bilirubin 2xULN, then the event is still to be reported 
as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
For this study, any event that meets the definition of Serious Adverse Event, even if 
considered disease-related, must be reported as an SAE.


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12.3.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools 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 thrombosis
Deep venous thrombosis or pulmonary embolus
Revascularization
This information should be recorded within one week of when the AE/SAE(s) are first 
reported.
12.4.
Death Events
In addition, all deaths will require a specific death data collection tool to be completed.  
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and noncardiovascular death.
This information should be recorded within one week of when the death is first reported.
12.5.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?”
12.6.
Recording of AEs and SAEs
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) relative 
to the event.  The investigator will then record all relevant information regarding an 
AE/SAE in the appropriate data collection tool.


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It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE data collection tool.  
However, there may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to submission 
of to GSK.
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.7.
Evaluating AEs and SAEs
12.7.1.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities.
Moderate:  An event that is sufficiently discomforting to interfere with normal everyday 
activities.
Severe:  An event that prevents normal everyday activities.
An AE that is assessed as severe will not be confused with an SAE.  Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.  An event is defined as ‘serious’ when it meets at least one of the pre-
defined outcomes as described in the definition of an SAE.
12.7.2.
Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE.  A "reasonable possibility" is meant to convey that there are 
facts/evidence 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 natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study treatment will be considered and investigated.  The investigator will also consult 
the Investigator Brochure (IB) and/or Product Information, for marketed products, in the 
determination of his/her assessment [GlaxoSmithKline Document Number 
RM2008/00267/07].  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.


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12.8.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All AEs and SAEs will be followed until 
resolution, until the condition stabilizes, until the event is otherwise explained, or until 
the subject is lost to follow-up.
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.   The 
investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.  If a subject dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any post-mortem 
findings, including histopathology.
New or updated information will be recorded in the originally completed data collection 
tool.  The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.9.
Prompt Reporting of SAEs to GSK
Once the investigator determines that an event meets the protocol definition of an SAE, 
the SAE will be reported to GSK within 24 hours.  Any follow-up information on a 
previously reported SAE will also be reported to GSK within 24 hours.
If the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying GSK of the event and completing the 
appropriate data collection tool.  The investigator will always provide an assessment of 
causality at the time of the initial report as described in Section 12.7.2, Assessment of 
Causality.
The primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool.  If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the GSK Medical Monitor.  Then the site will 
enter the serious adverse event data into the electronic system as soon as it becomes 
available.
The investigator will be required to confirm review of the SAE causality by ticking the 
‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of the 
SAE.
After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) 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, the site can report this information on a paper SAE form or to their 
GSK protocol contact by telephone.
GSK contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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12.10.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to 
regulatory authorities, IRBs and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.  An investigator who receives an investigator safety report 
describing an SAE(s) or other specific safety information (e.g., summary or listing of 
SAEs) from GSK will file it with the IB and will notify the IRB, if appropriate according 
to local requirements.
13.
LIVER CHEMISTRY FOLLOW-UP PROCEDURES
Refer to the diagram in Appendix 1 for a visual presentation of the procedures listed 
below
The procedures listed below are to be followed if a subject meets the liver chemistry 
stopping criteria defined in Section 4.5.1.2:

Immediately withdraw the subject from study treatment 

Notify the GSK medical monitor within 24 hours of learning of the abnormality 
to confirm the subject’s study treatment cessation and follow-up.

Complete the “Safety Follow-Up Procedures” listed below.

Complete the liver event case report forms.  If the event also meets the criteria of 
an SAE (See Section 12.2), the SAE data collection tool will be completed 
separately with the relevant details.

Upon completion of the safety follow-up withdraw the subject from the study
unless further safety follow up is required or GSK Medical Governance approval 
of drug restart is granted.

Do not restart investigational product unless written approval is granted by GSK 
Medical Governance, whereupon the subject continues in the study after 
completion of the liver chemistry monitoring.
Safety Follow-Up Procedures for subjects with ALT 3xULN:

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.


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Safety Follow-Up Procedures for subjects with ALT 3xULN and total bilirubin 
2xULN (>35% direct bilirubin); or ALT 3xULN and INR1 > 1.5:

This event is considered an SAE (See Section 12.2).  Serum bilirubin 
fractionation should be performed if testing is available.  If fractionation is 
unavailable, urinary bilirubin is to be measured via dipstick (a measurement of 
direct bilirubin, which would suggest liver injury).

Make every reasonable attempt to have subjects return to the clinic within 24 
hours for repeat liver chemistries, additional testing, and close monitoring (with 
specialist or hepatology consultation recommended).

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
In addition, for all subjects with ALT 3xULN, every attempt must be made to also 
obtain the following:

Viral hepatitis serology including:

Hepatitis A IgM antibody.

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM). 

Hepatitis C RNA. 

Cytomegalovirus IgM antibody.

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing).

Hepatitis E IgM antibody.

Blood sample for pharmacokinetic (PK) analysis, obtained within 72 hours of last 
dose.  Record the date/time of the PK blood sample draw and the date/time of the last 
dose of study treatment prior to blood sample draw in the eCRF.  If the date or time 
of the last dose is unclear, provide the subject’s best approximation.  If the date/time 
of the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample.  Instructions for sample 
handling and shipping are included in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Assess eosinophilia

Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) 
in the AE eCRF.
                                                
1 INR testing not required per protocol and the threshold value does not apply to subjects receiving 
anticoagulants.


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
Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins in the Concomitant Medications 
eCRF.

Record alcohol use in the Liver Events eCRF.
The following are required for subjects with ALT 3xULN and bilirubin 2xULN 
(>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in the 
preceding week [James, 2009]).

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.

The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these tests 
are performed.
14.
STUDY CONDUCT CONSIDERATIONS
14.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
14.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and, the guiding principles of the 2008
Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB review and favorable opinion/approval to conduct the study and of any 
subsequent relevant amended documents

Written informed consent (and any amendments) to be obtained for each subject 
before participation in the study

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to IRB).
Written informed consent must be obtained from each subject prior to participation in the 
study.


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14.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations including GCP, and GSK procedures, GSK 
monitors will contact the site prior to the start of the study to review with the site staff the 
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and 
GSK requirements.  When reviewing data collection procedures, the discussion will also 
include identification, agreement and documentation of data items for which the eCRF 
will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
14.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study.  In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
14.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, the monitor will conduct 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations including GCP, and GSK procedures.
In addition, GSK reserves the right to temporarily suspend or prematurely discontinue 
this study at any time for reasons including, but not limited to, safety or ethical issues or 
severe non-compliance.  If GSK determines such action is needed, GSK will discuss this 
with the investigator or the head of the medical institution (where applicable), including 
the reasons for taking such action.  When feasible, GSK will provide advance notification 
to the investigator or the head of the medical institution, where applicable, of the 
impending action prior to it taking effect.
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform investigators or the head of the medical institution (where applicable) 
and the regulatory authorities of the suspension or premature discontinuation of the study 
and the reason(s) for the action.  If required by applicable regulations, the investigator or 


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the head of the medical institution (where applicable) must inform the IRB promptly and 
provide the reason for the suspension or premature discontinuation.
14.6.
Records Retention
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records, except for those required by local 
regulations to be maintained by someone else, in a safe and secure location.  The records 
must be maintained to allow easy and timely retrieval, when needed (e.g., audit or 
inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and staff.  Where 
permitted by local laws/regulations or institutional policy, some or all of these records 
can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  The 
investigator must assure that all reproductions are legible and are a true and accurate copy 
of the original and meet accessibility and retrieval standards, including re-generating a 
hard copy, if required.  Furthermore, the investigator must ensure there is an acceptable 
back-up of these reproductions and that an acceptable quality control process exists for 
making these reproductions.
GSK will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 
requirements or local laws or regulations, or GSK standards/procedures; otherwise, the 
retention period will default to 15 years.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to, archival at an off-site facility or transfer of ownership of the records in 
the event the investigator leaves the site.
14.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  Investigators 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 investigators with the full summary of the study results.  
Investigators may share the summary results with the study subjects, as appropriate.
GSK will provide the investigator with the randomization codes for their site after 
completion of the full statistical analysis.
GSK aims to post a results summary to the GSK Clinical Study Register and other 
publicly available registers no later than 8 months after the last subject’s last visit (LSLV) 
[this applies to each data analysis phase for studies with multiple phases, e.g., primary 
analysis, follow up analysis etc].  In addition, the aim is to submit a manuscript to a peer-


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reviewed journal for publication within 18 months of LSLV.  GSK also aims to publish 
the full study protocol on the GSK Clinical Study Register at the time the results of the 
study are published as a manuscript in the scientific literature.  
When manuscript publication in a peer-reviewed journal is not feasible, further study 
information will be posted to the GSK Clinical Study Register to supplement the results 
summary.
14.8.
Data Management
For this study subject data will be entered into GSK defined electronic case report forms 
(eCRFs), transmitted electronically to GSK or designee and combined with data provided 
from other sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA (Medical Dictionary for Regulatory Activities) and 
an internal validated medication dictionary, GSKDrug.  eCRFs (including queries and 
audit trails) will be retained by GSK, and copies will be sent to the investigator to 
maintain as the investigator copy.  Subject initials will not be collected or transmitted 
to GSK according to GSK policy.


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15.
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wounds: HIF-1a induction in primary inflammatory cells by TNF- a. Am J Physiol Cell 
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Aragonés J, Schneider M, Van Geyte K, Fraisl P, et al. Deficiency or inhibition of 
oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat 
Genet. 2008 Feb;40(2):170-80.
Botusan IR, Sunkari VG, Savu O, Catrina AI, et al. Stabilization of HIF-1is critical to 
improve wound healing in diabetic mice. PNAS. 2008;105(49):19426-31.
Boulton AJM, Kirsner RS, Vileikyte L. Neuropathic diabetic foot ulcers. N Engl J Med. 
2004;351:48-55.
Boulton AJM, Vileiktye L, Ragnarson-Tennvall G, Apelqvist J. The global burden of 
diabetic foot disease. Lancet. 2005;366:1719-24.
Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. 
Science. 2001;294:1337-40.
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information and national estimates on diabetes in the United States, 2007. US 
Department of Health and Human Services, Centers for Disease Control and Prevention, 
Atlanta, GA; 2008.
Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, et al. Progenitor cell trafficking is 
regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 
2004;10(8):858-64. 
Chang EI, Loh SA, Ceradini DJ, Chang SL. Age decreases endothelial progenitor cell 
recruitment through decreases in hypoxia-inducible factor 1stabilization during 
ischemia. Circulation. 2007;116:2818-29.
Chowdhury R, Hardy A, Schofield CJ. The human oxygen sensing machinery and its 
manipulation. Chem Soc Rev. 2008;37(7):1308-19.
Eltzschig HK, Thompson LF, Karhausen J, Cotta RJ, et al. Endogenous adenosine 
produced during hypoxia attenuates neutrophil accumulation: coordination by 
extracellular nucleotide metabolism. Blood. 2004;104:3986-92.
Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 
2005;366(9498):1736-43.
Frykberg RG, et al. Diabetic foot disorders: a clinical practice guideline (rev. 2006). J 
Foot ankle Surg. 2006; 45(5):S-66.


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Fukuda R, Zhang H, Kim J-W, Shimoda L, et al. HIF-1 regulates cytochrome oxidase 
subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007;129:111-22. 
Galiano RD, Tepper OM, Pelo CR, Bhatt KA, et al. Topical vascular endothelial growth 
factor accelerates diabetic wound healing through increased angiogenesis and by 
mobilizing and recruiting bone marrow-derived cells. Am J Pathol. 2004;164(6):1935-47.
Galkowska H, Wojewodzka U, Olszewski WL. Chemokines, cytokines, and growth 
factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic 
foot ulcers. Wound Repair Regen. 2006;14(5):558-65.
Gallagher KA, Liu ZJ, Xiao M, Chen H, et al. Diabetic impairments in NO-mediated 
endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-
1 alpha. J Clin Invest. 2007;117(5):1249-59.
GlaxoSmithKline Document Number 2011N115609_00 Study ID PHI113634. 
PHI113634 Clinical Pharmacology Study Report. Effective Date: May 2012 
Goodridge D, Trepman E, Sloan J, et al. Quality of life of adults with unhealed and 
healed diabetic foot ulcers. Foot Ankle Int. 2006;27:274-80. 
GSK1278863 Investigator’s Brochure GlaxoSmithKline Document Number
RM2008/00267/07 Effective Date: October 2015
James LP. Pharmacokinetics of acetaminophen - protein adducts . liver failure. Drug 
Metab Disp. 2009; 37:1779-84.
Khaodhia L, et al.  The use of medical hyperspectral technology to evaluate 
microcirculatory changes in diabetic foot ulcers and to predict clinical outcomes. 
Diabetes Care , 2007; 30:903–910.
Li W, Guan S, Fan J, Cheng CF, et al. Extracellular heat shock protein-90: linking 
hypoxia to skin cell motility and wound healing. EMBO J. 2007;26(5):1221-33.
Liu L, Marti G, Wei X, Zhang X, et al. Age-dependent impairment of HIF-1a expression 
in diabetic mice: correction with electroporation-facilitated gene therapy increases wound 
healing, angiogenesis, and circulating angiogenic cells. J Cell Physiol. 2008;217:319-27. 
Lukashev D, Klebanov B, Kojima H, Grinberg A, et al. Cutting edge: hypoxia-inducible 
factor 1and its activation-inducible short isoform I.1 negatively regulate functions of 
CD4+ and CD8+ T lymphocytes. J Immunol. 2006;177(8):4962-5.
Mace KA, Yu DH, Paydar KZ, Boudreau N, Young D. Sustained expression of HIF-1
in the diabetic environment promotes angiogenesis and cutaneous wound repair. Wound 
Rep Reg. 2007;15:636-45.
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Myllyharju J. Prolyl 4-hydroxylases, key enzymes in the synthesis of collagens and 
regulation of the response to hypoxia, and their roles as treatment targets. Ann Med. 
2008;40(6):402-17. 
Reiber GE, Vileiktye L, Boyko EJ, delAguila M, Smith DG, et al. Causal pathways for 
incident lower-extremity ulcers in patients with diabetes from two settings. Diab Care. 
1999;22(1):157-62.
Semenza GL. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiol. 
2004;19:176-82. 
Sitkovsky MV, Lukashev D, Apasov S, Kojima H, et al. Physiological control of immune 
response and inflammatory tissue damage by hypoxia-inducible factors and adenosine 
A2A receptors. Annu Rev Immunol. 2004;22:657-82.
Thangarajah H, Yao D, Changa EI, Shia Y, et al. The molecular basis for impaired 
hypoxia-induced VEGF expression in diabetic tissues. PNQAS. 2009;106(32):13505-10.
Yamaguchi Y, Yoshikawa K. Cutaneous wound healing: an update. J Dermatol. 
2010;28100:521-34.
Zhang X, Liu L, Wei X, Tan YS, et al. Impaired angiogenesis and mobilization of 
circulating angiogenic cells in HIF-1heterozygous-null mice after burn wounding. 
Wound Rep Reg. 2010; 18:193-201.


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16.
APPENDICES
16.1.
Appendix 1: Liver Safety Algorithms
ALT≥3xULN ?
Bilirubin ≥ 2xULN
(>35% direct) or 
INR > 1.5 (if 
measured)* ?
No
No
Yes
Yes
Continue investigational product (IP)
Instruct subject to stop IP
Notify GSK within 24 hrs 
Obtain weekly liver chemistries until resolved, stabilized or returned 
to baseline values
Perform liver event follow up assessments (serology, PK sample, etc 
as in protocol) 
Complete liver event CRF
Withdraw subject from study after liver chemistry monitoring 
complete (unless protocol offers option to restart drug).
Instruct subject to stop IP
Notify GSK and arrange clinical followup within 24 hrs
Perform liver event follow up assessments (serology, PK sample etc 
as in protocol) 
Report as SAE (excl. hepatic impairment or cirrhosis studies); 
complete SAE & liver event CRF + liver imaging  
and biopsy CRFs (if these tests are performed)
Obtain twice weekly liver chemistries until resolved, stabilized or 
returned to baseline values 
Consultation with hepatologist/specialist recommended
Withdraw subject from study after liver chemistry monitoring 
complete (unless protocol offers option to restart drug).
*INR threshold does not apply to 
subjects receiving anticoagulants.


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16.2.
Appendix 2: Definitions
For the purposes of this study moist wound therapy consists of the investigational drug 
vehicle, a non-adherent dressing (See SPM for dressing selection) and an outer gauze 
wrap.
100% re-epithelialization is defined as full re-epithelialization of the wound surface 
with no trace of exudate or drainage, as determined by the investigator.
Wound closure is defined as 100% re-epithelialization that is confirmed at follow-up.
The date of complete wound closure is defined as the date of the first assessment of 
100% re-epithelialization.


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16.3.
Appendix 3: Protocol Amendment Changes
AMENDMENT 1
Where the Amendment Applies
This amendment applies to all sites participating in this study.
Summary of Amendment Changes with Rationale

This amendment reflects changes to the patient eligibility criteria.

Changes to the stopping criteria were made with the addition of 2 criteria and 
the modification of 2 existing criteria.

The number of tissue biopsies obtained during the study was reduced from 8 to 5 
(Days 1, 2, 8, 14 and 22).

An additional follow-up visit was added.

Additional (minor) wording changes were made to clarify existing instructions 
or to correct typographical errors. 
List of Specific Changes
Section 4.2 Discussion of Design and Treatment Plan
PREVIOUS TEXT
This is a randomized, placebo-controlled, single-blind (subjects and investigators will 
be blinded, GSK internal personnel will not be blinded), parallel-group, two part (Part 
A, Part B) trial in healthy volunteers and subjects with diabetic foot ulcers, to be 
conducted at two sites.
REVISED TEXT
This is a randomized, placebo-controlled, single-blind (subjects and investigators will be 
blinded, GSK internal personnel will not be blinded), parallel-group, two part (Part A, 
Part B) trial in healthy volunteers and subjects with diabetic foot ulcers.
Section 4.2.1.7 Follow-up Visits
PREVIOUS TEXT
A follow-up visit will occur 7 to 10 days following completion of dosing.  Any 
subject withdrawing from the trial prematurely will also be asked to complete follow-
up procedures 7-10 days after withdrawal.


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REVISED TEXT
Follow-up visits will occur 7 to 10 days and 28 to 32 days following completion of 
dosing.  Any subject withdrawing from the trial prematurely will also be asked to 
complete all follow-up procedures.
Section 4.2.2.4 Follow-up Visits
PREVIOUS TEXT
A follow-up visit will occur 7 to 10 days following completion of dosing.  Any 
subject withdrawing from the trial prematurely will also be asked to complete follow-
up procedures 7-10 days after withdrawal.
REVISED TEXT
Follow-up visits will occur 7 to 10 days and 28 to 32 days following completion of 
dosing.  Any subject withdrawing from the trial prematurely will also be asked to 
complete all follow-up procedures.
Section 4.5.1.1 Hemoglobin Stopping Criteria
PREVIOUS TEXT
A patient that experiences an absolute increase in hemoglobin of 2.5mg/dL above their 
baseline level at any time will be withdrawn from the study.
REVISED TEXT
A patient that experiences an absolute increase in hemoglobin of 1.0g/dL above their 
baseline level at any time will be withdrawn from the study.
Section 4.5.1.4 Other Dose Adjustment/Stopping Safety Criteria
PREVIOUS TEXT

Any other occurrence that raises significant safety concern in the mind of the 
investigator.

Upper GI bleeding or any GI bleeding resulting in clinically significant blood loss
(See Section 5.3 for additional guidance).

Diagnosis of cancer, with the exception of squamous cell and basal cell carcinoma 
(unless in proximity of the wound treated with GSK1278863).

Treatment emergent pulmonary hypertension, new onset or worsening retinopathy 
(e.g. proliferative retinopathy, or macular edema), or new onset or worsening non-
traumatic joint inflammation (e.g., rheumatic or psoriatic arthritis).


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REVISED TEXT

Any other occurrence that raises significant safety concern in the mind of the 
investigator.

Any patient who has an increase from baseline in total wound area > 20% at 
any time will be withdrawn from treatment

Any patient who develops at any time after randomization 3 of the following 6 
signs at the study wound site will be withdrawn from treatment:  local 
erythema, edema, pain, pus, local warmth, loss of function

Subjects with documented GI bleeding, new onset positive fecal occult blood 
test, or abdominal pain (other than transient, minor abdominal pain). See 
Section 5.3 for additional guidance.

Diagnosis of cancer, with the exception of squamous cell and basal cell carcinoma 
(unless in proximity of the wound treated with GSK1278863).

Treatment emergent pulmonary hypertension, new onset or worsening retinopathy 
(e.g. proliferative retinopathy, or macular edema), or new onset or worsening non-
traumatic joint inflammation (e.g., rheumatic or psoriatic arthritis).


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Section 4.6.1 Time and Events Table Part A
PREVIOUS TEXT
Study 
Population
Procedure
Screening
(up to 28 
days prior 
to Day 1)
Study Day (each dosing period)
Follow-
up
Visit
Day 1
Day 
2
Day 3
Day 
4
7-10 
days 
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48
h
72
h
All 
Subjects
Check in
X
Informed Consent
X
Demographics
X
Full Physical Exam
X
Brief Physical 
Exam
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
X
12-lead ECG1
X
X
X
X
Vital signs2
X
X
X
X
Urine 
pregnancy(women)
X
X
HIV, Hep B and 
Hep C
X
Hema/Chem Safety 
Labs3
X
X
X
X
Blood for HIF
Samples (e.g., 
hepcidin, 
EPO,VEGF)4  
X
X
X
X4
X


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Study 
Population
Procedure
Screening
(up to 28 
days prior 
to Day 1)
Study Day (each dosing period)
Follow-
up
Visit
Day 1
Day 
2
Day 3
Day 
4
7-10 
days 
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48
h
72
h
Study treatment 
dosing
X
Pharmacokinetic 
Sampling5
X
X
X
X
X
X
X
X5
X
X
X
Concomitant 
Medications
=============================================================
X
Adverse Event 
Review6
=============================================================
X
Subjects 
with DFUs7
Only
Gene Expression 
(mRNA) Tissue 
Samples8
X
X
X
X
Biomarker fluid 
samples (e.g., for 
cytokines, growth 
factors, and 
bioburden)9
X
X
X
Physical 
Characteristics 
(e.g., photos and 
wound 
measurement post-
debridement, 
volume) 
X
X
X
X
Clinical 
Characteristics10  
X
X
X
X
X
X
X
X
X
X


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1.
Single ECGs will be taken Screening, and pre-dose on Day 1 and at the 48h post-last-dose on Day 3, and at Follow-up.  ECGs should be taken while subject is supine for at least 
5 minutes.  Additional ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
2.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Day 1 and at the 48h post-last-dose on Day 3, and at Follow-
up.  Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
3.
Blood samples for safety analyses will be collected fasting at Screening and on Day 1 and at the 48h post-last-dose on Day 3, and at Follow-up.  Refer to Section 7.2.4 for specific 
laboratory parameters to be tested.
4.
Blood samples HIFactivation on Day 1 will be collected at pre-dose, 8 and 10-12 hour window.  Refer to Section 7.6 for additional details on the collection and processing of 
these samples.
5.
Serial blood samples for the determination of the PK for GSK127886 and metabolites will be collected at immediately pre-dose (time 0), 0.25, 0.5, 1, 2, 4, 8, 10-12 (once within the 
10-12 window for out-patients only)/12 (in-patient subjects only), 24, 48 and 72hrs post-‘dose.  Refer to Section 7.13 for details on the collection and processing of PK samples.  
PK sampling times may be changed based on observed GSK1278863 PK profile, but the total number of samples will not change.
6.
Adverse events are to be collected from first dose through the Follow-up visit.
7.
These assessments are to be performed only when IP is applied to the ulcer not to the patient’s intact skin
8.
Microarray and Taqman will be performed at all timepoints.
9.
Wound fluid and tissue samples for biomarkers of cytokines and bioburden will be collected at pre-dose (time 0) on Days 1and 4 and at the Follow-up Visit.
10. Clinical characteristic assessments of the DFU begin with Section 7.11 and contain instructions for completing the assessments including the irritation/symptom scale as needed.  
Assessments are recorded in the eCRF


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REVISED TEXT
Study 
Population
Procedure
Screening
(up to 28 
days prior 
to Day 1)
Study Day (each dosing period)
Follow Up
Day 1
Day 
2
Day 3
Day 
4
7-10 
days 
post 
last 
dose
28-
32 
days 
post 
last 
dose
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48
h
72
h
All 
Subjects
Check in
X
Informed Consent
X
Demographics
X
Full Physical Exam
X
Brief Physical 
Exam
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
X
12-lead ECG1
X
X
X
X
Vital signs2
X
X
X
X
X
Urine 
pregnancy(women)
X
X
HIV, Hep B and 
Hep C
X
Hema/Chem Safety 
Labs3
X
X
X
X
Blood for HIF
Samples (e.g., 
hepcidin, 
EPO,VEGF)4  
X
X
X
X4
X


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Study 
Population
Procedure
Screening
(up to 28 
days prior 
to Day 1)
Study Day (each dosing period)
Follow Up
Day 1
Day 
2
Day 3
Day 
4
7-10 
days 
post 
last 
dose
28-
32 
days 
post 
last 
dose
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48
h
72
h
Study treatment 
dosing
X
Pharmacokinetic 
Sampling5
X
X
X
X
X
X
X
X5
X
X
X
Concomitant 
Medications
=============================================================
X
Adverse Event 
Review6
=============================================================
X
X
Subjects 
with DFUs7
Only
Gene Expression 
(mRNA) Tissue 
Samples8
X
X
X
X
Biomarker fluid 
samples (e.g., for 
cytokines, growth 
factors, and 
bioburden)9
X
X
X


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Study 
Population
Procedure
Screening
(up to 28 
days prior 
to Day 1)
Study Day (each dosing period)
Follow Up
Day 1
Day 
2
Day 3
Day 
4
7-10 
days 
post 
last 
dose
28-
32 
days 
post 
last 
dose
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48
h
72
h
Physical 
Characteristics 
(e.g., photos and 
wound 
measurement post-
debridement, 
volume) 
X
X
X
X
Clinical 
Characteristics10
X
X
X
X
X
X
X
X
X
X


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1.
Single ECGs will be taken Screening, and pre-dose on Day 1 and at the 48h post-last-dose on Day 3, and at Follow-up.  ECGs should be taken while subject is supine for 
at least 5 minutes.  Additional ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
2.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Day 1 and at the 48h post-last-dose on Day 3, and at 
the 7-10 day Follow-up Visit.  Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
3.
Blood samples for safety analyses will be collected fasting at Screening and on Day 1 and at the 48h post-last-dose on Day 3, and at the 7-10 day Follow-u p Visit.  
Refer to Section 7.2.4 for specific laboratory parameters to be tested.
4.
Blood samples HIFactivation on Day 1 will be collected at pre-dose, 8 and 10-12 hour window.  Refer to Section 7.6 for additional details on the collection and 
processing of these samples.
5.
Serial blood samples for the determination of the PK for GSK127886 and metabolites will be collected at immediately pre-dose (time 0), 0.25, 0.5, 1, 2, 4, 8, 10-12 (once 
within the 10-12 window for out-patients only)/12 (in-patient subjects only), 24, 48 and 72hrs post-‘dose.  Refer to Section 7.13 for details on the collection and processing 
of PK samples.  PK sampling times may be changed based on observed GSK1278863 PK profile, but the total number of samples will not change.
6.
Adverse events are to be collected from first dose through the final Follow-up visit.
7.
These assessments are to be performed only when IP is applied to the ulcer not to the patient’s intact skin
8.
Microarray and Taqman will be performed at all timepoints.
9.
Wound fluid for biomarkers of cytokines and bioburden will be collected at pre-dose (time 0) on Days 1and 4 and at the 7- 10 day Follow-up Visit.
10. Clinical characteristic assessments of the DFU begin with Section 7.11 and contain instructions for completing the assessments including the irritation/symptom scale as 
needed.  Assessments are recorded in the eCRF


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Section 4.6.2 Time and Events Table Part B
PREVIOUS TEXT
Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-
up
Day 1
Day 8
Visit Window 
(relative to Day 1)
-28 to -1 
days
Exams/samples 
pre-dose
Washout
Exams/samples 
pre-dose
7-10 
days 
post last 
dose
Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
Informed Consent
X
Demographics
X
Complete physical
X
Brief physical
X
X
X
X
X
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
12-lead ECG1
X
X
X
Vital signs2
X
X
X
X
X
X
Urine 
pregnancy(females)
X
X
`
X
HIV, Hep B and Hep C 
screen
X
Hema/Chem/ Safety 
Labs3
X
X
X
X
X
X
Blood samples for 
HIF, (e.g., EPO, 
Hepcidin, VEGF)
X
X4
X4
X
X
Standard of Care 
Treatment5
X
X
X
X


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Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-
up
Day 1
Day 8
Study 
Treatment/Dosing
In the Clinic6
X
X
X
X
X
X
X
PK serial blood 
sampling7
X
X (truncated)
X
X
X
X
X
PK Trough Sample7
X
Gene Expression 
(mRNA) Samples 
Tissue Biopsies8
X
X
X
X
X
X
X
X
Biomarker Samples:  
Wound fluid for 
cytokines and 
bioburden9
X
X
X
(Day 3 
only9)
X
X
X
X
X
Macrophages
X
X
X
X
X
X
X
X
SensiLase (Dopplar 
blood flow)
X
X
X
X
X
Physical 
Characteristics
(assessed pre-dose)11
X11
X
X
X
X
X
X
X
Clinical 
Characteristics12
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medication Review
X
=============================================================
X
Adverse Event 
Assessment13
X
=============================================================
X


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1.
Single ECGs will be taken at Screening and pre-dose on Day 1(SD) and 24h post-last-RD dose on Day 22.  ECGs should be taken while subject is supine for at least 5 
minutes.  Additional ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
2.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Days 1 (SD) and 8(RD), 15, 22 (24h post-last-RD dose) , 
and at Follow-up.  Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
3.
Blood samples for safety will be collected fasting at Screening and pre-dose/equivalent time on Days 1,8,14, 22 (24h post-last-dose), and at Follow-up.  Refer to Section 
7.2.4 for specific laboratory parameters to be tested.
4.
Blood samples for HIFactivation on Day 1 and Day 8 will be collected at pre-dose, 8 and 10-12 hour window.  On all other indicated days one sample will be collected at 
pre-dose/equivalent time.  
5.
During washout times all subjects will be on SOC (Section 7.4).
6.
In between clinic visits, subjects with perform applications of study drug at home.
7.
See separate Time and Events table for serial PK sampling details for Days 1, 8, 14 and 21.  Trough sample will be taken prior to dosing on Day 18.  Refer to Section 7.13 for 
details on the collection and processing of PK samples.  PK sampling times may be changed based on observed GSK1278863 PK profile, but the total number of samples 
will not change.
8.
Direct wound tissue samples for analysis of gene expression will be collected at pre-dose on Days 1, 2, 8, 11, 14, 21, 22 and at the Follow-up Visit.  TaqMan analysis will be 
performed on each day.  Microarray analysis will be performed on the following Days 1, 2, 8, 14, 22 and Follow-up, however based on emerging data additional time points 
may be added.  Refer to Section 7.4 for additional details on the collection and processing of gene expression samples.
9.
Wound fluid and tissue samples for biomarkers of cytokines and bioburden will be collected at pre-dose on Days 1, 2. 3, 8, 14, 15, 22 and at the Follow-up Visit.  Refer to the 
Section 7.5.3 for additional details on the collection and processing of biomarker tissue samples.
10. May be conducted at only one or both sites, dependent upon feasibility.  Will be performed in a select cohort of patients.  The precise procedure will be dependent upon the 
outcome of feasibility work. 
11. Physical characteristics of the wound (e.g., photos of the wound and wound measurement assessments) will be assessed at Screening (acetate tracings only), and pre-
dose/equivalent time on Days 1, 8, 11, 14, 18, 22 and at the Follow-up Visit.  Any subject that is participating in additional cohorts during Part B would need to be assessed 
for wound healing rate for 14 days (as in the regular screen) to ensure healing rate is less than 30%. 
12. Clinical characteristic assessments of the DFU begin with Section 7.11 and contain instructions for completing the assessments including the irritation/symptom scale as 
needed.  Assessments are recorded in the eCRF.
13. Adverse events are to be collected from first dose through the Follow-up visit.


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REVISED TEXT
Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 
7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
Visit Window 
(relative to Day 1)
-28 to -1 
days
Exams/samples 
pre-dose
Washout
Exams/samples 
pre-dose
7-10 
days 
post 
last 
dose
28-32 
days 
post 
last 
dose
Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
Informed Consent
X
Demographics
X
Complete physical
X
Brief physical
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
12-lead ECG1
X
X
X
Vital signs2
X
X
X
X
X
X
X
Urine 
pregnancy(females)
X
X
`
X
HIV, Hep B and Hep C 
screen
X
Hema/Chem/ Safety 
Labs3
X
X
X
X
X
X
Blood samples for 
HIF, (e.g., EPO, 
Hepcidin, VEGF)
X
X4
X4
X
X
Standard of Care 
Treatment5
X
X
X
X
Study 
Treatment/Dosing
In the Clinic6
X
X
X
X
X
X
X


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Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 
7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
PK serial blood 
sampling7
X
X
X
X (truncated)
X
X
X
X
X
PK Trough Sample7
X
Gene Expression 
(mRNA) Samples 
Tissue Biopsies8
X
X
X
X
X
Biomarker Samples:  
Wound fluid for 
cytokines and 
bioburden9
X
X
X
(Day 3 
only9)
X
X
X
X
X
Macrophages10
X
X
X
X
X
X
X
X
SensiLase (Dopplar 
blood flow)
X
X
X
X
X
Physical 
Characteristics
(assessed pre-dose)11
X11
X
X
X
X
X
X
X
Clinical 
Characteristics12
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medication Review
X
=============================================================
X
Adverse Event 
Assessment13
X
=============================================================
X
X


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1.
Single ECGs will be taken at Screening and pre-dose on Day 1(SD) and 24h post-last-RD dose on Day 22.  ECGs should be taken while subject is supine for at least 5 minutes. 
Additional ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
2.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Days 1 (SD) and 8(RD), 15, 22 (24h post-last-RD dose) , and 
at Follow-up Visits.  Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
3.
Blood samples for safety will be collected fasting at Screening and pre-dose/equivalent time on Days 1,8,14, 22 (24h post-last-dose), and at the 7-10 day Follow-up Visit.  Refer 
to Section 7.2.4 for specific laboratory parameters to be tested.
4.
Blood samples for HIFactivation on Day 1 and Day 8 will be collected at pre-dose, 8 and 10-12 hour window.  On all other indicated days one sample will be collected at pre-
dose/equivalent time.  
5.
During washout times all subjects will be on SOC (Section 7.4).
6.
In between clinic visits, subjects with perform applications of study drug at home.
7.
See separate Time and Events table for serial PK sampling details for Days 1, 8, 14 and 21 and the associated 24, 48 and 72 hr time points.  Trough sample will be taken prior 
to dosing on Day 18.  Refer to Section 7.13 for details on the collection and processing of PK samples.  PK sampling times may be changed based on observed GSK1278863 PK 
profile, but the total number of samples will not change.
8.
Direct wound tissue samples for analysis of gene expression will be collected at pre-dose on Days 1, 2, 8, 14 and 22, however based on emerging data additional time points may 
be added. Refer to Section 7.4 for additional details on the collection and processing of gene expression samples.
9.
Wound fluid for biomarkers of cytokines and bioburden will be collected at pre-dose on Days 1, 2. 3, 8, 14, 15, 22 and at the 7-10 day Follow-up Visit.  Refer to the Section 7.5.3 
for additional details on the collection and processing of biomarker tissue samples.
10. May be conducted at only one or both sites, dependent upon feasibility.  Will be performed in a select cohort of patients.  The precise procedure will be dependent upon the 
outcome of feasibility work. 
11. Physical characteristics of the wound (e.g., photos of the wound and wound measurement assessments) will be assessed at Screening (acetate tracings only), and pre-
dose/equivalent time on Days 1, 8, 11, 14, 18, 22 and at the 7-10 day Follow-up Visit.  Any subject that is participating in additional cohorts during Part B would need to be 
assessed for wound healing rate for 14 days (as in the regular screen) to ensure healing rate is less than 30%. 
12. Clinical characteristic assessments of the DFU begin with Section 7.11 and contain instructions for completing the assessments including the irritation/symptom scale as needed.   
Assessments are recorded in the eCRF.
13. Adverse events are to be collected from first dose through the final Follow-up visit.


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Section 4.6.3 Serial PK Time and Events Table Part B
PREVIOUS TEXT
Procedure
Part B Serial PK Sampling1,2 
Hours (h)
Pre-
dose
0.25h
0.5h
1h
2h
4h
6h
8h
10h
11h
12h
24h
48h
72h
Single Dose Sampling OUT-PATIENTS
X
X
X
X
X
X
X
X3
X
X
X
Single Dose Sampling IN-PATIENTS
X
X
X
X
X
X
X
X
X
X
X
Repeated Dose Day 8 (Start of Repeated 
Dose)
X
X
X
X
X
Repeated Dose Day 15 OUT-PATIENTS 
X
X
X
X
X
X
X
X3
X
Repeated Dose Day 15 IN-PATIENTS
X
X
X
X
X
X
X
X
X
Repeated Dose Day 21 OUT-PATIENTS
X
X
X
X
X
X
X
X3
X
X
Repeated Dose Day 21 IN-PATIENTS
X
X
X
X
X
X
X
X
X
X
1.
Patients are permitted to either stay in clinic (in-patients) or be discharged and return for clinic visits (out-patients).  Refer to Section 7.13 for details on the collection and 
processing of PK samples.  
2.
PK sampling times may be changed based on observed GSK1278863 PK profile, but the total number of samples will not change.
3.
Sample must be taken within the 10 to 12 hour time window.


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REVISED TEXT
Procedure
Part B Serial PK Sampling1,2 
Hours (h)
Pre-
dose
0.25h
0.5h
1h
2h
4h
6h
8h
10h
11h
12h
24h
48h
72h
Single Dose Sampling OUT-PATIENTS
X
X
X
X
X
X
X
X3
X
X
X
Single Dose Sampling IN-PATIENTS
X
X
X
X
X
X
X
X
X
X
X
Repeated Dose Day 8 Truncated (Start of 
Repeated Dose)
X
X
X
X
X
Repeated Dose Day 14 OUT-PATIENTS 
X
X
X
X
X
X
X
X3
X
Repeated Dose Day 14 IN-PATIENTS
X
X
X
X
X
X
X
X
X
Repeated Dose Day 21 OUT-PATIENTS
X
X
X
X
X
X
X
X3
X
X
Repeated Dose Day 21 IN-PATIENTS
X
X
X
X
X
X
X
X
X
X
1.
Patients are permitted to either stay in clinic (in-patients) or be discharged and return for clinic visits (out-patients).  Refer to Section 7.13 for details on the collection and 
processing of PK samples.  
2.
PK sampling times may be changed based on observed GSK1278863 PK profile, but the total number of samples will not change.
3.
Sample must be taken within the 10 to 12 hour time window.


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Section 5.2.2 Exclusion Criteria – Healthy Volunteers (Part A Cohort 1)
PREVIOUS TEXT
8.
History of sensitivity to any of the study medications, or components thereof 
or a history of drug or other allergy that, in the opinion of the investigator or GSK 
Medical Monitor, contraindicates their participation.
Where participation in the study would result in donation of blood or blood products 
in excess of 500mL within a 56 day period.
9.
Pregnant females as determined by positive urine hCG test at screening or 
prior to dosing.
10.
Unwillingness or inability to follow the procedures outlined in the protocol.
11.
Subject is mentally or legally incapacitated
REVISED TEXT
8.
History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or GSK Medical 
Monitor, contraindicates their participation.
9.
Where participation in the study would result in donation of blood or blood 
products in excess of 500mL within a 56 day period
10.
Pregnant females as determined by positive urine hCG test at screening or prior to 
dosing.
11.
Unwillingness or inability to follow the procedures outlined in the protocol.
12.
Subject is mentally or legally incapacitated
Section 5.3.1 Inclusion Criteria –DFU Subjects
PREVIOUS TEXT
A DFU subject will be eligible for inclusion in this study only if all of the criteria listed 
for healthy volunteers are met (Section 5.2), with the exception of criterion 3, as well as 
following criteria:
REVISED TEXT
A DFU subject will be eligible for inclusion in this study only if all of the criteria 
listed for healthy volunteers are met (Section 5.2) as well as following criteria:


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Section 5.3.2 Exclusion Criteria –DFU Subjects
PREVIOUS TEXT
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is required.
Diabetic subjects that are being considered for this study will not be eligible for inclusion 
in this study if any of the following criteria apply or if the exclusion criteria outlined in 
Section 5.2.2 apply, with the exception of criterion 8.
1.
Subjects with:
•
Ulcers accompanied by infected cellulitis, osteomyelitis, or clinical signs or 
symptoms of infection,
•
Gangrene on any part of affected limb,
•
Active Charcot’s foot on the study limb,
•
Planned vascular surgery, angioplasty or thrombolysis, 
•
Ulcers involving exposure of tendon, bone, or joint capsule. (It is acceptable to 
have ulcers extending through the dermis and into subcutaneous tissue with presence of 
granulation tissue),
•
Ulcers due to non-diabetic etiology.
2.
Any unstable vascular syndromes (such as TIA, CVA, unstable angina, acute MI 
or ACS event) and/or any major changes (per investigator’s judgment) to related 
medications within 3 months prior to randomization.
3.
Active malignancy or last treatment for malignancy within 6 months of 
randomization (patients with basal or squamous cell carcinoma of the skin are not 
excluded).
4.
Other clinically significant cardiovascular, pulmonary, renal, endocrine, hepatic, 
neurological, psychiatric, immunological, gastrointestinal, hematological, or metabolic 
disease that is, in the opinion of the Investigator or the GSK Medical Monitor, not 
stabilized or may otherwise impact the results of the study.
5.
Patients with active treatment for retinal neovascularization (e.g., diabetic 
proliferative retinopathy or age related macular degeneration) within three months of 
randomization.
6.
Patients undergoing hemodialysis.
7.
History of venous thrombosis defined as deep vein thrombosis, pulmonary 
embolism or other venous thrombotic condition within 6 months prior to screening.


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8.
Active peptic, duodenal, or esophageal ulcer disease, or any gastrointestinal 
bleeding, within 12 weeks prior to screening.
9.
Patients with known pulmonary hypertension.
10.
Use of prohibited medications as described in Section 9.1 of the protocol.
REVISED TEXT
Deviations from inclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject 
safety.  Therefore, adherence to the criteria as specified in the protocol is required.
Diabetic subjects that are being considered for this study will not be eligible for 
inclusion in this study if any of the following criteria apply or if the exclusion criteria 
outlined in Section 5.2.2 apply.
1.
Subjects with:
•
Ulcers accompanied by infected cellulitis, osteomyelitis, or clinical signs or 
symptoms of infection,
•
Gangrene on any part of affected limb,
•
Active Charcot’s foot on the study limb,
•
Planned vascular surgery, angioplasty or thrombolysis, 
•
Ulcers involving exposure of tendon, bone, or joint capsule. (It is acceptable 
to have ulcers extending through the dermis and into subcutaneous tissue with 
presence of granulation tissue),
•
Ulcers due to non-diabetic etiology.
2.
Any unstable vascular syndromes (such as TIA, CVA, unstable angina, acute 
MI or ACS event) and/or any major changes (per investigator’s judgment) to related 
medications within 6 months prior to randomization.
3.
History of malignancy within 5 years of Screening or those with a strong 
family history of cancer (e.g., familial cancer disorders), with the exception of 
squamous cell or basal cell carcinoma of the skin that has been definitively 
treated.
4.
Other clinically significant cardiovascular, pulmonary, renal, endocrine, 
hepatic, neurological, psychiatric, immunological, gastrointestinal, hematological, or 
metabolic disease that is, in the opinion of the Investigator or the GSK Medical 
Monitor, not stabilized or may otherwise impact the results of the study.


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5.
Patients with active treatment for retinal neovascularization (e.g., diabetic 
proliferative retinopathy or age related macular degeneration) within 6 months of 
randomization.
6.
Patients undergoing hemodialysis.
7.
History of venous thrombosis defined as deep vein thrombosis, pulmonary 
embolism or other venous thrombotic condition within 1 year prior to screening.
8.
Active peptic, duodenal, or esophageal ulcer disease, or any gastrointestinal 
bleeding, within 1 year prior to screening.
9.
Subjects with a platelet count <100,000/mm3 at screening. 
10.
Subjects with an International Normalized Ratio (INR) >1.5 at screening.
11.
Subjects with a hemoglobin level above the gender-specific upper limit of 
normal at screening.
12.
Subjects with a history of non-traumatic joint inflammation (with the 
exception of inflammation due to osteoarthritis).
13.
Patients with known pulmonary hypertension.
14.
Use of prohibited medications as described in Section 9.1 of the protocol.
Section 7.5.3 Fluid and Tissue Collection for Biomarkers was deleted to enhance the flow 
of the document and improve clarity.
Section 7.5.3.1 Wound Fluid Collection Directions was moved to Section 7.7.1 to 
enhance the flow of the document and improve clarity.
Section 7.7 Biomarkers (e.g., Cytokines and Bioburden)
PREVIOUS TEXT
7.7.
Biomarkers (e.g., Cytokines and Bioburden)
Wound tissue samples for biomarker assessments will be collected according to the table 
in Section 4.6.
REVISED TEXT
7.7.
Biomarkers (e.g., Cytokines, Bioburden and Gene Expression) Collection and 
Processing)
Wound tissue and fluid samples for biomarker assessments will be collected according to 
the table in Section 4.6.


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Section 7.9 Vascular Perfusion was renamed Angiogenesis: Tissue Perfusion 
Assessment/Oxygen Availability for consistency (A new heading of 7.9.1 was created for 
Vascular Perfusion)
7.9.2. Oxygen Dynamics/Angiogenisis
PREVIOUS TEXT
7.10
Oxygen Dynamics /Angiogenisis
Oxygen dynamics and angiogenesis may be assessed by hyperspectral imaging according 
to the table in Section 4.6, as site feasibility allows.
REVISED TEXT
7.9.2. Oxygen Dynamics/Angiogenisis
Oxygen dynamics and angiogenesis may be assessed by hyperspectral imaging as site 
feasibility allows.
Section 7.11 Clinical Characteristics of the DFU
PREVIOUS TEXT
Section 7.12 Clinical Characteristics of the DFU
At each study visit, the investigator will assess the characteristics of the ulcer being 
treated.  The investigator will assess, using the chart below, the wound edge, base color, 
periwound condition, periwound color, degree of edema, amount of exudate, type of 
exudate and percent of granulation tissue present.
REVISED TEXT
Section 7.11 Clinical Characteristics of the DFU
At each study visit, the investigator will assess the characteristics of the ulcer being 
treated.  The investigator will assess, using the chart below (Table 6), the wound edge, 
base color, periwound condition, periwound color, degree of edema, amount of exudate 
(drainage), type of exudate and percent of granulation tissue present.
Section 7.11.2 Ulcer Exudate
PREVIOUS TEXT
7.12.1. Ulcer Exudate
The Investigator will determine the amount and type of study ulcer exudate. The 
Investigator must take into account the amount of exudate absorbed into the study ulcer 
dressing. The following categories will be used to quantify the amount of ulcer exudate:


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• No exudate
• Minimal amount
• Light (scant) or small amount
• Moderate amount
• Heavy/large/copious amounts
REVISED TEXT
Section 7.11.2 Ulcer Exudate
Using the categories below as guidance, the Investigator will determine the amount and 
type of study ulcer exudate.  The Investigator must take into account the amount of 
exudate absorbed into the study ulcer dressing. The following categories will be used to 
quantify the amount of ulcer exudate:
•
No exudate
•
Minimal amount: Light (scant) or small amount
•
Moderate amount
•
Heavy/large/copious amounts


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AMENDMENT 2
Where the Amendment Applies
This amendment applies to all sites.
Summary of Amendment Changes with Rationale

This amendment reflects changes to Inclusion Criteria –DFU Subjects #7

This amendment corrects the dosage found in Table 2 and Table 4 of Section 
4.3. Treatment Assignment

This amendment reflects changes to the Time and Events Tables for Part A and 
B.

This amendment changes the screening procedures for subjects participating in 
more than one cohort in Part A

Additional (minor) wording changes were made to clarify existing instructions 
or to correct typographical errors.
List of Specific Changes
Section 3.3.1.Gene Expression Analysis, Paragraph 1
PREVIOUS TEXT
Expression of genes important in a range of dynamic cellular processes (including 
inflammation, angiogenesis and extracellular matrix deposition) is expected to change as 
wound healing progresses.  Moreover, with active drug treatment, genes coding for direct 
downstream targets of HIF signaling (e.g., HMOX1, VEGF and NOS2) should be 
upregulated.  Gene expression will therefore be assessed by RT-PCR using tissue 
samples taken from the wound area.  Most of these genes will be probed for using a 
focused array covering approximately 600 genes.  TaqMan PCR will be employed to 
validate gene expression for a number of signature genes for each of the signaling
pathways/cellular processes of interest and for any other genes of interest not captured in 
the focused array.
REVISED TEXT
Expression of genes important in a range of dynamic cellular processes (including 
inflammation, angiogenesis and extracellular matrix deposition) is expected to change as 
wound healing progresses.  Moreover, with active drug treatment, genes coding for direct 
downstream targets of HIF signaling (e.g., HMOX1, VEGF and NOS2) should be 
upregulated.  Genetic markers of bioburden may also change with active drug 
treatment.  Gene expression will therefore be assessed by RT-PCR using tissue samples 
taken from the wound area.  Most of these genes will be probed for using a focused array 
covering approximately 600 genes.  TaqMan PCR will be employed to validate gene 
expression for a number of signature genes for each of the signaling pathways/cellular 
processes of interest and for any other genes of interest not captured in the focused array.


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Section 4.2.1.Part A – Single Doses in Healthy Volunteers and DFU Patients 
(Cohorts 1 through 4), Paragraph 1, Sentence 4
PREVIOUS TEXT
Participation in more than one cohort in Part A, or participation in Part A then Part B, 
will require the subject to be screened again.
REVISED TEXT
Participation in more than one cohort in Part A, or participation in Part A then Part B will 
not require the subject to be screened again.
Section 4.2.1.1. Screening (Part A), Paragraph 1 
PREVIOUS TEXT
For the purposes of subject eligibility for enrollment in the study, screening assessments 
are defined as any assessments performed prior to the first dose of study drug in each 
part.
REVISED TEXT
For the purposes of subject eligibility for enrollment in the study, fasting screening 
assessments are defined as any assessments performed prior to the first dose of study 
drug in each part.
Section 4.2.1.2. Cohort 1 – Healthy Volunteers (Part A), Paragraph 1, Sentence 3 
and Paragraph 2, Sentence 7
PREVIOUS TEXT
The first application will be with a dose of 0.3mg (by utilization of 300mg of 0.01%).
Subjects will then return to the clinic 7 to 10 days after dosing for a follow-up visit.
REVISED TEXT
The first application will be with a dose of 0.3mg (by utilization of 300mg of 0.01%
0.1%).
Subjects will then return to the clinic 7 to 10 days and 1 month after dosing for a follow-
up visits.
Section 4.2.1.5. Cohorts 3 and 4 (Part A), Paragraph 1 
PREVIOUS TEXT
If subjects are re-enrolling from a previous cohort ensure that there has been a minimum 
of a 10 day washout.


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REVISED TEXT
.If subjects are re-enrolling from a previous cohort ensure that there has been a minimum 
of a 10 day washout prior to initiating the 14 day run-in to assess healing rate.
4.2.2. Part B – Single Dose/Repeat Doses in Diabetic Foot Ulcer Subjects (Cohorts 5, 
6 and 7), Paragraph 6
PREVIOUS TEXT
Subjects may not participate in more than one cohort in Part B.
REVISED TEXT
Subjects may not participate in more than one cohort in Part B.  Subjects may 
participate in Part A and then Part B which will require the subject to be screened 
again.
Section 4.3. Treatment Assignment, Table 2 Part A Doses
PREVIOUS TEXT
Cohort
Regimen
Dose (mg)
Treatment Area by 
Period
1
2
1
P
Placebo1
Intact
Intact
A
0.150mg
B
TBD2
2
P
Placebo
Intact
Wound
C
TBD
3
P
Placebo
Wound
N/A
D
TBD
4(or final)
P
Placebo
Wound
Intact
E
TBD
O (Optional)3
P
Placebo
Wound
N/A
F
TBD
1.
Placebo = vehicle
2.
Actual doses to be determined as preliminary PK data are reviewed and predicted exposures can be calculated.
3.
More than one optional cohort may be used.


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REVISED TEXT
Cohort
Regimen
Dose (mg)
Treatment Area by 
Period
1
2
1
P
Placebo1
Intact
Intact
A
0.150mg0.3mg
B
TBD2
2
P
Placebo
Intact
Wound
C
TBD
3
P
Placebo
Wound
N/A
D
TBD
4(or final)
P
Placebo
Wound
Intact
E
TBD
O (Optional)3
P
Placebo
Wound
N/A
F
TBD
1.
Placebo = vehicle
2.
Actual doses to be determined as preliminary PK data are reviewed and predicted exposures can be calculated.
3.
More than one optional cohort may be used.
Section 4.3. Treatment Assignment, Table 4 Example Treatment Options
PREVIOUS TEXT
Cohort
Regimen/
Dosing Period
Dose (mg)
Treatment Area
1 (HVT)
P1
Placebo1
Intact Skin
A
0.150mg
Intact Skin
P1
Placebo
Intact Skin
B
TBD2
Intact Skin
2
P1
Placebo
Intact Skin
C1
TBD
Intact Skin
P2
Placebo
Wound
C2
TBD
Wound
3
P2
Placebo
Wound
D
TBD
Wound
4(or final)
P2
Placebo
Wound
E1
TBD
Wound
P1
Placebo
Intact Skin
E2
TBD
Intact Skin
O (Optional)3
P2
Placebo
Wound 
F
TBD
Wound
1.
Placebo = vehicle
2.
Actual doses to be determined as preliminary PK data are reviewed and predicted exposures can be calculated.
3.
More than one optional cohort may be used.


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REVISED TEXT
Cohort
Regimen/
Dosing Period
Dose (mg)
Treatment Area
1 (HVT)
P1
Placebo1
Intact Skin
A
0.150mg 0.3mg
Intact Skin
P1
Placebo
Intact Skin
B
TBD2
Intact Skin
2
P1
Placebo
Intact Skin
C1
TBD
Intact Skin
P2
Placebo
Wound
C2
TBD
Wound
3
P2
Placebo
Wound
D
TBD
Wound
4(or final)
P2
Placebo
Wound
E1
TBD
Wound
P1
Placebo
Intact Skin
E2
TBD
Intact Skin
O (Optional)3
P2
Placebo
Wound 
F
TBD
Wound
1.
Placebo = vehicle
2.
Actual doses to be determined as preliminary PK data are reviewed and predicted exposures can be calculated.
3.
More than one optional cohort may be used.


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Section 4.6.1. Time and Events Table Part A
PREVIOUS TEXT
Study 
Population
Procedure
Screening
(up to 28 
days prior 
to Day 1)
Study Day (each dosing period)
Follow Up
Day 1
Day 
2
Day 
3
Day 
4
7-10 
days 
post last 
dose
28-32 
days 
post last 
dose
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48h
72h
All Subjects
Check in
X
Informed Consent
X
Demographics
X
Full Physical Exam
X
Brief Physical Exam
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
X
12-lead ECG1
X
X
X
X
Vital signs2
X
X
X
X
X
Urine pregnancy(women)
X
X
HIV, Hep B and Hep C
X
Hema/Chem Safety Labs3
X
X
X
X
Blood for HIFSamples 
(e.g., hepcidin, EPO,VEGF)4  
X
X
X
X4
X
Study treatment dosing
X
Pharmacokinetic Sampling5
X
X
X
X
X
X
X
X5
X
X
X
Concomitant Medications
=============================================================
X
Adverse Event Review6
=============================================================
X
X


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Study 
Population
Procedure
Screening
(up to 28 
days prior 
to Day 1)
Study Day (each dosing period)
Follow Up
Day 1
Day 
2
Day 
3
Day 
4
7-10 
days 
post last 
dose
28-32 
days 
post last 
dose
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48h
72h
Subjects with 
DFUs7 Only
Gene Expression (mRNA) 
Tissue Samples8
X
X
X
X
Biomarker fluid samples 
(e.g., for cytokines, growth 
factors, and bioburden)9
X
X
X
Physical Characteristics 
(e.g., photos and wound 
measurement post-
debridement, volume) 
X
X
X
X
Clinical Characteristics10
X
X
X
X
X
X
X
X
X
X
1.
Single ECGs will be taken Screening, and pre-dose on Day 1 and at the 48h post-last-dose on Day 3, and at the 7-10 day Follow-up Visit.  ECGs should be taken while subject is 
supine for at least 5 minutes.  Additional ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
2.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Day 1 and at the 48h post-last-dose on Day 3, and at the 
Follow-up Visits.  Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
3.
Blood samples for safety analyses will be collected fasting at Screening and on Day 1 and at the 48h post-last-dose on Day 3, and at the 7-10 day Follow-up Visit.  Refer to 
Section 7.2.4 for specific laboratory parameters to be tested.
4.
Blood samples HIFactivation on Day 1 will be collected at pre-dose, 8 and 10-12 hour window.  Refer to Section 7.6 for additional details on the collection and processing of 
these samples.
5.
Serial blood samples for the determination of the PK for GSK127886 and metabolites will be collected at immediately pre-dose (time 0), 0.25, 0.5, 1, 2, 4, 8, 10-12 (once within the 
10-12 window for out-patients only)/12 (in-patient subjects only), 24, 48 and 72hrs post-‘dose.  Refer to Section 7.13 for details on the collection and processing of PK samples.  
PK sampling times may be changed based on observed GSK1278863 PK profile, but the total number of samples will not change.
6.
Adverse events are to be collected from first dose through the final Follow-up visit.
7.
These assessments are to be performed only when IP is applied to the ulcer not to the patient’s intact skin
8.
Microarray and Taqman will be performed at all timepoints.
9.
Wound fluid for biomarkers of cytokines and bioburden will be collected at pre-dose (time 0) on Days 1and 4 and at the 7-10 day Follow-up Visit.
10. Clinical characteristic assessments of the DFU begin with Section 7.11 and contain instructions for completing the assessments including the irritation/symptom scale as needed.  
Assessments are recorded in the eCRF


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REVISED TEXT
Study 
Population
Procedure
Screening1
(HVT: -28 to 
-1 days; 
DFU: -28 to  
-14 days 
prior to Day 
1)
Study Day (each dosing period)
Follow Up
Day 1
Day 
2
Day 
3
Day 
4
7-10 
days 
post 
last 
dose
28-32 
days 
post 
last 
dose
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48
h
72
h
All Subjects
Check in
X
Informed Consent
X
Demographics
X
Full Physical Exam
X
Brief Physical Exam
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
X
12-lead ECG2
X
X
X
X
Vital signs3
X
X
X
X
X
Urine pregnancy(women)
X
X
HIV, Hep B and Hep C
X
Hema/Chem Safety Labs4
X
X
X
X
Blood for HIFSamples 
(e.g., hepcidin, 
EPO,VEGF)5  
X
X
X5
X
Study treatment dosing
X
Pharmacokinetic 
Sampling6
X
X
X
X
X
X
X
X5
X
X
X
Concomitant Medications
=============================================================
X
Adverse Event Review7
=============================================================
X
X


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Study 
Population
Procedure
Screening1
(HVT: -28 to 
-1 days; 
DFU: -28 to  
-14 days 
prior to Day 
1)
Study Day (each dosing period)
Follow Up
Day 1
Day 
2
Day 
3
Day 
4
7-10 
days 
post 
last 
dose
28-32 
days 
post 
last 
dose
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48
h
72
h
Subjects 
with DFUs8
Only
Gene Expression 
(mRNA) Tissue Samples
X
X
X
X
Biomarker fluid samples 
(e.g., for cytokines, 
growth factors, and 
bioburden)9
X
X
X
Physical Characteristics 
(e.g., photos and wound 
measurement post-
debridement, volume) 
X
X
X
X
Clinical Characteristics10
X
X
X
X
X
X
X
X
X
X
Vascular Perfusion 
Eligibility 
Assessments11
X
1.
For subjects with DFUs to be eligible for the study or for entry into more than one cohort in Part A, rate of healing must be assessed in the 14 days prior to Day 1.
2.
Single ECGs will be taken Screening, and pre-dose on Day 1 and at the 48h post-last-dose on Day 3, and at the 7-10 day Follow-up Visit.  ECGs should be taken while subject is 
supine for at least 5 minutes.  Additional ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
3.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Day 1 and at the 48h post-last-dose on Day 3, and at the 
Follow-up Visits.  Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
4.
Blood samples for safety analyses will be collected fasting at Screening and on Day 1 and at the 48h post-last-dose on Day 3, and at the 7-10 day Follow-up Visit.  Refer to 
Section 7.2.4 for specific laboratory parameters to be tested.
5.
Blood samples HIFactivation on Day 1 will be collected at pre-dose, 8 and 10-12 hour window.  Refer to Section 7.6 for additional details on the collection and processing of 
these samples.


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6.
Serial blood samples for the determination of the PK for GSK127886 and metabolites will be collected at immediately pre-dose (time 0), 0.25, 0.5, 1, 2, 4, 8, 10-12 (once within the 
10-12 window for out-patients only)/12 (in-patient subjects only), 24, 48 and 72hrs post-‘dose.  Refer to Section 7.13 for details on the collection and processing of PK samples.  
PK sampling times may be changed based on observed GSK1278863 PK profile, but the total number of samples will not change.
7.
Adverse events are to be collected from first dose through the final Follow-up visit.
8.
These assessments are to be performed only when IP is applied to the ulcer not to the patient’s intact skin.  
9.
Microarray and Taqman will be performed at all timepoints.
10. Wound fluid for biomarkers of cytokines and bioburden will be collected at pre-dose (time 0) on Days 1and 4 and at the 7-10 day Follow-up Visit.
11. Clinical characteristic assessments of the DFU begin with Section 7.11 and contain instructions for completing the assessments including the irritation/symptom scale as needed.    
Assessments are recorded in the eCRF
12. See Item 7 in the Inclusion Criteria – DFU Subjects for acceptable perfusion parameters.  Only 1 test of the 4 (TcPO2, ABI/TcPO2, toe pressure, Doppler ultrasound) is required 
for eligibility. 
Section 4.6.2. Time and Events Table Part B
PREVIOUS TEXT
Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
Visit Window 
(relative to Day 1)
-28 to -1 
days
Exams/samples 
pre-dose
Washout
Exams/samples 
pre-dose
7-10 
days 
post last 
dose
28-32 
days 
post last 
dose
Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
Informed Consent
X
Demographics
X
Complete physical
X
Brief physical
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
12-lead ECG1
X
X
X
Vital signs2
X
X
X
X
X
X
X


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Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
Urine 
pregnancy(females)
X
X
`
X
HIV, Hep B and Hep 
C screen
X
Hema/Chem/ Safety 
Labs3
X
X
X
X
X
X
Blood samples for 
HIF, (e.g., EPO, 
Hepcidin, VEGF)
X
X4
X4
X
X
Standard of Care 
Treatment5
X
X
X
X
Study 
Treatment/Dosing
In the Clinic6
X
X
X
X
X
X
X
PK serial blood 
sampling7
X
X
X
X (truncated)
X
X
X
X
X
PK Trough Sample7
X
Gene Expression 
(mRNA) Samples 
Tissue Biopsies8
X
X
X
X
X
Biomarker Samples:  
Wound fluid for 
cytokines and 
bioburden9
X
X
X
(Day 
3 
only9)
X
X
X
X
X
Macrophages10
X
X
X
X
X
X
X
X
SensiLase (Dopplar 
blood flow)
X
X
X
X
X


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Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
Physical 
Characteristics
(assessed pre-
dose)11
X11
X
X
X
X
X
X
X
Clinical 
Characteristics12
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medication Review
X
=============================================================
X
Adverse Event 
Assessment13
X
=============================================================
X
X
1.
Single ECGs will be taken at Screening and pre-dose on Day 1(SD) and 24h post-last-RD dose on Day 22.  ECGs should be taken while subject is supine for at least 5 
minutes.  Additional ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
2.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Days 1 (SD) and 8(RD), 15, 22 (24h post-last-RD dose) , 
and at Follow-up.  Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
3.
Blood samples for safety will be collected fasting at Screening and pre-dose/equivalent time on Days 1,8,14, 22 (24h post-last-dose), and at Follow-up.  Refer to Section 
7.2.4 for specific laboratory parameters to be tested.
4.
Blood samples for HIFactivation on Day 1 and Day 8 will be collected at pre-dose, 8 and 10-12 hour window.  On all other indicated days one sample will be collected at 
pre-dose/equivalent time.  
5.
During washout times all subjects will be on SOC (Section 7.4).
6.
In between clinic visits, subjects with perform applications of study drug at home.
7.
See separate Time and Events table for serial PK sampling details for Days 1, 8, 14 and 21.  Trough sample will be taken prior to dosing on Day 18.  Refer to Section 7.13 for 
details on the collection and processing of PK samples.  PK sampling times may be changed based on observed GSK1278863 PK profile, but the total number of samples 
will not change.
8.
Direct wound tissue samples for analysis of gene expression will be collected at pre-dose on Days 1, 2, 8, 11, 14, 21, 22 and at the Follow-up Visit.  TaqMan analysis will be 
performed on each day.  Microarray analysis will be performed on the following Days 1, 2, 8, 14, 22 and Follow-up, however based on emerging data additional time points 
may be added.  Refer to Section 7.4 for additional details on the collection and processing of gene expression samples.
9.
Wound fluid and tissue samples for biomarkers of cytokines and bioburden will be collected at pre-dose on Days 1, 2. 3, 8, 14, 15, 22 and at the Follow-up Visit.  Refer to the 
Section 7.5.3 for additional details on the collection and processing of biomarker tissue samples.
10. May be conducted at only one or both sites, dependent upon feasibility.  Will be performed in a select cohort of patients.  The precise procedure will be dependent upon the 
outcome of feasibility work. 


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11. Physical characteristics of the wound (e.g., photos of the wound and wound measurement assessments) will be assessed at Screening (acetate tracings only), and pre-
dose/equivalent time on Days 1, 8, 11, 14, 18, 22 and at the Follow-up Visit.  Any subject that is participating in additional cohorts during Part B would need to be assessed 
for wound healing rate for 14 days (as in the regular screen) to ensure healing rate is less than 30%. 
12. Clinical characteristic assessments of the DFU begin with Section 7.11 and contain instructions for completing the assessments including the irritation/symptom scale as 
needed.  Assessments are recorded in the eCRF.
13. Adverse events are to be collected from first dose through the Follow-up visit.
REVISED TEXT
Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
Visit Window 
(relative to Day 1)
-28 to -14 
days
Exams/samples 
pre-dose
Washout
Exams/samples 
pre-dose
7-10 
days 
post last 
dose
28-32 
days 
post last 
dose
Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Informed Consent
X
Demographics
X
Complete physical
X
Brief physical
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
12-lead ECG1
X
X
X
Vital signs2
X
X
X
X
X
X
X
Urine 
pregnancy(females)
X
X
`
X
HIV, Hep B and Hep 
C screen
X
Hema/Chem/ Safety 
Labs3
X
X
X
X
X
X
Vascular Perfusion 
X


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Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
Eligibility 
Assessments4
Blood samples for 
HIF, (e.g., EPO, 
Hepcidin, VEGF)
X
X5
X5
X
X
Standard of Care 
Treatment6
X
X
X
X
Study 
Treatment/Dosing
In the Clinic7
X
X
X
X
X
X
X
PK serial blood 
sampling8
X
X
X
X (truncated)
X
X
X
X
X
PK Trough Sample8
X
Gene Expression 
(mRNA) Samples 
Tissue Biopsies9
X
X
X
X
X
Biomarker Samples:  
Wound fluid for 
cytokines and 
bioburden10
X
X
X
(Day 
3 
only10)
X
X
X
X
X
Macrophages11
X
X
X
X
X
X
X
X
SensiLase (Doppler 
blood flow) 
X
X
X
X
X
Hyperspectral 
Imaging12
X
X
X
X
X


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Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
Physical 
Characteristics
(assessed pre-
dose)13
X11
X
X
X
X
X
X
X
Clinical 
Characteristics14
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medication Review
X
=============================================================
X
Adverse Event 
Assessment15
X
=============================================================
X
X
1.
Single ECGs will be taken at Screening and pre-dose on Day 1(SD) and 24h post-last RD dose on Day 22.  ECGs should be taken while subject is supine for at least 5 minutes.  
Additional ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
2.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Days 1 (SD) and 8(RD), 14, 22 (24h post-last-RD dose) , and 
at Follow-up Visits.  Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
3.
Blood samples for safety will be collected fasting at Screening and pre-dose/equivalent time on Days 1,8,14, 22 (24h post-last-dose), and at the 7-10 day Follow-up Visit.  Refer to 
Section 7.2.4 for specific laboratory parameters to be tested.
4.
See Item 7 in the Inclusion Criteria – DFU Subjects for acceptable perfusion parameters.  Only 1 test of the 4 (TcPO2, ABI/TcPO2, toe pressure, Doppler ultrasound) is 
required for eligibility.
5.
Blood samples for HIFactivation on Day 1 and Day 8 will be collected at pre-dose, 8 and 10-12 hour window.  On all other indicated days one sample will be collected at pre-
dose/equivalent time.  
6.
During washout times all subjects will be on SOC (Section 7.4).
7.
In between clinic visits, subjects with perform applications of study drug at home.
8.
See separate Time and Events table for serial PK sampling details for Days 1, 8, 14 and 21 and the associated 24, 48 and 72 hr time points.  Trough sample will be taken prior to 
dosing on Day 18.  Refer to Section 7.13 for details on the collection and processing of PK samples.  PK sampling times may be changed based on observed GSK1278863 PK 
profile, but the total number of samples will not change.
9.
Direct wound tissue samples for analysis of gene expression will be collected at pre-dose/equivalent on Days 1, 8, 14 and 22, however based on emerging data additional time 
points may be added.  Refer to Section 7.5 for additional details on the collection and processing of gene expression samples.
10. Wound fluid for biomarkers of cytokines and bioburden will be collected at pre-dose/equivalent on Days 1, 2. 3, 8, 14, 15, 22 and at the 7-10 day Follow-up Visit.  Refer to the 
Section 7.7 for additional details on the collection and processing of biomarker tissue samples.
11. May be conducted at only one or both sites, dependent upon feasibility.  Will be performed in a select cohort of patients.  The precise procedure will be dependent upon the 
outcome of feasibility work.
11. Will be performed based on hyperspectral imaging capabilities at each site. 


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12. Physical characteristics of the wound (e.g., photos of the wound and wound measurement assessments) will be assessed at Screening (acetate tracings only), and pre-
dose/equivalent time on Days 1, 8, 11, 14, 18, 22 and at the 7-10 day Follow-up Visit.  Any subject that is participating in additional cohorts during Part B would need to be 
assessed for wound healing rate for 14 days (as in the regular screen) to ensure healing rate is less than 30%.
13. Clinical characteristic assessments of the DFU begin with Section 7.11 and contain instructions for completing the assessments including the irritation/symptom scale as needed.  
Assessments are recorded in the eCRF.
14. Adverse events are to be collected from first dose through the final Follow-up visit.


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5.3.1. Inclusion Criteria – DFU Subjects, Criteria #7
PREVIOUS TEXT
7. Adequate vascular perfusion of the affected limb, as defined by at least one of the 
following:
a) TcPO2 > 35mmHg within 30 days of screening.
b) Ankle-Brachial Index (ABI) ≥ 0.6 and ≤ 1.2, confirmed by TcPO2 
>35mmHg.
c) Toe pressure (plethysmography) > 50mmHg.
d) Doppler ultrasound (biphasic or triphasic waveforms) consistent with 
adequate blood flow to the affected extremity, as determined by SoC.
REVISED TEXT
7. Adequate vascular perfusion of the affected limb within 30 days of screening, as 
defined by at least one of the following:
e) TcPO2 > 35mmHg within 30 days of screening.
f)
Ankle-Brachial Index (ABI) ≥ 0.6 and ≤ 1.2, confirmed by TcPO2 
>35mmHg.
g) Toe pressure (plethysmography) > 50mmHg.
h) Doppler ultrasound (biphasic or triphasic waveforms) consistent with 
adequate blood flow to the affected extremity, as determined by SoC.
7.8.1. Sample Collection for Macrophage Immunostaining, Paragraph 1
PREVIOUS TEXT
Upon collection, the biopsy will be placed in an embedding mold containing freezing 
medium (such as OCT embedding compound) and frozen immediately before storing at -
80oC prior to tissue sectioning and immunostaining according to standard procedures.
REVISED TEXT
Upon collection, the biopsy will be placed in an embedding mold containing freezing 
medium (such as OCT embedding compound) and frozen immediately before storing at -
80oC prior to tissue sectioning and immunostaining according to standard procedures a 
pre-labeled cryovial and snap frozen in liquid nitrogen.  The cryovials will be 
transferred to a pre-labelled freezer box and then moved immediately into a -80C 
freezer.  Samples will be shipped to laboratory within 8 months of collection.  
Shipping instructions are in the Study Procedures Manual.


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AMENDMENT 3
Where the Amendment Applies
This amendment applies to all sites.
Summary of Amendment Changes with Rationale
This amendment clarifies an eligibility criterion and DFU clinical assessments as well as 
minor edits for clarity.
List of Specific Changes
1.4.1.1 Single Dose Strategy, Paragraph 3, Sentence 2
PREVIOUS TEXT
The starting dose in this cohort will be 0.1% GSK1278863 petrolatum ointment at 
25mg/cm2 to a 12cm2 section of intact skin (300mg total mass of the formulation) on the 
lower limb, which will deliver 300g GSK1278863.
REVISED TEXT
The starting dose in this cohort will be 0.1% GSK1278863 petrolatum ointment at 
25mg/cm2 to a 12cm2 section of intact skin (300mg total mass of the formulation) on the 
foot lower limb, which will deliver 300g GSK1278863.
4.2.1. Part A – Single Doses in Healthy Volunteers and DFU Patients (Cohorts 1 
through 4), sentence 3
PREVIOUS TEXT
Diabetic subjects may participate in more than one cohort in Part A (requires a minimum 
of a 14 day washout between cohorts to ensure a healing rate of less than 30%) and may 
also participate in Part B (requires a minimum of a 14 day washout between cohorts to 
ensure a healing rate of less than 30%) provided the subject meets all selection criteria 
and this participation will not result in blood withdrawal over the limit (Section 5.2.2.).
REVISED TEXT
Diabetic subjects may participate in more than one cohort in Part A (requires a minimum 
of a 14 days washout between cohorts to ensure a healing rate of less than 30%) and may 
also participate in Part B (requires a minimum of a 14 days washout between cohorts to 
ensure a healing rate of less than 30%) provided the subject meets all selection criteria 
and this participation will not result in blood withdrawal over the limit (Section 5.2.2).


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Section 4.2.1.3. Run-In period (Part A)
PREVIOUS TEXT
For all diabetic subjects in Part A, each subject’s DFU will be measured at screening and 
Day 1; if, after 14 days from screening, the subject’s DFU has reduced in size by greater 
than 30 %, the subject will not be randomized to receive investigational product.  
Subjects that do not meet randomization eligibility will be discontinued from the study.
REVISED TEXT
For all diabetic subjects in Part A, each subject’s DFU will be measured at screening and 
Day 1; if, after 14 days from screening, the subject’s DFU has reduced in size by greater 
than 30 %, the subject will not be randomized to receive investigational product.  If 
Screening and Day 1 are not 14 days (1 day) apart, an additional visit (Baseline 
Run-In) will need to be scheduled prior to Day 1 to meet the Run-In requirement. 
Subjects that do not meet randomization eligibility will be discontinued from the study.
Section 4.2.1.5. Cohorts 3 and 4 (Part A)
PREVIOUS TEXT
If subjects are re-enrolling from a previous cohort, ensure that there has been a minimum 
of a 10 day washout prior to initiating the 14 day run-in to assess healing rate.  
REVISED TEXT
If subjects are re-enrolling from a previous cohort,they must complete the second 
Follow-up visit (Day 28-32 post last dose) and therefore the 14 day Run-in period 
may begin 14 days prior to this visit. ensure that there has been a minimum of a 10 day 
washout prior to initiating the 14 day run-in to assess healing rate.  
Section 4.2.2.2. Run-In Period (Part B), sentence 3
PREVIOU TEXT
For all subjects in Part B, each subject’s DFU will be measured at screening and Day 1; 
if, after 14 days from screening, the subject’s DFU has reduced in size by greater than 30 
%, the subject will not be randomized to receive investigational product.  Subjects that do 
not meet randomization eligibility will be discontinued from the study.
REVISED TEXT
For all subjects in Part B, each subject’s DFU will be measured at screening and Day 1; 
if, after 14 days from screening, the subject’s DFU has reduced in size by greater than 30 
%, the subject will not be randomized to receive investigational product.  If Screening 
and Day 1 are not 14 days (1 day) apart, an additional visit (Baseline Run In) will 
need to be scheduled prior to Day 1 to meet the Run In requirement. Subjects that do 
not meet randomization eligibility will be discontinued from the study.


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Section 4.3.1 Subject Numbering, Paragraph1, sentences 1 and 2
PREVIOUS TEXT
The site will assign screening numbers using their own unique schema.  Screening 
numbers are not collected by GSK.  Subjects will be assigned a unique Subject Number 
at admission to the clinic for each cohort the subject opts to participate in.  
REVISED TEXT
The site will assign screening numbers using their own unique schema.  Screening 
numbers are not collected by GSK.  Subjects will be assigned a unique Subject Number 
at admission to the clinicScreening for each cohort the subject opts to participate in.  
Section 5.3.1 Inclusion Criteria – DFU Subjects, Criteria 7. b)
PREVIOUS TEXT
b) Ankle-Brachial Index (ABI) ≥ 0.6 and ≤ 1.2, confirmed by TcPO2 >35mmHg.
REVISED TEXT
b) Ankle-Brachial Index (ABI) ≥ 0.6 and ≤ 1.2, confirmed by TcPO2 >35mmHg.
Section 7.10.2.1. Photo Capture – Wound Images
PREVIOUS TEXT
Photographic documentation of the wound should be obtained after debridement.  
Randomization and weekly imaging of the wound should occur after cleansing and before 
treatment with study drug.
When using the camera to photograph the target ulcer the base of the camera at its widest 
should lay perpendicular to the underlying bone as if they were cutting it.  For toe 
wounds and very small wounds, this instruction should be used as far as possible.  If this 
is not possible, the same position in which the first photograph was taken should be 
followed for all subsequent photos.
At each visit 2 photographs are to be taken of the subject card that records; subject 
number, date, visit number, study name and subject initials.  Two photographs are to be 
taken approximately 8 inches from the wound.  Two additional photographs are to be 
taken of the wound approximately 24 inches from the wound.  
To ensure the subject meets the inclusion criteria of the change in ulcer size between 
screening and randomization, percent reduction of wound size must be calculated using a 
program provided to the sites and the guide in the case report form.


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Photographic documentation should be sent electronically to the core lab as soon as 
possible, preferably on the same day the picture was taken.
Photographs of tracings and wounds will be stored on individual memory cards, as well 
as, downloaded to a computer at each site and uploaded to the wound core lab website.  
Refer to the SPM for details.
Photo 1- ID card

Complete ID card with subjects study number and date then place in photographic 
field.

View camera image to ensure complete ID card is in photograph.

Take 2 photos.
Photo 2- Close-up view

Locate ulcer to be photographed (if more than one ulcer on the target limb determine 
target ulcer.

Identify target ulcer using sticker provided.

Camera is to be oriented with the top of the camera directed towards the direction of 
the subject’s head.

Camera is to be held 8 inches from target ulcer.

Depress focus button half way until the view of the ulcer is sharp.

Take 2 photos.
Photo 3- Global view

Camera is to be oriented with the top of the camera directed towards the direction of 
the subject’s head.

Camera is to be held at a distance that allows the entire limb from just below the 
knee and encompassing the entire foot to be viewed.

The target ulcer must be visible in photo.

Depress focus button half way until the view of the limb is sharp.

Take 2 photos.
Saving Photos
Using the cable supplied connect the camera to a computer with a USB port, save 
photographs to computer desktop.
REVISED TEXT
Photographic documentation of the wound should be obtained after debridement.  
Randomization and weekly imaging of the wound should occur after cleansing and before 
treatment with study drug.


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When using the camera to photograph the target ulcer the base of the camera at its widest 
should lay perpendicular to the underlying bone as if they were cutting it.  For toe 
wounds and very small wounds, this instruction should be used as far as possible.  If this 
is not possible, the same position in which the first photograph was taken should be 
followed for all subsequent photos.
At each visit 2 photographs are to be taken of the subject card that records; subject 
number, date, visit number, study name and subject initials.  Two photographs are to be 
taken approximately 8 inches from the wound.  Two additional photographs are to be 
taken of the wound approximately 24 inches from the wound.  
To ensure the subject meets the inclusion criteria of the change in ulcer size between 
screening and randomization, percent reduction of wound size must be calculated using a 
program provided to the sites and the guide in the case report form.
Photographic documentation should be sent electronically to the core lab as soon as 
possible, preferably on the same day the picture was taken.
Photographs of tracings and wounds will be stored locally on individual memory cards, 
as well as, downloaded to a computer at each site and uploaded to the wound core lab 
website.  Refer to the SPM for details.
Photo 1- ID card

Complete ID card with subjects study number and date then place in photographic 
field.

View camera image to ensure complete ID card is in photograph.

Take 2 photos.
Photo 2- Close-up view

Locate ulcer to be photographed (if more than one ulcer on the target limb determine 
target ulcer.

Identify target ulcer using sticker provided.

Camera is to be oriented with the top of the camera directed towards the direction of 
the subject’s head.

Camera is to be held 8 inches from target ulcer.

Depress focus button half way until the view of the ulcer is sharp.

Take 2 photos.
Photo 3- Global view

Camera is to be oriented with the top of the camera directed towards the direction of 
the subject’s head.

Camera is to be held at a distance that allows the entire limb from just below the 
knee and encompassing the entire foot to be viewed.


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
The target ulcer must be visible in photo.

Depress focus button half way until the view of the limb is sharp.

Take 2 photos.
Saving Photos
Using the cable supplied connect the camera to a computer with a USB port, save 
photographs to computer desktop.
7.10.2.2. Wound Tracings
PREVIOUS TEXT
Each wound tracing is to be captured with a digital photograph using a camera provided 
to each site.  The header information on the acetate tracing; study name, date, visit 
number, subject number, subject initials must be completed before the photograph is 
taken. Two pictures are to be taken of each tracing.
Printed copies of the photograph of the wound tracing are to be retained as source 
documents in the subjects’ study files.  Original tracings are to be sent to the wound core 
lab (see the Study Procedures Manual for shipping instructions).

Complete header information on the Cover acetate (acetate with printed header 
information) using 0.5 mm Itoya pen including the subject’s initials, unique study 
identifier, date and visit number.

Place Blank acetate over the wound area.

Then place Cover acetate over Blank acetate.

Trace the ulcer using one continuous line around the wound edge (do not include any 
islands in the tracing).

Ensure all gaps are closed and that the tracing is a solid line.

Place the top film centered on the cardboard backer and discard the bottom film.

Make a copy of the tracing and file the copy with the subject’s source 
documentation.

Using the camera  take  a picture of the Cover acetate:

Ensure the camera is set to C2.

Look through the viewfinder and ensure the entire acetate page will be captured 
in the photograph, and that the acetate page fills the majority of the picture.

Depress the focus button ½ way and ensure the acetate is in focus.

Take two pictures.

Using the cable supplied connect the camera to a computer with a USB port.
Save photograph to computer desktop.


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REVISED TEXT
To ensure the subject meets the randomization eligibility of the change in ulcer size 
between screening (or optional Run In visit, if different from day of screening) and 
randomization on Day 1, percent reduction of wound size must be calculated by the 
Investigator or designee using the method for measuring wound area provided in 
the SPM.  The core lab may be consulted for assistance with area measurements or 
percent reduction determinations if necessary.
All Each wound tracing are is to be scanned and sent to the core lab along with 
wound photographs (Section 7.10.2.1).  captured with a digital photograph using a 
camera provided to each site.  The header information on the acetate tracing; protocol 
number, date, visit number, subject number, subject initials must be completed before 
the acetate is scanned photograph is taken.  Two pictures are to be taken of each tracing.
Original Printed copies of the photograph of the wound tracing are to be retained as 
source documents in the subjects’ study files.  Original tracings may are to be sent to the 
wound core lab when a quality scan cannot be obtained.  Refer to the SPM for 
additional details (see the Study Procedures Manual for shipping instructions).

Complete header information on the Cover acetate (acetate with printed header 
information) using 0.5 mm Itoya pen including the subject’s initials, unique study 
identifier, date and visit number.

Place Blank acetate over the wound area.

Then place Cover acetate over Blank acetate.

Trace the ulcer using one continuous line around the wound edge (do not include any 
islands in the tracing).

Ensure all gaps are closed and that the tracing is a solid line.

Place the top film centered on the cardboard backer and discard the bottom film.

Make a copy of the tracing and file the copy with the subject’s source 
documentation.

Using the camera  take  a picture of the Cover acetate:

Ensure the camera is set to C2.

Look through the viewfinder and ensure the entire acetate page will be captured 
in the photograph, and that the acetate page fills the majority of the picture.

Depress the focus button ½ way and ensure the acetate is in focus.

Take two pictures.

Using the cable supplied connect the camera to a computer with a USB port.
Save photograph to computer desktop.


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7.10.2.3. Volume Measurement and 7.10.2.4 Ulcer Depth
PREVIOUS TEXT
7.10.2.3 Volume Measurement
The ARANZ Medical Silhouette system will be used for wound volume measurement.  
All photographic parameters, including lighting, distance, and exposure, should comply 
with the ARANZ Silhouette Digital Camera Instruction Manual specifications.  The 
volume measurement will be obtained directly from the camera and the measurement 
recorded on the case report form.  .
7.10.2.4 Ulcer Depth
Ulcer Depth (Depth, D) will be measured at all study visits.  Unit of measurement to be 
used is millimeters.
REVISED TEXT
7.10.2.3 Depth and Volume Measurements
The ARANZ Medical Silhouette system will be used for wound depth and volume 
measurement.  All photographic parameters, including lighting, distance, and exposure, 
should comply with the ARANZ Silhouette Digital Camera Instruction Manual 
specifications.  The volume measurement will be obtained directly from the camera and 
the measurement recorded on the case report form.  Sites that do not have access to the 
ARANZ Medical Silhouette system will not be required to collect these exploratory 
data.
7.10.2.4 Ulcer Depth
The ARANZ Medical Silhouette system will be used for wound depth measurement.  All 
photographic parameters, including lighting, distance, and exposure, should comply with 
the ARANZ Silhouette Digital Camera Instruction Manual specifications.  The depth 
measurement will be obtained directly from the camera and the measurement recorded on 
the case report form.  Sites that do not have access to the ARANZ Medical Silhouette 
system will not be required to collect these exploratory data. Ulcer Depth (Depth, D) will 
be measured at all study visits.  Unit of measurement to be used is millimeters.
7.10.2.4. Ulcer Size Reduction
PREVIOUS TEXT
Percent change in study ulcer area will be determined by a central planimetry contractor 
after the subject has completed the two-week Run-in period in order to determine if the 
subject qualifies for randomization.


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REVISED TEXT
Percent change in study ulcer area will be determined by a central planimetry contractor 
the site after the subject has completed the two-week Run-in period in order to determine 
if the subject qualifies for randomization.
7.11. Clinical Characteristics of the DFU, Paragraph 1
PREVIOUS TEXT
At each study visit, the investigator will assess the characteristics of the ulcer being 
treated.  The investigator will assess, using the chart below (Table 6), the wound edge, 
base color, periwound condition, periwound color, degree of edema, amount of exudate 
(drainage), type of exudate and percent of granulation tissue present.  
REVISED TEXT
At each study visit, the investigator will assess the characteristics of the ulcer being 
treated.  The investigator will assess, using the chart below (Table 6), the wound edge, 
base color, periwound condition, periwound color, degree of edema, amount of exudate 
(drainage), type of exudate and percent of granulation tissue present.  The investigator 
will also assess whether the wound is healed or not healed.
12.3 Cardiovascular Events, Added section
12.3 Cardiovascular Events
Investigators will be required to fill out event specific data collection tools 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 thrombosis
Deep venous thrombosis or pulmonary embolus
Revascularization
This information should be recorded within one week of when the AE/SAE(s) are 
first reported.


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AMENDMENT 4
Where the Amendment Applies
This amendment applies to all sites.
Summary of Amendment Changes with Rationale
This amendment reflects changes in the container type used to supply the bulk ointment.  
Minor edits are also included for clarity.
List of Specific Changes
Section 4.4 Investigational Product and Other Study Treatment 
Dosage/Administration, Line 8 of the table
PREVIOUS TEXT
Device:
Part A: Amber Bottle
Part B: White Tube
Part A: Amber Bottle
Part B: White Tube
REVISED TEXT
Device:
Part A: Amber Bottle or White Tube
Part B: White Tube
Part A: Amber Bottle or White Tube
Part B: White Tube
Section 4.6.1 Time and Events Table – Part A, Footnote # 8 and 9 
PREVIOUS TEXT
8.
These assessments are to be performed only when IP is applied to the ulcer not to the patient’s intact skin.
9.
Clinical characteristic assessments of the DFU begin with Section 7.11 and contain instructions for 
completing the assessments including the irritation/symptom scale as needed. Assessments are recorded in 
the eCRF
  
REVISED TEXT
8.
These assessments are to be performed only when IP is applied to the ulcer not to the patient’s intact skin 
unless for screening/eligibility purposes.  
9.
Clinical characteristic assessments of the DFU begin with Section 7.11 and contain instructions for 
completing the assessments including the irritation/symptom scale as needed.  The 12 hr assessment can 
be done once within the 10-12h window for out-patients and at 12 hrs for in-patient subjects. 
Assessments are recorded in the eCRF


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Section 5.3.1 Inclusion Criteria – DFU Subjects, Inclusion Criteria #5
PREVIOUS TEXT
5.  DFU between 1cm² and 20cm² at screening.
REVISED TEXT
5. DFU between 1cm² and 2016cm² at screening.


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AMENDMENT 5
Where the Amendment Applies
This amendment applies to all sites.
Summary of Amendment Changes with Rationale
This amendment reflects modifications to the DFU inclusion and exclusion criteria, 
hemoglobin stopping criteria and a change in biopsy collection expectations.  Minor edits 
are also included for clarity. 
List of Specific Changes
Section 4.5.1.1. Hemoglobin Stopping Criteria, Paragraph 1
PREVIOUS TEXT
A patient that experiences an absolute increase in hemoglobin of 1.0g/dL above their 
baseline level at any time will be withdrawn from the study.
REVISED TEXT
A patient that experiences an absolute increase in hemoglobin of 1.5g/dL above their 
baseline level at any time will be withdrawn from the study.


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Section 4.6.1 Time and Events Table – Part A, Urine pregnancy (women)
PREVIOUS TEXT
Study 
Population
Procedure
Screening1
(HVT: -28 to 
-1 days; 
DFU: -28 to  
-14 days 
prior to Day 
1)
Study Day (each dosing period)
Follow Up
Day 1
Day 
2
Day 
3
Day 
4
7-10 
days 
post 
last 
dose
28-32 
days 
post 
last 
dose
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48
h
72
h
Urine 
pregnancy(women)
X
X


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REVISED TEXT
Study 
Population
Procedure
Screening1
(HVT: -28 to 
-1 days; 
DFU: -28 to  
-14 days 
prior to Day 
1)
Study Day (each dosing period)
Follow Up
Day 1
Day 
2
Day 
3
Day 
4
7-10 
days 
post 
last 
dose
28-32 
days 
post 
last 
dose
Pre-
dose
0h
0.25h
0.5h
1h
2h
4h
8h
12h
24h
48
h
72
h
Urine 
pregnancy(women)
X
X
X


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Section 4.6.1 Time and Events Table – Part A, Addition of footnote # 9 with 
associated re-numbering
PREVIOUS TEXT
1.
For subjects with DFUs to be eligible for the study or for entry into more than one cohort in Part A, rate of healing 
must be assessed in the 14 days prior to Day 1.
2.
Single ECGs will be taken at Screening,  pre-dose on Day 1, at 48h post-last-dose on Day 3 and at the 7-10 day 
Follow-up Visit.  ECGs should be taken while subject is supine for at least 5 minutes.  Additional ECGs may be 
taken at the discretion of the investigator as needed based on symptoms or ECG findings.
3.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose 
on Day 1 and at the 48h post-last-dose on Day 3, and at the Follow-up Visits.  Vital signs should be performed 
after resting in a supine or semi-supine position for at least 5 minutes.
4.
Blood samples for safety analyses will be collected fasting at Screening, on Day 1, at 48h post-last-dose on Day 3 
and at the 7-10 day Follow-up Visit.  Refer to Section 7.2.4 for specific laboratory parameters to be tested.
5.
Blood samples HIFactivation on Day 1 will be collected at pre-dose, 8 and 10-12 hour window.  Refer to Section 
7.6 for additional details on the collection and processing of these samples.
6.
Serial blood samples for the determination of the PK for GSK127886 and metabolites will be collected 
immediately pre-dose and 0.25, 0.5, 1, 2, 4, 8, 10-12 (once within the 10-12 window for out-patients only)/12 (in-
patient subjects only), 24, 48 and 72hrs post-dose.  Refer to Section 7.12 for details on the collection and 
processing of PK samples.  PK sampling times may be changed based on the observed GSK1278863 PK profile, 
but the total number of samples will not change.
7.
Adverse events are to be collected from first dose through the final Follow-up Visit.
8.
These assessments are to be performed only when IP is applied to the ulcer not to the patient’s intact skin unless 
for screening/eligibility purposes.  
9.
Clinical characteristic assessments of the DFU begin with Section 7.10 and contain instructions for completing the 
assessments including the irritation/symptom scale as needed.  The 12 hr assessment can be done once within 
the 10-12 window for out-patients and at 12 hrs for in-patient subjects. Assessments are recorded in the eCRF
10. See Item 7 in the Inclusion Criteria – DFU Subjects for acceptable perfusion parameters.  Only 1 test of the 4 
(TcPO2, ABI/TcPO2, toe pressure, Doppler ultrasound) is required for eligibility. 


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REVISED TEXT
1.
For subjects with DFUs to be eligible for the study or for entry into more than one cohort in Part A, rate of healing 
must be assessed in the 14 days prior to Day 1.
2.
Single ECGs will be taken at Screening,  pre-dose on Day 1, at 48h post-last-dose on Day 3 and at the 7-10 day 
Follow-up Visit.  ECGs should be taken while subject is supine for at least 5 minutes.  Additional ECGs may be 
taken at the discretion of the investigator as needed based on symptoms or ECG findings.
3.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose 
on Day 1 and at the 48h post-last-dose on Day 3, and at the Follow-up Visits.  Vital signs should be performed 
after resting in a supine or semi-supine position for at least 5 minutes.
4.
Blood samples for safety analyses will be collected fasting at Screening, on Day 1, at 48h post-last-dose on Day 3 
and at the 7-10 day Follow-up Visit.  Refer to Section 7.2.4 for specific laboratory parameters to be tested.
5.
Blood samples HIFactivation on Day 1 will be collected at pre-dose, 8 and 10-12 hour window.  Refer to Section 
7.6 for additional details on the collection and processing of these samples.
6.
Serial blood samples for the determination of the PK for GSK127886 and metabolites will be collected 
immediately pre-dose and 0.25, 0.5, 1, 2, 4, 8, 10-12 (once within the 10-12 window for out-patients only)/12 (in-
patient subjects only), 24, 48 and 72hrs post-dose.  Refer to Section 7.12 for details on the collection and 
processing of PK samples.  PK sampling times may be changed based on the observed GSK1278863 PK profile, 
but the total number of samples will not change.
7.
Adverse events are to be collected from first dose through the final Follow-up Visit.
8.
These assessments are to be performed only when IP is applied to the ulcer not to the patient’s intact skin unless 
for screening/eligibility purposes.  
9.
Tissue sample collection at Pre-dose, Day 4 and the 7-10 Follow-up Visit is at the discretion of the PI or 
designee.  Wounds that have healed such that biopsies would be disruptive to the continued healing 
process are exempt.
10. Clinical characteristic assessments of the DFU begin with Section 7.10 and contain instructions for completing the 
assessments including the irritation/symptom scale as needed.  The 12 hr assessment can be done once within 
the 10-12 window for out-patients and at 12 hrs for in-patient subjects. Assessments are recorded in the eCRF
11. See Item 7 in the Inclusion Criteria – DFU Subjects for acceptable perfusion parameters.  Only 1 test of the 4 
(TcPO2, ABI/TcPO2, toe pressure, Doppler ultrasound) is required for eligibility. 


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Section 4.6.1 Time and Events Table – Part B, Gene Expression Tissue Biopsies, Macrophages and Wound Fluid
PREVIOUS TEXT
Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
Visit Window 
(relative to Day 1)
-28 to -14 
days
Exams/samples 
pre-dose
Washout
Exams/samples 
pre-dose
7-10 
days 
post last 
dose
28-32 
days 
post last 
dose
Gene Expression 
(mRNA) Samples 
Tissue Biopsies9
X
X
X
X
Biomarker Samples:  
Wound fluid for 
cytokines and 
bioburden10
X
X
X
(Day 3 
only10)
X
X
X
X
X
Macrophages
X
X
X
X
SensiLase (Doppler 
blood flow) 
X
X
X
X
X


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REVISED TEXT
Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
Visit Window 
(relative to Day 1)
-28 to -14 
days
Exams/samples 
pre-dose
Washout
Exams/samples 
pre-dose
7-10 
days 
post last 
dose
28-32 
days 
post last 
dose
Gene Expression 
(mRNA) Samples
Tissue Biopsies 
(gene expression, 
macrophage and 
bioburden 
analysis)9
X
X
X
X
Biomarker Samples
Wound Fluid 
(cytokine and 
bioburden analysis)10
X
X
X
(Day 3 
only10)
X
X
X
X
X
Macrophages
X
X
X
X
SensiLase (Doppler 
blood flow) 
X
X
X
X
X


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Section 4.6.1 Time and Events Table – Part B, Footnote # 9
PREVIOUS TEXT
9.
Direct wound tissue samples for analysis of gene expression will be collected at pre-dose/equivalent on Days 1, 8, 
14 and 22, however based on emerging data additional time points may be added.  Refer to Section 7.7.2 for 
additional details on the collection and processing of gene expression samples.
REVISED TEXT
9.
Direct wound tissue samples for analysis of gene expression will be collected at pre-dose/equivalent on Days 1, 8, 
14 and 22, however based on emerging data, time points may be added or deleted; wounds that have healed 
sufficiently may be exempt.  Refer to Section 7.7.2 for additional details on the collection and processing of 
gene expression samples tissue biopsies.
Section 5.2.1 Inclusion Criteria – Healthy Volunteers (Part A, Cohort 1), 
Inclusion Criteria #5 and #6
PREVIOUS TEXT
5. A female subject is eligible to participate if she is of:
1. Non-childbearing potential (NCBP) defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy; or postmenopausal defined as 12 
months of spontaneous amenorrhea [in questionable cases a blood sample 
with simultaneous follicle stimulating hormone (FSH) > 40MlU/ml and 
estradiol < 40pg/mL (<147pmol/L) is confirmatory].  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the contraception methods in Section 8.1 if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT 
to allow confirmation of post-menopausal status prior to study enrollment.  
For most forms of HRT, at least 2-4 weeks should elapse between the 
cessation of therapy and the blood draw; this interval depends on the type and 
dosage of HRT (consult with GSK Medical Monitor).  Following 
confirmation of their post-menopausal status, they can resume use of HRT 
during the study without use of a contraceptive method.
6. Male subjects with female partners of child-bearing potential must agree to use one of 
the contraception methods listed in Section 8.18.1.  This criterion must be followed 
from the time of the first dose of study medication until Follow-up.
REVISED TEXT
5. A female subject is eligible to participate if she is of:
1.
Childbearing potential, must agree to use one of the approved 
contraception methods as outlined in Section 8.1 from Screening until 
completion of the Follow-up Visit OR 
2.
Non-childbearing potential (NCBP) defined as pre-menopausal females 
with a documented tubal ligation or hysterectomy; or postmenopausal defined as 
12 months of spontaneous amenorrhea [in questionable cases a blood sample with 


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simultaneous follicle stimulating hormone (FSH) > 40MlU/ml and estradiol < 
40pg/mL (<147pmol/L) is confirmatory].  Females on hormone replacement 
therapy (HRT) and whose menopausal status is in doubt will be required to use 
one of the contraception methods in Section 8.1 if they wish to continue their 
HRT during the study.  Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status prior to study enrollment.  For most forms 
of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the 
blood draw; this interval depends on the type and dosage of HRT (consult with 
GSK Medical Monitor).  Following confirmation of their post-menopausal status, 
they can resume use of HRT during the study without use of a contraceptive 
method.
6.
Male subjects with female partners of child-bearing potential must agree to use one 
of the contraception methods listed in Section 8.18.1.  This criterion must be 
followed from the time of the first dose of study medication until Follow-up.
Section 5.3.1 Inclusion Criteria – DFU Subjects
PREVIOUS TEXT
A DFU subject will be eligible for inclusion in this study only if all of the criteria listed 
for healthy volunteers are met (Section 5.2) as well as the following criteria:
1. Diagnosed with Type I or Type II diabetes mellitus.
2. HbA1c, ≤ 12%.
3. QTc < 480msec in subjects with bundle branch block.
4. Lower extremity diabetic foot ulcer of 30-364 days’ duration.
5. DFU between 1cm² and 16cm² at screening.
6. Presence of at least one DFU that meets all of the following criteria:
a.
Ulcer has been diagnosed as a full-thickness, neuropathic DFU and is located 
at or distal to the malleolus (excluding ulcers between the toes but including 
those of the heel).
b. There is a minimum 2cm margin between the qualifying study ulcer and any 
other ulcers on the specified foot.
c.
Ulcer size (area) ≥ 1cm2 and ≤ 12cm2 (post-debridement at time of 
randomization).
d. Wagner Grade 1.
e.
Depth ≤ 5mm with no capsule, tendon or bone exposed and no tunneling, 
undermining, or sinus tracts.
Note: If the subject has more than one qualifying DFU, the ulcer designated as the study 
ulcer will be at the discretion of the Investigator.  Non-study ulcers being treated during 
the course of the study will be treated with moist wound therapy Standard of Care (SoC) 
identified under this study).


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7. Adequate vascular perfusion of the affected limb within 30 days of screening, as 
defined by at least one of the following:
i)
TcPO2 > 35mmHg.
j)
Ankle-Brachial Index (ABI) ≥ 0.6 and ≤ 1.2
k) Toe pressure (plethysmography) > 50mmHg.
l)
Doppler ultrasound (biphasic or triphasic waveforms) consistent with 
adequate blood flow to the affected extremity, as determined by SoC.
REVISED TEXT
A DFU subject will be eligible for inclusion in this study only if all of the criteria listed
for healthy volunteers are met. (Section 5.25.2) as well as the following criteria:
1. Diagnosed with Type I or Type II diabetes mellitus.
2. HbA1c, ≤ 12%.
3. Single QTc < 450msec, or QTc < 480msec in subjects with bundle branch block.
4. Lower extremity diabetic foot ulcer of 30-364 days’ duration.
5. DFU between 1cm² and 16cm² at screening.
6. Presence of at least one DFU that meets all of the following criteria:
f.
Ulcer has been diagnosed as a full-thickness, neuropathic DFU and is located 
at or distal to the malleolus (excluding ulcers between the toes but including 
those of the heel).
g. There is a minimum 2cm margin between the qualifying study ulcer and any 
other ulcers on the specified foot.
h. Ulcer size (area) ≥ 1cm2 and ≤ 12cm2 (post-debridement at time of 
randomization).
i.
Wagner Grade 1.
j.
Depth ≤ 5mm with no capsule, tendon or bone exposed and no tunneling, 
undermining, or sinus tracts.
Note: If the subject has more than one qualifying DFU, the ulcer designated as the study 
ulcer will be at the discretion of the Investigator.  Non-study ulcers being treated during 
the course of the study will be treated with moist wound therapy Standard of Care (SoC) 
identified under this study).
7. Adequate vascular perfusion of the affected limb within 30 days of screening, as 
defined by at least one of the following:
e) TcPO2 > 35mmHg.
f)
Ankle-Brachial Index (ABI) ≥ 0.6 and ≤ 1.2
g) Toe pressure (plethysmography) > 50mmHg.


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h) Doppler ultrasound (biphasic or triphasic waveforms) consistent with 
adequate blood flow to the affected extremity, as determined by SoC.
8. ALT, alkaline phosphatase and bilirubin 1.5xULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin 
<35%).
9. Male or female between 18 and 90 years of age inclusive, at the time of 
signing the informed consent.
10. A female subject is eligible to participate if she is of:
1. Childbearing potential, and agrees to use one of the approved 
contraception methods as outlined in Section 8.1 from Screening until 
completion of the Follow-up Visit OR
2. Non-childbearing potential (NCBP) defined as pre-menopausal females 
with a documented tubal ligation or hysterectomy; or postmenopausal 
defined as 12 months of spontaneous amenorrhea [in questionable cases a 
blood sample with simultaneous follicle stimulating hormone (FSH) > 
40MlU/ml and estradiol < 40pg/mL (<147pmol/L) is confirmatory].  Females 
on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the contraception methods in Section 8.1 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of post-menopausal status prior to 
study enrollment.  For most forms of HRT, at least 2-4 weeks should elapse 
between the cessation of therapy and the blood draw; this interval depends 
on the type and dosage of HRT (consult with GSK Medical Monitor).  
Following confirmation of their post-menopausal status, they can resume use 
of HRT during the study without use of a contraceptive method.
Section 5.3.2 Exclusion Criteria – DFU Subjects
PREVIOUS TEXT
Diabetic subjects that are being considered for this study will not be eligible for inclusion 
in this study if any of the following criteria apply or if the exclusion criteria outlined in 
Section 5.2.2 apply.
1. Subjects with:

Ulcers accompanied by infected cellulitis, osteomyelitis, or clinical signs or 
symptoms of infection,

Gangrene on any part of affected limb,,

Active Charcot’s foot on the study limb,

Planned vascular surgery, angioplasty or thrombolysis, 

Ulcers involving exposure of tendon, bone, or joint capsule (It is acceptable 
to have ulcers extending through the dermis and into subcutaneous tissue 
with presence of granulation tissue),


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
Ulcers due to non-diabetic etiology.
2. Any unstable vascular syndromes (such as TIA, CVA, unstable angina, acute MI 
or ACS event) and/or any major changes (per investigator’s judgment) to related 
medications within 6 months prior to randomization.
3. History or malignancy within 5 years of screening or those with a strong family 
history of cancer (e.g. familial cancer disorders), with the exception of squamous 
cell or basal cell carcinoma of the skin that has been definitively treated.
4. Other clinically significant cardiovascular, pulmonary, renal, endocrine, hepatic, 
neurological, psychiatric, immunological, gastrointestinal, hematological, or 
metabolic disease that is, in the opinion of the Investigator or the GSK Medical 
Monitor, not stabilized or may otherwise impact the results of the study.
5. Patients with active treatment for retinal neovascularization (e.g., diabetic 
proliferative retinopathy or age related macular degeneration) within 6 months of 
randomization.
6. Patients undergoing hemodialysis.
7. History of venous thrombosis defined as deep vein thrombosis, pulmonary 
embolism or other venous thrombotic condition within 1 year prior to screening.
8. Active peptic, duodenal, or esophageal ulcer disease or any gastrointestinal 
bleeding, within 1 year prior to screening.
9. Subjects with a platelet count <100,000/mm3 at screening. 
10. Subjects with an International Normalized Ratio (INR) >1.5 at screening.
11. Subjects with a hemoglobin level above the gender-specific upper limit of normal 
at screening.
12. Subjects with a history of non-traumatic joint inflammation (with the exception of 
inflammation due to osteoarthritis).
13. Patients with known pulmonary hypertension.
14. Use of prohibited medications as described in Section 9.1 of the protocol.
REVISED TEXT
Diabetic subjects that are being considered for this study will not be eligible for inclusion 
in this study if any of the following criteria apply or if the exclusion criteria outlined in 
Section 5.2.2 apply.
1. Subjects with:

Ulcers accompanied by infected cellulitis, osteomyelitis, or clinical signs or 
symptoms of infection,

Gangrene on any part of affected limb,,

Active Charcot’s foot on the study limb,

Planned vascular surgery, angioplasty or thrombolysis, 


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
Ulcers involving exposure of tendon, bone, or joint capsule (It is acceptable 
to have ulcers extending through the dermis and into subcutaneous tissue 
with presence of granulation tissue),

Ulcers due to non-diabetic etiology.
2. Any unstable vascular syndromes (such as TIA, CVA, unstable angina, acute MI 
or ACS event) and/or any major changes (per investigator’s judgment) to related 
medications within 6 months prior to randomization.
3. History or malignancy within 5 years of screening or those with a strong family 
history of cancer (e.g. familial cancer disorders), with the exception of squamous 
cell or basal cell carcinoma of the skin that has been definitively treated.
4. Other clinically significant cardiovascular, pulmonary, renal, endocrine, hepatic, 
neurological, psychiatric, immunological, gastrointestinal, hematological, or 
metabolic disease that is, in the opinion of the Investigator or the GSK Medical 
Monitor, not stabilized or may otherwise impact the results of the study.
5. Patients with active treatment for retinal neovascularization (e.g., diabetic 
proliferative retinopathy or age related macular degeneration) within 6 months of 
randomization.
6. Patients undergoing hemodialysis.
7. History of venous thrombosis defined as deep vein thrombosis, pulmonary 
embolism or other venous thrombotic condition within 1 year prior to screening.
8. Active peptic, duodenal, or esophageal ulcer disease or any gastrointestinal 
bleeding, within 1 year prior to screening.
9. Subjects with a platelet count <100,000/mm3 at screening. 
10. Subjects with an International Normalized Ratio (INR) >1.5 at screening.
11. Subjects with a hemoglobin level above the gender-specific upper limit of normal 
at screening.
12. Subjects with a history of non-traumatic joint inflammation (with the exception of 
inflammation due to osteoarthritis).
13. Patients with known pulmonary hypertension.
14. Use of prohibited medications as described in Section 9.1 of the protocol.
15. A history of drug or alcohol abuse in the past year, or a history of regular 
alcohol consumption within 6 months of the study defined as an average 
weekly intake of >14 drinks for males or >7 drinks for females.  One drink is 
equivalent to 12g of alcohol: 12 ounces (360mL) of beer, 5 ounces (150mL) of 
wine or 1.5 ounces (45mL) of 80 proof distilled spirits.
16. The subject has participated in a clinical trial and has received an 
investigational product within the following time period prior to the first 
dosing day in the current study: 30 days, 5 half-lives (whichever is longer).


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17. History of sensitivity to any of the study medications, or components thereof 
or a history of drug or other allergy that, in the opinion of the investigator or 
GSK Medical Monitor, contraindicates their participation.
18. Where participation in the study would result in donation of blood or blood 
products in excess of 500mL within a 56 day period.
19. Pregnant females as determined by positive urine hCG test at screening or 
prior to dosing.
20. Unwillingness or inability to follow the procedures outlined in the protocol.
21. Subject is mentally or legally incapacitated.
Section 7.3 DFU Assessments, Paragraph 1
PREVIOUS TEXT
The following assessments will be performed in Part A and Part B of the study.
REVISED TEXT
The following assessments will be performed in Part A and Part B of the study according 
to site designation, capability and feasibility.
Section 7.7 Biomarkers (e.g., Cytokines, Bioburden and Gene Expression) 
Collection and Processing, Paragraph 1
PREVIOUS TEXT
Wound tissue and fluid samples for biomarker assessments will be collected according to 
the table in Section 4.6
REVISED TEXT
Wound tissue and fluid samples for biomarker assessments will be collected according to 
the table in Section 4.6
With the subject’s consent, wound biopsy tissue, wound fluid and blood sample(s) 
will be collected during this study to  be used for the purposes of measuring novel 
biomarkers to identify factors that may influence wound healing and tissue repair 
and/or medically related conditions, as well as the biological and clinical responses 
to GSK.1278863.  If relevant, this approach will be extended to include the 
identification of biomarkers associated with adverse events.
Samples will be collected at the timepoints indicated in Section 4.6.  The timing of 
the collections may be adjusted on the basis of emerging PK or PD data from this 
study or other new information in order to ensure optimal evaluation of the PD 
endpoints.
Novel candidate biomarkers and subsequently discovered biomarkers of the 
biological response associated with wound healing and tissue repair or medically 


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related conditions and/or the action of GSK1278863 may be assessed in accordance 
with the objectives and endpoints of the study.
All samples will be retained for a maximum of 15 years after the last subject 
completes the trial.
Section 7.7.2 Punch Biopsy Directions, Bullet point added
REVISED TEXT

Study wounds that have healed sufficiently will be exempt from further 
biopsies.  This determination is at the discretion of the Principal Investigator or 
designee.
Section 7.7.3 Exploratory Biomarkers, Paragraphs 1-4
PREVIOUS TEXT
Section 7.7.3 Exploratory Biomarkers
With the subject’s consent, wound biopsy tissue, wound fluid and blood sample(s) will be 
collected during this study to  be used for the purposes of measuring novel biomarkers to 
identify factors that may influence wound healing and tissue repair and/or medically 
related conditions, as well as the biological and clinical responses to GSK.1278863.  If 
relevant, this approach will be extended to include the identification of biomarkers 
associated with adverse events.
Samples will be collected at the timepoints indicated in Section 4.6.  The timing of the 
collections may be adjusted on the basis of emerging PK or PD data from this study or 
other new information in order to ensure optimal evaluation of the PD endpoints.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with wound healing and tissue repair or medically related conditions 
and/or the action of GSK1278863.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial.
REVISED TEXT
Section 7.7.3 Exploratory Biomarkers
With the subject’s consent, wound biopsy tissue, wound fluid and blood sample(s) will be 
collected during this study to  be used for the purposes of measuring novel biomarkers to 
identify factors that may influence wound healing and tissue repair and/or medically 
related conditions, as well as the biological and clinical responses to GSK.1278863.  If 
relevant, this approach will be extended to include the identification of biomarkers 
associated with adverse events.
Samples will be collected at the timepoints indicated in Section 4.6.  The timing of the 
collections may be adjusted on the basis of emerging PK or PD data from this study or 
other new information in order to ensure optimal evaluation of the PD endpoints.


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Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with wound healing and tissue repair or medically related conditions 
and/or the action of GSK1278863.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial.
Section 8.1.1 Female Subjects
PREVIOUS TEXT
For female subjects on HRT and menopausal status is not confirmed, these contraceptive 
methods, classified as highly effective, are required.
REVISED TEXT
For female subjects who can become pregnant and for those on HRT and for whom
menopausal status is not confirmed, at least one of these contraceptive methods, 
classified as highly effective, is required.
Section 9.2 Permitted Medications
PREVIOUS TEXT
Section 9.2 Permitted Medications
Occasional use of acetaminophen, defined as doses of 2 grams/day up to 48 hours prior 
to the first dose of study drug and until completion of follow-up procedures may be 
acceptable, at the discretion of the Principal Investigator or his/her designee.
REVISED TEXT
Section 9.2 Permitted Medications
Occasional use of acetaminophen, defined as doses of 2 grams/day up to 48 hours prior 
to the first dose of study drug and until completion of follow-up procedures may be 
acceptable, at the discretion of the Principal Investigator or his/her designee.
Section 9.3 DFU – General Considerations, Heading title, Paragraph 4
PREVIOUS TEXT
Section 9.3 DFU –General Considerations
Women receiving HRT are permitted to continue therapy while on study.  See Section 
9.2.
REVISED TEXT
Section 9.2 DFU – General Considerations


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Women receiving HRT are permitted to continue therapy while on study.  See Section 9.2
5.2.1 or Section 5.3.1. 
Section 11.1 At-Home Dosing, Sentence Added
PREVIOUS TEXT
Pharmacists should dispense study drug for at-home dosing and label the container “Take 
as directed”.  A dosing card will be given to the subject, depending on the group they are 
randomized to, for instruction on at-home dosing.  The dosing card will include detailed 
contact information for contacting study staff 24 hours per day.  The patients’ wound size 
will be determined and the amount of ointment for daily administration will be recorded 
on the dosing card.  As above: 
Compliance with study medication will be checked every time the subject returns for a 
study visit.  The ointment tubes will be weighed prior to dispensing and during office 
visits to assess a daily averaged administrated amount.
REVISED TEXT
Pharmacists should dispense study drug for at-home dosing and label the container “Take 
as directed”.  A dosing card will be given to the subject, depending on the group they are 
randomized to, for instruction on at-home dosing.  The dosing card will include detailed 
contact information for contacting study staff 24 hours per day.  The patients’ wound size 
will be determined and the amount of ointment for daily administration will be recorded 
on the dosing card.  As above: 
A conversion of ointment amount to ribbon length measured with the placard will 
be provided by GSK.
Compliance with study medication will be checked every time the subject returns for a 
study visit.  The ointment tubes will be weighed prior to dispensing and during office 
visits to assess a daily averaged administrated amount.


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AMENDMENT 6
Where the Amendment Applies
This amendment applies to all sites participating in this study.
Summary of Amendment Changes with Rationale
Due to emerging data, specific areas of Part B of the protocol were redesigned to better 
meet the needs of the study.  To date Part A GSK1278863 systemic exposure is below 
analytical limits of quantification and therefore the stand alone single dose assessement in 
Part B is no longer required.  DFU exclusion criteria 10 was adjusted to better  reflect the 
patient population.  Other minor edits were also included for clarity.  
List of Specific Changes
SECTION 1.4 STUDY DESIGN STRATEGY AND SECTION 4.1 STUDY 
DESIGN/SCHEMATIC
Previous Text


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Revised Text
SECTION 1.4.1.2 SINGLE DOSE SELECTION RATIONALE, EQUATION 1
PREVIOUS TEXT


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REVISED TEXT
SECTION 1.4.1.3 REPEAT DOSING, PARAGRAPH 1 SENTENCES 4-6; 
PARAGRAPH 2
PREVIOUS TEXT
Three doses will be identified based on pharmacokinetics, systemic exposure level, and 
its relevance to known effects on Hb, safety and tolerability.  There will be an initial 
single dose application and PK samples collected out to a time that has been deemed 
appropriate based on the single dose application to characterize the PK for accumulation 
calculations.  After a one week washout period, the same dose will be applied daily for 
two weeks.
For practical reasons, a dosing period of approximately 24 hours could not be maintained 
and therefore a dosing period of ~22.5 hours will be followed for both the single and 
repeat dosing parts of this study.  This allows for subject hygiene and dehydration of the 
skin prior to reapplication of the next dose.  The amount of ointment applied to the DFUs 
may change based on wound size following one week of dosing to maintain consistency 
of amount applied/cm2 of wound size, which would also result in a reduction of the total 
mass of drug applied .  If deemed appropriate, intermittent dosing, i.e., a dosing interval 
greater than 24 hours, may be implemented.
REVISED TEXT
Three Doses will be identified based on pharmacokinetics, systemic exposure level, and 
its relevance to known effects on Hb, safety and tolerability.  There will be an initial 
single dose application and PK samples collected out to a time that has been deemed 
appropriate based on the single dose application to characterize the PK for accumulation 
calculations.  After a one week washout period, The same percent (strength) ointment
dose will be applied daily for two weeks.
For practical reasons, a dosing period of approximately 24 hours could not be maintained 
and therefore a dosing period of ~22.5 hours will be followed for the both the single and 


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repeat dosing parts of this study.  This allows for subject hygiene and dehydration of the 
skin prior to reapplication of the next dose.  The amount of ointment applied to the DFUs 
may change based on wound size following one week of initial dosing to maintain 
consistency of amount applied/cm2 of wound size, which would also result in a reduction
change of the total mass of drug applied .  If deemed appropriate, intermittent dosing, 
i.e., a dosing interval greater than 24 hours, may be implemented.
SECTION 4.2 DISCUSSION OF DESIGN AND TREATMENT PLAN, 
PARAGRAPH 2, SENTENCE 3; PARAGRAPH 3, SENTENCE 2 AND 
PARAGRAPH 5, SENTENCE 2
PREVIOUS TEXT
Part B is designed to evaluate first single, and then repeat applications of GSK1278863 in 
diabetics, both in the clinic and by subjects at home.  
For both parts of the protocol, additional cohorts may be added as necessary to obtain 
relevant safety, pharmacokinetic or pharmacodynamic data.  
Enrollment to each cohort may be staggered (i.e., cohorts do not have to be enrolled 
as one group).  However, all enrollments should occur within ~4 weeks for each 
cohort.
REVISED TEXT
Part B is designed to evaluate first single, and then repeat applications of GSK1278863 in 
diabetics, both in the clinic and by subjects at home.  
For both parts of the protocol, additional cohorts may be added as necessary to obtain 
relevant safety, pharmacokinetic or pharmacodynamic data.  Based on emerging data, 
the number of cohorts and subjects may be reduced to avoid unnecessary exposure.
Enrollment to each cohort may be staggered (i.e., cohorts do not have to be enrolled 
as one group).  However, all enrollments should occur within ~4 weeks for each 
cohort.
4.2.1. PART A – SINGLE DOSES IN HEALTHY VOLUNTEERS AND DFU 
PATIENTS (COHORTS 1 THROUGH 4), PARAGRAPH 1, SENTENCE 2
PREVIOUS TEXT
Each cohort in Part A will enroll enough subjects to complete 6 on active drug and 2 on 
placebo (assumes ~10 subjects will be recruited per cohort to achieve 6:2 ratio).  


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REVISED TEXT
Each cohort in Part A will enroll enough subjects to complete approximately 6 on active
drug and 2 on placebo (assumes ~10 subjects will be recruited per cohort to achieve 6:2 
ratio).  
4.2.1.6.
OPTIONAL COHORTS (PART A), 1ST BULLET; PARAGRAPH 3;
PARAGRAPH 4, SENTENCE 1
PREVIOUS TEXT

If the data at the end of Cohort 4 are considered sufficient to establish dosing for 
Part B, subjects from that cohort will be asked to return to the clinic for a SD 
administration of the compound to intact skin in order to make comparisons of 
systemic PK for linearity between low and high doses and a within-patient 
comparison of application of drug to intact skin versus DFU.
The timing of the final cohort, in which application to intact skin is assessed, may overlap 
with the first cohort of Part B, as long as all doses of GSK1278863 in previous cohorts 
are well tolerated and provide sufficient PK for Part B predictions.
GSK1278863 PK data from the cohorts of Part A will be used for the predictions of the 
expected systemic exposures in Part B (data permitting).
REVISED TEXT

If the data from at the end of Cohort 4 are considered sufficient to establish 
dosing for Part B, subjects from that cohort will be asked to return to the clinic for 
a SD administration of the compound to intact skin in order to make comparisons 
of systemic PK for linearity between low and high doses and a within-patient 
comparison of application of drug to intact skin versus DFU. 
The timing of the final cohort, in which application to intact skin is assessed, may overlap 
with the first cohort of Part B, as long as all doses of GSK1278863 in previous cohorts 
are well tolerated and provide sufficient PK for Part B predictions.  Systemic exposures 
may or may not permit predictions for dose selection and therefore dose 
determination will be selected based on available safety and tolerability data.
GSK1278863 PK data from the cohorts of Part A will be used for the predictions of the 
expected systemic exposures in Part B (data permitting).


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4.2.2. PART B – SINGLE DOSE/REPEAT DOSES IN DIABETIC FOOT ULCER 
SUBJECTS (COHORTS 5,6, AND 7), HEADING TITLE; PARAGRAPH 1, 
SENTENCE 2; PARAGRAPH 2; PARAGRAPH 3, SENTENCE 1 AND 2; 
PARAGRAPH 4
PREVIOUS TEXT
Section 4.2.2. Part B – Single Dose/Repeat Doses in Diabetic Foot Ulcer Subjects 
(Cohorts 5,6, and 7)
Enough subjects will be enrolled in each cohort to complete 16 diabetic subjects with 
diabetic foot ulcer.
Each cohort will enroll a new group of subjects, randomized descending doses of 
GSK1278863.  
For each cohort, subjects will first be given a single application of GSK1278863 or 
placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then 
repeat applications for 14 days, starting on Day 8.  The initial application and the first day 
of the 14-day repeat application period will be conducted in the clinic. 
Doses for the cohorts in Part B will be determined from safety, tolerability and PK data 
from Part A.  Each cohort will enroll a new group of subjects, randomized to ascending 
doses of GSK1278863.  All applications in Part B will be made directly to the subject’s 
DFU.  Doses may be adjusted based on wound size at each weekly visit.  All applications 
in Part B will be made directly to the subject’s DFU.  Doses may be adjusted based on 
wound size at each weekly visit.
Blood for PK sampling will be collected on Days 1-4 (single dose) and Days 8, 14, 15 
and Days 21-23(repeat dosing).  See Section 4.6.3 for specific time points for drawing 
samples.
REVISED TEXT
Section 4.2.2. Part B – Single Dose/Repeat Doses in Diabetic Foot Ulcer Subjects 
(Cohorts 5,6, and 7)
Enough subjects will be enrolled in each cohort to complete approximately 16 diabetic 
subjects with diabetic foot ulcer.
Doses for the cohorts in Part B will be determined from safety, tolerability and PK data 
from Part A.  Each cohort will enroll a new group of subjects, randomized to either the 
same dose, ascending dose or descending doses of GSK1278863.  All applications in 
Part B will be made directly to the subject’s DFU.  Doses may be adjusted based on 
wound size at each weekly visit.


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For each cohort, subjects will undergo repeat applications first be given a single 
application of GSK1278863 or placebo, at the dose chosen for that cohort, followed by a 
7-day washout period, and then repeat applications for 14 days, starting on Day 8.  The 
initial application and the first day of the 14-day repeat application period will be 
conducted in the clinic.  
Doses for the cohorts in Part B will be determined from safety, tolerability and PK data 
from Part A.  Each cohort will enroll a new group of subjects, randomized to the same 
dose, ascending dose or descending doses of GSK1278863.  All applications in Part B 
will be made directly to the subject’s DFU.  Doses may be adjusted based on wound size 
at each weekly visit.
Blood for PK sampling will be collected on Days 1, 7-4 (single dose) and Days 8, 14, 15 
and 16 Days 21-23(repeat dosing).  See Section 4.6.3 for specific time points for drawing 
samples.
4.2.2.2.  RUN-IN PERIOD (PART B), PARAGRAPH 1, SENTENCE 2 AND 3
PREVIOUS TEXT
For all subjects in Part B, each subject’s DFU will be measured at screening and Day 1; 
if, after 14 days from screening, the subject’s DFU has reduced in size by greater than 30 
%, the subject will not be randomized to receive investigational product.  If Screening 
and Day 1 are not 14 days (1 day) apart, an additional visit (Baseline Run In) will need 
to be scheduled prior to Day 1 to meet the Run In requirement.
REVISED TEXT
For all subjects in Part B, each subject’s DFU will be measured at screening and Day 1; 
if, after 14 days from screening, the subject’s DFU has reduced in size by greater than 30 
%, the subject will not be randomized to receive investigational product and is 
considered a Run In Failure.  If Screening and Day 1 are not 14 days (1 day) apart, an 
additional visit (Optional Baseline Run In) will need to be scheduled prior to Day 1 to 
meet the Run In requirement.
4.2.2.3 TREATMENT PERIOD – (PART B)
PREVIOUS TEXT
Cohorts 5, 6 and 7 (numbering assumes no optional cohorts are enrolled in Part A) will 
each enroll sufficient subjects so that 48 DFU patients who fulfill screening criteria 
complete all study visits.
Single Dose (Part B)
Subjects will be randomized to receive single applications of GSK1278863 or placebo 
directly to the DFU on Day 1 for evaluation of safety and tolerability, PK of 


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GSK1278863 and PD.  Subjects may be discharged from the clinic once all Day 1 
assessments have been completed.  Subjects will return to the clinic fasting early in the 
morning on Day 2 and Day 3 for PK trough samples and safety assessments.
See Section 4.6 for details regarding all study procedures performed during the course 
of this trial.
Washout Period
Subjects will receive standard-of-care (moist occlusion) treatment (Section 7.4) for 
the week between Day 1of single dosing and Day 8, which is the first day of repeat
14-day dosing.
14-Day Dosing (Part B)
Approximately one week after receiving the single dose (Day 8), subjects will return 
to the clinic to begin 14 days of dosing with the GSK1278863 dose they were 
randomized to for the previous single dose.  Subjects may remain overnight (if 
elected), leaving in the morning of Day 9.  Subjects will then perform the applications 
of study drug at home, returning on Day 11 for assessments and drug application.  
Patients will then apply study drug at home on days 12-13, and then return on day 14 
for scheduled assessments and dosing. Subjects may again remain overnight if they 
elect for the purposes of serial PK sampling.  After scheduled assessments on Day 15, 
subjects will again perform applications at home and return to the clinic on Day 18 
and then again on days 21-23 (electing to stay overnight if desired) for scheduled 
assessments.
It should be noted that on days where serial PK sampling occurs it is permissible to 
allow subjects to check out of the clinic after the 8 hour PK time point has been 
collected as long as the subject can return for sample collection within the 10 to 12 
hour PK window.  Subjects that opt to remain in clinic will have PK samples drawn at 
8 and 12 hours post dose.
Subjects will be given detailed instructions for application of GSK1278863 at home, 
and enough study for applications at home between clinic visits.  See Section 11.1 for 
further instructions on at-home dosing.
Doses for subsequent cohorts may be adjusted based on PK results, and/or safety
data.
REVISED TEXT
Cohorts 5, 6 and 7 (numbering assumes no optional cohorts are enrolled in Part A) will 
each enroll sufficient subjects so that approximately 48 DFU patients who fulfill 
screening criteria complete all study visits.
Single Dose (Part B)
Subjects will be randomized to receive single applications of GSK1278863 or placebo 
directly to the DFU on Day 1 for evaluation of safety and tolerability, PK of 
GSK1278863 and PD.  Subjects may be discharged from the clinic once all Day 1 


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assessments have been completed.  Subjects will return to the clinic fasting early in the 
morning on Day 2 and Day 3 for PK trough samples and safety assessments.
See Section 4.6 for details regarding all study procedures performed during the course 
of this trial.
Washout Period
Subjects will receive standard-of-care (moist occlusion) treatment (Section 74) for the 
week between Day 1of single dosing and Day 8, which is the first day of repeat 14-
day dosing.
14-Day Dosing (Part B)
Approximately one week after receiving the single dose (Day 8), subjects will return 
to the clinic to begin 14 days of dosing with the GSK1278863 dose they were 
randomized to for the previous single dose.  Subjects may remain overnight (if 
elected), leaving in the morning of Day 9.  Subjects will then perform the applications 
of study drug at home, returning on Day 11 for assessments and drug application.  
Patients will then apply study drug at home on days 12-13, and then return on day 14 
for scheduled assessments and dosing. Subjects may again remain overnight if they 
elect for the purposes of serial PK sampling.  After scheduled assessments on Day 15, 
subjects will again perform applications at home and return to the clinic on Day 18 
and then again on days 21-23 (electing to stay overnight if desired) for scheduled 
assessments. Subjects will be randomized to receive applications of GSK1278863 
or placebo directly to the DFU on Day 1 for evaluation of safety and tolerability, 
PK of GSK1278863 and PD.  Applications of study drug will be done in clinic on 
Days 1, 4, 7, 11, and 14.  Subjects are responsible for study drug application on 
Days 2-3, 5- 6, 8-10, 12-13.
It should be noted that on days where serial PK sampling occurs it is permissible to 
allow subjects to check out of the clinic after the 8 hour PK time point has been 
collected as long as the subject can return for sample collection within the 10 to 12 
hour PK window.  Subjects that opt to remain in clinic will have PK samples drawn at 
8 and 12 hours post dose.  If subjects elect to stay overnight, they should be 
encouraged to apply the study ointment and complete the diary entries 
themselves before being discharged in the morning.  Study staff can take this 
opportunity to provide additional instruction to subjects.
Subjects will be given detailed instructions for application of GSK1278863 at home 
and enough study drug for applications at home between clinic visits.  See Section 
11.1 for further instructions on at-home dosing.
Doses for subsequent cohorts may be adjusted based on PK results, and/or safety and 
tolerability data.


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4.3.
TREATMENT ASSIGNMENT, PARAGRAPH 6
PREVIOUS TEXT
Drug volume to be administered will be based on wound area, which may vary during the 
treatment period.  See Section 4.4 for details.  Actual doses will be chosen based on 
preliminary PK data from Part A.
REVISED TEXT
Drug volume to be administered will be based on wound area, which may vary during the 
treatment period.  See Section 4.4 for details.  Actual doses will be chosen based on 
preliminary PK data (data permitting, See Section 4.2.1.6) from Part A.
4.6.1 TIME AND EVENT TABLE PART A, FOOTNOTE ADDED
REVISED TEXT
4. HIV, Hep B and Hep C are only assessed in the Healthy Volunteer population


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4.6.3 TIME AND EVENTS TABLE PART B
PREVIOUS TEXT
Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
Visit Window 
(relative to Day 1)
-28 to -14 
days
Exams/samples 
pre-dose
Washout
Exams/samples 
pre-dose
7-10 
days 
post last 
dose
28-32 
days 
post last 
dose
Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Informed Consent
X
Demographics
X
Complete physical
X
Brief physical
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
12-lead ECG1
X
X
X
Vital signs2
X
X
X
X
X
X
X
Urine 
pregnancy(females)
X
X
`
X
X
HIV, Hep B and Hep 
C screen
X
Hema/Chem/ Safety 
Labs3
X
X
X
X
X
X
Vascular Perfusion 
Eligibility 
Assessments4
X
Blood samples for 
HIF, (e.g., EPO, 
Hepcidin, VEGF)
X5
X5
X
X
Standard of Care 
X
X
X
X


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Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
Treatment6
Study 
Treatment/Dosing
In the Clinic7
X
X
X
X
X
X
X
PK serial blood 
sampling8
X
X
X
X (truncated)
X
X
X
X
X
PK Trough Sample8
X
Tissue Biopsies 
(gene expression, 
macrophage and 
bioburden analysis)9
X
X
X
X
Wound Fluid 
(cytokine and 
bioburden analysis)10
X
X
X
(Day 
3 
only10)
X
X
X
X
X
SensiLase (Doppler 
blood flow) 
X
X
X
X
X
Hyperspectral 
Imaging11
X
X
X
X
X
Physical 
Characteristics
(assessed pre-
dose)12
X11
X
X
X
X
X
X
X
Clinical 
Characteristics13
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medication Review
X
=============================================================
X


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Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 thru 7
14 Day Repeat 
Dose 
Day
11
Day
14
Day
15
Day
18
Day 
21
Day
22
Day
23
Follow-up
Day 1
Day 8
Adverse Event 
Assessment14
X
=============================================================
X
X
1.
Single ECGs will be taken at Screening and pre-dose on Day 1(SD) and 24h post-last RD dose on Day 22.  ECGs should be taken while subject is supine for at least 5 minutes.  
Additional ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
2.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Days 1 (SD) and 8(RD), 14, 22 (24h post-last-RD dose), and 
at Follow-up Visits.  Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
3.
Blood samples for safety will be collected fasting at Screening and pre-dose/equivalent time on Days 1,8,14, 22 (24h post-last-dose), and at the 7-10 day Follow-up Visit.  Refer to 
Section 7.2.4 for specific laboratory parameters to be tested.
4.
See Item 7 in the Inclusion Criteria – DFU Subjects for acceptable perfusion parameters.  Only 1 test of the 4 (TcPO2, ABI/TcPO2, toe pressure, Doppler ultrasound) is required 
for eligibility.
5.
Blood samples for HIFactivation on Day 1 and Day 8 will be collected at pre-dose, 8 and 10-12 hour window.  On all other indicated days one sample will be collected at pre-
dose/equivalent time.  
6.
During washout times all subjects will be on SOC (Section 7.4).
7.
In between clinic visits during RD, subjects will perform applications of study drug at home.
8.
See separate Time and Events table for serial PK sampling details for Days 1, 8, 14 and 21 and the associated 24, 48 and 72 hr time points.  Trough sample will be taken prior to 
dosing on Day 18.  Refer to Section 7.12 for details on the collection and processing of PK samples.  PK sampling times may be changed based on the observed GSK1278863 
PK profile, but the total number of samples will not change.
9.
Direct wound tissue biopsies will be collected at pre-dose/equivalent on Days 1, 8, 14 and 22, however based on emerging data, time points may be added or deleted; wounds 
that have healed sufficiently may be exempt.  Refer to Section 7.7.2 for additional details on the collection and processing of tissue biopsies.
10. Wound fluid will be collected at pre-dose/equivalent on Days 1, 2. 3, 8, 14, 15, 22 and at the 7-10 day Follow-up Visit.  Refer to the Section 7.7.1 for additional details on the 
collection and processing of wound fluid samples.
11. Will be performed based on hyperspectral imaging capabilities at each site.
12. Physical characteristics of the wound (i.e., photos of the wound and wound measurement assessments) will be assessed at Screening (acetate tracings only), at pre-
dose/equivalent time on Days 1, 8, 11, 14, 18, 22 and at the 7-10 day Follow-up Visit.
13. Clinical characteristic assessments of the DFU begin with Section 7.10 and contain instructions for completing the assessments including the irritation/symptom scale as needed.  
Assessments are recorded in the eCRF.
14. Adverse events are to be collected from first dose through the final Follow-up visit.


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REVISED TEXT
Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 
thru 
7
14 Day Repeat 
Dose 
Day
11 4
Day
14 7
Day
15
Day
18 11
Day 
2114
Day
22 15
Day
23 16
Follow-up
Optional 
Baseline Run 
In1Day 1
Day 8 1
Visit Window 
(relative to Day 1)
-28 to -14 
days
Exams/samples 
pre-dose
Washout
Exams/samples 
pre-dose
7-10 
days 
post 
last 
dose
28-
32 
days 
post 
last 
dose
Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Informed Consent
X
Demographics
X
Complete physical
X
Brief physical
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
X
12-lead ECG12
X
X
X
Vital signs23
X
X
X
X
X
X
X
Urine 
pregnancy(females)
X
X
`
X
X
HIV, Hep B and 
Hep C screen
X
Hema/Chem/ 
Safety Labs34
X
X
X
X
X
X
Vascular Perfusion 
Eligibility 
Assessments4 5
X
Blood samples for 
HIF, (e.g., EPO, 
Hepcidin, VEGF)
X
X5 6
X
X


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Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 
thru 
7
14 Day Repeat 
Dose 
Day
11 4
Day
14 7
Day
15
Day
18 11
Day 
2114
Day
22 15
Day
23 16
Follow-up
Optional 
Baseline Run 
In1Day 1
Day 8 1
Standard of Care 
Treatment67
X
X
X
X
X
=============================================================
X
X
Study 
Treatment/Dosing
In the Clinic78
X
X
X
X
X
X
X
PK serial blood 
sampling89
X
X
X
X (truncated)
X
X
X
X
X
PK Trough 
Sample89
X
Tissue Biopsies 
(gene expression, 
macrophage and 
bioburden 
analysis)910
X
X
X
X
Wound Fluid 
(cytokine and 
bioburden 
analysis)10 11
X
X
X
(Day 3 
only10)
X
X
X
X
X
SensiLase (Doppler 
blood flow) 
X
X
X
X
X
Hyperspectral 
Imaging1112
X
X
X
X
X
Physical 
Characteristics
(assessed pre-
dose)1213
X11
X
X
X
X
X
X
X
Clinical 
Characteristics1314
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedures
Screening
Single Dose
Day
2
Days
3 and 
4
Days
5 
thru 
7
14 Day Repeat 
Dose 
Day
11 4
Day
14 7
Day
15
Day
18 11
Day 
2114
Day
22 15
Day
23 16
Follow-up
Optional 
Baseline Run 
In1Day 1
Day 8 1
Concomitant 
Medication Review
X
=============================================================
X
Adverse Event 
Assessment14 15
X
=============================================================
X
X
1.
Optional Baseline Run In visit:  This optional visit is for subjects that will exceed the 14 (1 day) Run-in window between screening and Day 1.
2.
Single ECGs will be taken at Screening and pre-dose on Day 1(SD) and 24h post-last RD dose on Day 22 15.  ECGs should be taken while subject is supine for at least 5 
minutes.  Additional ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
3.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Days 1, 7 (SD) and 8(RD), 14 15 (24h post-last-RD dose), and 
at the Follow-up Visits.  Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
4.
Blood samples for safety will be collected fasting at Screening and pre-dose/equivalent time on Days 1,8 7,14, 22 15 (24h post-last-dose), and at the 7-10 day Follow-up Visit.  
Refer to Section 7.2.4 for specific laboratory parameters to be tested.
5.
See Item 7 in the Inclusion Criteria – DFU Subjects for acceptable perfusion parameters.  Only 1 test of the 4 (TcPO2, ABI/TcPO2, toe pressure, Doppler ultrasound) is required 
for eligibility.
6.
Blood samples for HIFactivation on Day 1 and Day 8 will be collected at pre-dose, 8 and 10-12 hour window.  On all other indicated days one sample will be collected at pre-
dose/equivalent time.  
7.
During washout times All subjects will be on SOC throughout the study (Section 7.4).
8.
In between clinic visits during RD, subjects will perform applications of study drug at home.
9.
See separate Time and Events table for serial PK sampling details for Days 1, 87, 14 and 21 and the associated 24,and 48 and 72 hr time points.  Trough sample will be taken 
prior to dosing on Day 18 11.  Refer to Section 7.12 for details on the collection and processing of PK samples.  PK sampling times may be changed based on the observed 
GSK1278863 PK profile, but the total number of samples will not change.
10. Direct wound tissue biopsies will be collected at pre-dose/equivalent on Days 1, 8, 14 and 22, however based on emerging data, time points may be added or deleted; wounds 
that have healed sufficiently may be exempt.  Refer to Section 7.7.2 for additional details on the collection and processing of tissue biopsies.
11. Wound fluid will be collected at pre-dose/equivalent on Days 1, 2. 3, 8, 14, 15, 22 and at the 7-10 day Follow-up Visit.  Refer to the Section 7.7.1 for additional details on the 
collection and processing of wound fluid samples.
12. Will be performed based on hyperspectral imaging capabilities at each site.
13. Physical characteristics of the wound (i.e., photos of the wound and wound measurement assessments) will be assessed at Screening (acetate tracings only), at pre-
dose/equivalent time on Days 1, 8, 11, 14, 18, 22 and at the 7-10 day Follow-up Visit.
14. Clinical characteristic assessments of the DFU begin with Section 7.10 and contain instructions for completing the assessments including the irritation/symptom scale as needed.
15.   Assessments are recorded in the eCRF.


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4.6.3 SERIAL PK TIME AND EVENTS TABLE PART B
PREVIOUS TEXT
Procedure
Part B Serial PK Sampling1,2 
Hours (h)
Pre-
dose
0.25h
0.5h
1h
2h
4h
6h
8h
10h
11h
12h
24h
48h
72h
Single Dose Sampling 
OUT-PATIENTS
X
X
X
X
X
X
X
X3
X
X
X
Single Dose Sampling IN-
PATIENTS
X
X
X
X
X
X
X
X
X
X
X
Repeated Dose Day 8 
Truncated (Start of 
Repeated Dose)
X
X
X
X
X
Repeated Dose Day 14 
OUT-PATIENTS 
X
X
X
X
X
X
X
X3
X
Repeated Dose Day 14 
IN-PATIENTS
X
X
X
X
X
X
X
X
X
Repeated Dose Day 21 
OUT-PATIENTS
X
X
X
X
X
X
X
X3
X
X
Repeated Dose Day 21 
IN-PATIENTS
X
X
X
X
X
X
X
X
X
X
1.
Patients are permitted to either stay in clinic (in-patients) or be discharged and return for clinic visits (out-patients).  
Refer to Section 7.12 for details on the collection and processing of PK samples.  
2.
PK sampling times may be changed based on observed GSK1278863 PK profile, but the total number of samples 
will not change.
3.
Sample must be taken within the 10 to 12 hour time window.
REVISED TEXT
Procedure
Part B Serial PK Sampling1,2 
Hours (h)
Pre-
dose
0.25h
0.5h
1h
2h
4h
6h
8h
10h
11h
12h
24h
48h
72h
Single Dose Sampling
OUT-PATIENTS Day 1
X
X
X
X
X
X
X
X
X3
X
X
X
Single Dose Sampling IN-
PATIENTS
X
X
X
X
X
X
X
X
X
X
X
Repeated Dose Day 8 
Truncated (Start of 
Repeated Dose)
X
X
X
X
X
Repeated Dose Day 14 7
OUT-PATIENTS
X
X
X
X
X
X
X
X3
X
Repeated Dose Day 14 
IN-PATIENTS
X
X
X
X
X
X
X
X
X


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Procedure
Part B Serial PK Sampling1,2 
Hours (h)
Pre-
dose
0.25h
0.5h
1h
2h
4h
6h
8h
10h
11h
12h
24h
48h
72h
Repeated Dose Day 21
14 OUT-PATIENTS
X
X
X
X
X
X
X
X3
X
X
Repeated Dose Day 21
14 IN-PATIENTS
X
X
X
X
X
X
X
X
X
X
1.
Patients are permitted to either stay in clinic (in-patients) or be discharged and return for clinic visits (out-patients).  
Refer to Section 7.12 for details on the collection and processing of PK samples.  
2.
PK sampling times may be changed based on observed GSK1278863 PK profile, but the total number of samples 
will not change.
3.
Sample must be taken within the 10 to 12 hour time window.
5.1. NUMBER OF SUBJECTS, PARAGRAPH 2
PREVIOUS TEXT
In Part B, enough subjects will be enrolled such that approximately 48 subjects in Part B 
(~16 DFU subjects per cohort) complete dosing and critical assessments.
REVISED TEXT
In Part B, enough subjects will be enrolled such that approximately 48 subjects in Part B 
(~16 DFU subjects per cohort) complete dosing and critical assessments (assumes 
approximately 3 cohorts).
5.3.2. EXCLUSION CRITERIA – DFU SUBJECTS, EXCLUSION CRITERIA # 
10
PREVIOUS TEXT
10.  Subjects with an International Normalized Ratio (INR) >1.5 at screening.  
REVISED TEXT
10.  Subjects with an International Normalized Ratio (INR) >1.5 1.1 at screening.  If on 
warfarin, then >2.5.
6.3.3.3. MRNA, PROTEIN AND BIOMARKER DATA ANALYSIS, PARAGRAPH 
1
PREVIOUS TEXT
Biomarker data will be summarized by regimen for Part A, and regimen and visit for Part 
B.


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REVISED TEXT
Biomarker data will be summarized by regimen for Part A, and regimen and visit for Part 
A and Part B.
7.7.2. PUNCH BIOPSY DIRECTIONS, BULLETED ITEM ADDED
PREVIOUS TEXT

Prior to obtaining biopsies, the wound is to be cleansed with saline solution.  
REVISED TEXT

Whenever feasible, tissue biopsies should be done at the time of debridement.

Prior to obtaining biopsies, the wound is to be cleansed with saline solution.
7.9.1.Location of the Study Ulcer
PREVIOUS TEXT
The location of the study ulcer will be recorded as foot (left or right), surface (plantar or
dorsal), and area [forefoot, midfoot, hindfoot (including the calcaneus)]. If more than 
one ulcer is located in the same proximity, be certain to clearly identify the specific study 
ulcer.
REVISED TEXT
The location of the study ulcer will be recorded as foot (left or right), surface (plantar, or 
dorsal, medial aspect of heel, medial aspect of great toe, posterior or lateral), and area 
[forefoot, midfoot, hindfoot (including the calcaneus), first through fifth metatarals or 
proximal to the foot on the ankle].  If more than one ulcer is located in the same 
proximity, be certain to clearly identify the specific study ulcer. 
  
7.9.2.2 WOUND TRACINGS, PARAGRAPH 1
PREVIOUS TEXT
To ensure the subject meets the randomization eligibility of the change in ulcer size 
between screening (or optional Run In visit, if different from day of screening) and 
randomization on Day 1, percent reduction of wound size must be calculated by the 
Investigator or designee using the method for measuring wound area provided in the 
SPM.  The core lab may be consulted for assistance with area measurements or percent 
reduction determinations if necessary.


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REVISED TEXT
Tracings of the wound should be obtained after debridement. To ensure the subject 
meets the randomization eligibility of the change in ulcer size between screening (or 
optional Baseline Run In visit, if different from day of screening) and randomization on 
Day 1, percent reduction of wound size must be calculated by the Investigator or 
designee using the method for measuring wound area provided in the SPM.  The core lab 
may be consulted for assistance with area measurements or percent reduction 
determinations if necessary.
7.13.3 Action to be Taken if Pregnancy Occurs in a Female Partner of a 
Male Study Subject, Section Title; Paragraph 1
PREVIOUS TEXT
7.13.3 Action to be Taken if Pregnancy Occurs in a Female Partner of a Male Study 
Subject, Section Title; Paragraph 1
The investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  The 
investigator will record pregnancy information on the appropriate form and submit it to 
GSK within 2 weeks of learning of the partner’s pregnancy.  The partner will also be 
followed to determine the outcome of the pregnancy.  Information on the status of the
mother and child will be forwarded to GSK.  Generally, follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date.  Any premature termination of the 
pregnancy will be reported.
REVISED TEXT
The investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  The 
investigator will record pregnancy information on the appropriate form and submit it to 
GSK within 2 weeks of learning of the partner’s pregnancy.  The partner will also be 
followed to determine the outcome of the pregnancy.  Information on the status of the 
mother and child will be forwarded to GSK.  Generally, follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date.  Any premature termination of the 
pregnancy will be reported.
12. 9 PROMPT REPORTING OF SAES TO GSK
PREVIOUS TEXT
The primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool.  If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the GSK Medical Monitor.  Then the site will 
enter the serious adverse event data into the electronic system as soon as it becomes 
available.


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After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) 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, the site can report this information on a paper SAE form or to their 
GSK protocol contact by telephone.
REVISED TEXT
The primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool.  If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the GSK Medical Monitor.  Then the site will 
enter the serious adverse event data into the electronic system as soon as it becomes 
available.
The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE
After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) 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, the site can report this information on a paper SAE form or to their 
GSK protocol contact by telephone.


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AMENDMENT 7
Where the Amendment Applies
This amendment applies to all sites participating in this study.
Summary of Amendment Changes with Rationale
This amendment contains modifications to inclusion criteria 3, 5 and 6 and exclusion 
criteria 2, 3.  Exclusion criteria 5 and 7 -13 were removed.  
Rationale for Inclusion Criterion 3:  The results of a thorough QT study utilizing oral 
doses of GSK1278863 support the conclusion that there appears to be no clinically 
significant effect on ΔΔQTcF after administration of doses up to 500 mg in healthy 
subjects.  (GSK Document #2015N233454_00 PHI113635 14Dec 2015). These results, 
in addition to the limited systemic exposure demonstrated with topical application of 
GSK1278863, support the use of expanded QT enrolment criteria.
Rationale for Inclusion Criterion 5 and 6c: Systemic concentrations of GSK1278863 
measured from patients administered 1% w/w (at 100mg/cm2) have been below the 
LLOQ of the analytical assay (0.10 ng/mL). A larger upper limit of 
screening/randomization ulcer size results in maximum systemic exposure predictions 
(following once daily application of ointment strengths up to 10% w/w GSK1278863 (at 
100 mg/cm2) for 14 days) well below this study’s intended systemic exposure limits (395 
ng.h/mL and 198 ng/mL for AUC and Cmax, respectively). This prediction supports an 
increase in allowable ulcer size.
Rationale for Exclusion Criterion 2, 3, 5, 7-13: As of June 2016, GSK1278863 has been 
administered orally to over 1000 subjects, including those with chronic kidney disease 
(either not on dialysis or on dialysis), in single doses up to 500 mg, in repeat-doses up to 
100 mg daily for 4 weeks and up to 25 mg daily for 24 weeks.  Overall, the safety profile 
was consistent with the patient population and there were no adverse events that have 
been identified as related to treatment with GSK1278863.  Planned phase 3 studies have 
thus adopted revised exclusion criteria consistent with those above in patients with 
anemia due to chronic kidney disease, a vulnerable population with respect to vascular 
events.
Systemic concentrations of GSK1278863 measured from DFU subjects administered 1% 
w/w (at 100mg/cm2) have been below the LLOQ of the analytical assay (0.10 ng/mL) 
and systemic exposures following once daily application of ointment strengths up to 10% 
w/w GSK1278863 (at 100 mg/cm2) in DFU subjects are predicted to be well below this 
study’s intended systemic exposure limits (395 ng.h/mL and 198 ng/mL for AUC and 
Cmax, respectively).  
The decision to modify the exclusion criteria was therefore based on the safety profile 
demonstrated in the oral program in patients with a similar or greater risk profile who are 
exposed to systemic concentrations of GSK1278863 which are well above those in the 
topical program.  


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Stopping and withdrawal criteria were also modified to align with the updated 
inclusion/exclusion criteria as appropriate.
Other changes include updates to Part B that occurred in stream based on emerging data, 
but did not require a protocol amendment. Other minor edits for clarity.
List of Specific Changes
4.2.2.  Part B –Repeat Doses in Diabetic Foot Ulcer Subjects (Cohorts 5, 6 
and 7), PARAGRAPH 4
Previous Text
Blood for PK sampling will be collected on Days 1, 7, 11, 14, 15 and 16.  See Section 
4.6.3 for specific time points for drawing samples.
Revised Text
Blood for PK sampling will be collected on Days 1, 7, 11, 14, and 15 and 16.  See 
Section 4.6.3 for specific time points for drawing samples.
4.2.2.3. Treatment Period – (Part B), PARAGRAPH 2
PREVIOUS TEXT
Subjects will be randomized to receive applications of GSK1278863 or placebo directly 
to the DFU on Day 1 for evaluation of safety and tolerability, PK of GSK1278863 and 
PD.  Applications of study drug will be done in clinic on Days 1, 4, 7, 11, and 14.  
Subjects are responsible for study drug application on Days 2-3, 5- 6, 8-10, 12-13.
REVISED TEXT
Subjects will be randomized to receive applications of GSK1278863 or placebo directly 
to the DFU on Day 1 for evaluation of safety and tolerability, PK of GSK1278863 and 
PD.  Applications of study drug will be done in clinic on Days 1, 4, 7, 11, and 14.  
Subjects are responsible for study drug application on Days 2-3, 5- 6 and 8-10, 1213.
4.5.1.3. QTc Withdrawal Criteria, DFU Patients (Part A Cohorts 2 through 
Final Cohort, Part B All Cohorts)
PREVIOUS TEXT

QTc > 500msec or uncorrected QT >600msec

If subject has underlying bundle branch block then the QTc withdrawal criteria 
depends on the baseline value:


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Baseline QTc 
value with 
underlying 
bundle branch 
block)
QTc withdrawal 
criteria
<450msec
>500msec
450-480msec
530msec
REVISED TEXT

QTc > 530500msec or uncorrected QT >600msec

If subject has underlying bundle branch block then the QTc withdrawal criteria 
depends on the baseline value:
Baseline QTc value with 
underlying bundle branch 
block)
QTc withdrawal 
criteria
≤500 450 
>500msec530msec
≤530 450-
480msec
530msec550msec
4.5.1.4  Other Dose Adjustment/Stopping Safety Criteria; DELETED TEXT
PREVIOUS TEXT

Subjects with documented GI bleeding, new onset positive fecal occult blood test, or 
abdominal pain (other than transient, minor abdominal pain).  See Section 5.3 for 
additional guidance.

Treatment emergent pulmonary hypertension, new onset or worsening retinopathy 
(e.g. proliferative retinopathy, or macular edema), or new onset or worsening non-
traumatic joint inflammation (e.g., rheumatic or psoriatic arthritis).
REVISED TEXT

Subjects with documented GI bleeding, new onset positive fecal occult blood test, or 
abdominal pain (other than transient, minor abdominal pain).  See Section 5.3 for 
additional guidance.

Treatment emergent pulmonary hypertension, new onset or worsening retinopathy 
(e.g. proliferative retinopathy, or macular edema), or new onset or worsening non-
traumatic joint inflammation (e.g., rheumatic or psoriatic arthritis).


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4.6.2. Time and Events Table Part B
PREVIOUS TEXT
Procedures
Screening
Optional 
Baseline 
Run In 
Visit1
Day 1
Day
4
Day
7
Day
11
Day 
14
Day
15
Day
16
Follow-up
Visit Window 
(relative to Day 1)
-28 to -14 
days
Exams/samples 
pre-dose
7-10 days 
post last 
dose
28-32 days 
post last 
dose
Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
Informed Consent
X
Demographics
X
Complete physical
X
Brief physical
X
X
X
X
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
X
12-lead ECG2
X
X
X
Vital signs3
X
X
X
X
X
X
Urine 
pregnancy(females)
X
X
X
Hema/Chem/ Safety 
Labs4
X
X
X
X
X
Vascular Perfusion 
Eligibility 
Assessments5
X
Blood samples for 
HIF, (e.g., EPO, 
Hepcidin, VEGF)
X6
X
X
Standard of Care 
Treatment7
X
X
===========================================
X
X


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Procedures
Screening
Optional 
Baseline 
Run In 
Visit1
Day 1
Day
4
Day
7
Day
11
Day 
14
Day
15
Day
16
Follow-up
Study 
Treatment/Dosing
In the Clinic8
X
X
X
X
X
PK serial blood 
sampling9
X
X
X
X
X
PK Trough Sample9
X
Tissue Biopsies 
(gene expression, 
macrophage and 
bioburden 
analysis)10
X
X
X
Wound Fluid 
(cytokine and 
bioburden 
analysis)11
X
X
X
X
SensiLase (Doppler 
blood flow) 
X
X
X
X
Hyperspectral 
Imaging12
X
X
X
X
Physical 
Characteristics
(assessed pre-
dose)13
X11
X
X
X
X
X
X
X
Clinical 
Characteristics14
X
X
X
X
X
X
X
X
X
Concomitant 
Medication Review
X
=========================================
X
X


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Procedures
Screening
Optional 
Baseline 
Run In 
Visit1
Day 1
Day
4
Day
7
Day
11
Day 
14
Day
15
Day
16
Follow-up
Adverse Event 
Assessment15
X
=========================================
X
X
1.
Optional Baseline Run In visit:  This optional visit is for subjects that will exceed the 14 (1 day) Run-in window between screening and Day 1.
2.
Single ECGs will be taken at Screening and pre-dose on Day 1 and 24h post-last dose on Day15.  ECGs should be taken while subject is supine for at least 5 minutes.  Additional 
ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
3.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Days 1, 7, 15 (24h post-last dose), and at Follow-up Visits.  
Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
4.
Blood samples for safety will be collected fasting at Screening and pre-dose/equivalent time on Days 1, 7, 15 (24h post-last-dose), and at the 7-10 day Follow-up Visit.  Refer to 
Section 7.2.4 for specific laboratory parameters to be tested.
5.
See Item 7 in the Inclusion Criteria – DFU Subjects for acceptable perfusion parameters.  Only 1 test of the 4 (TcPO2, ABI, toe pressure, Doppler ultrasound) is required for 
eligibility.
6.
Blood samples for HIFactivation on  Day 7 will be collected at pre-dose, 8 and 10-12 hour window.  On all other indicated days one sample will be collected at pre-
dose/equivalent time.  
7.
All subjects will be on SOC throughout the study (Section 7.4).
8.
In between clinic visits , subjects will perform applications of study drug at home.
9.
See separate Time and Events table for serial PK sampling details for Days 1, 7 and 14 and the associated 24and 48 hr time points.  Trough sample will be taken prior to dosing 
on Day 11.  Refer to Section 7.12 for details on the collection and processing of PK samples.  PK sampling times may be changed based on the observed GSK1278863 PK 
profile.
10. Direct wound tissue biopsies will be collected at pre-dose/equivalent on Days 1, 7, and 15, however based on emerging data, time points may be added or deleted; wounds that 
have healed sufficiently may be exempt.  Refer to Section 7.7.2 for additional details on the collection and processing of tissue biopsies.
11. Wound fluid will be collected at pre-dose/equivalent on Days 1, 7, 15 and at the 7-10 day Follow-up Visit.  Refer to the Section 7.7.1 for additional details on the collection and 
processing of wound fluid samples.
12. Will be performed based on hyperspectral imaging capabilities at each site.
13. Physical characteristics of the wound (i.e., photos of the wound and wound measurement assessments) will be assessed at Screening (Optional Baseline Run In Visit), at pre-
dose/equivalent time on Days 1, 4, 7, 11, 15 and at the 7-10 day Follow-up Visit.
14. Clinical characteristic assessments of the DFU begin with Section 7.10 and contain instructions for completing the assessments including the irritation/symptom scale as needed.  
Assessments are recorded in the eCRF.
15. Adverse events are to be collected from first dose through the final Follow-up visit.


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REVISED TEXT
Procedures
Screening
Optional 
Baseline 
Run In 
Visit1
Day 1
Day
4
Day
7
Day
11
Day 
14
Day
15
Day
16
Follow-up
Visit Window 
(relative to Day 1)
-28 to -14 
days
Exams/samples 
pre-dose
7-10 days 
post last 
dose
28-32 days 
post last 
dose
Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
Informed Consent
X
Demographics
X
Complete physical
X
Brief physical
X
X
X
X
X
X
X
X
X
X
Medical/medication/
drug/alcohol history
X
X
12-lead ECG2
X
X
X
Vital signs3
X
X
X
X
X
X
Urine 
pregnancy(females)
X
X
X
Hema/Chem/ Safety 
Labs4
X
X
X
X
X
Vascular Perfusion 
Eligibility 
Assessments5
X
Blood samples for 
HIF, (e.g., EPO, 
Hepcidin, VEGF)
X6
X
X
Standard of Care 
Treatment7
X
X
===========================================
X
X
Study 
Treatment/Dosing
In the Clinic8
X
X
X
X
X


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Procedures
Screening
Optional 
Baseline 
Run In 
Visit1
Day 1
Day
4
Day
7
Day
11
Day 
14
Day
15
Day
16
Follow-up
PK serial blood 
sampling9
X
X
X
X
X
PK Trough Sample9
X
Tissue Biopsies 
(gene expression, 
macrophage and 
bioburden 
analysis)10
X
X
X
Wound Fluid 
(cytokine and 
bioburden 
analysis)11
X
X
X
X
SensiLase (Doppler 
blood flow) 
X
X
X
X
Hyperspectral 
Imaging12
X
X
X
X
Physical 
Characteristics
(assessed pre-
dose)13
X11
X
X
X
X
X
X
X
Clinical 
Characteristics14
X
X
X
X
X
X
X
X
X
Concomitant 
Medication Review
X
=========================================
X
X
Adverse Event 
Assessment15
X
=========================================
X
X


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1.
Optional Baseline Run In visit:  This optional visit is for subjects that will exceed the 14 (1 day) Run-in window between screening and Day 1.
2.
Single ECGs will be taken at Screening and pre-dose on Day 1 and 24h post-last dose on Day15.  ECGs should be taken while subject is supine for at least 5 minutes.  Additional 
ECGs may be taken at the discretion of the investigator as needed based on symptoms or ECG findings.
3.
Assessment of vital signs (including blood pressure and heart rate) will be performed at Screening and pre-dose on Days 1, 7, 15 (24h post-last dose), and at Follow-up Visits.  
Vital signs should be performed after resting in a supine or semi-supine position for at least 5 minutes.
4.
Blood samples for safety will be collected fasting at Screening and pre-dose/equivalent time on Days 1, 7, 15 (24h post-last-dose), and at the 7-10 day Follow-up Visit.  Refer to 
Section 7.2.4 for specific laboratory parameters to be tested.
5.
See Item 7 in the Inclusion Criteria – DFU Subjects for acceptable perfusion parameters.  Only 1 test of the 4 (TcPO2, ABI, toe pressure, Doppler ultrasound) is required for 
eligibility.
6.
Blood samples for HIFactivation on Day 7 will be collected at pre-dose, 8 and 10-12 hour window.  On all other indicated days one sample will be collected at pre-
dose/equivalent time.  
7.
All subjects will be on SOC throughout the study (Section 7.4).
8.
In between clinic visits, subjects will perform applications of study drug at home.
9.
See separate Time and Events table for serial PK sampling details for Days 1, 7 and 14 and the associated 24and 48 hr time points.  Trough sample will be taken prior to dosing 
on Day 11.  Refer to Section 7.12 for details on the collection and processing of PK samples.  PK sampling times may be changed based on the observed GSK1278863 PK 
profile.
10. Direct wound tissue biopsies will be collected at pre-dose/equivalent on Days 1, 7, and 15, however based on emerging data, time points may be added or deleted; wounds that 
have healed sufficiently may be exempt.  Refer to Section 7.7.2 for additional details on the collection and processing of tissue biopsies.
11. Wound fluid will be collected at pre-dose/equivalent on Days 1, 7, 15 and at the 7-10 day Follow-up Visit.  Refer to the Section 7.7.1 for additional details on the collection and 
processing of wound fluid samples.
12. Will be performed based on hyperspectral imaging capabilities at each site.
13. Physical characteristics of the wound (i.e., photos of the wound and wound measurement assessments) will be assessed at Screening (Optional Baseline Run In Visit), at pre-
dose/equivalent time on Days 1, 4, 7, 11, 15 and at the 7-10 day Follow-up Visit.
14. Clinical characteristic assessments of the DFU begin with Section 7.10 and contain instructions for completing the assessments including the irritation/symptom scale as needed.  
Assessments are recorded in the eCRF.
15. Adverse events are to be collected from first dose through the final Follow-up visit.


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4.6.3. Serial PK Time and Events Table Part B
PREVIOUS TEXT
Procedure
Part B Serial PK Sampling1,2 
Hours (h)
Pre-
dose
0.5h
1h
2h
4h
6h
8h
10h
11h
12h
24h
48h
72h
Day 1 
X
X
X
X
X
X
X
X3
Day 7 
X
X
X
X
X
X3
Day 14 OUT-PATIENTS
X
X
X
X
X
X3
X
X
Day 14 IN-PATIENTS
X
X
X
X
X
X
X
X
REVISED TEXT
Procedure  VISIT DAY
Part B Serial PK Sampling1,2 
Hours (h)
Pre-
dose
0.5h
1h
2h
4h
6h
8h
10h
11h
12h
24h
48h
72h
Day 1 
X
X
X
X
X
X
X
X3
Day 7 
X
X
X
X
X
X3


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Procedure  VISIT DAY
Part B Serial PK Sampling1,2 
Hours (h)
Pre-
dose
0.5h
1h
2h
4h
6h
8h
10h
11h
12h
24h
48h
72h
Day 14 OUT-PATIENTS
X
X
X
X
X
X3
X
X
Day 14 IN-PATIENTS
X
X
X
X
X
X
X
X


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5.3.1. Inclusion Criteria – DFU Subjects; CRITERIA 3, 5, 6c
PREVIOUS TEXT
3. Single QTc < 450msec, or < 480msec in subjects with bundle branch block.
5. DFU between 1cm² and 16cm² at screening.
6. c.  Ulcer size (area) ≥ 1cm2 and ≤ 12cm2 (post-debridement at time of 
randomization).
REVISED TEXT
3. Single QTc < 450 ≤500msec, or < 480 ≤530msec in subjects with bundle branch 
block. No QTc exclusion for subjects with a predominantly paced rhythm.
5. DFU between 1cm² and 16 22cm² at screening.
6. c.  Ulcer size (area) ≥ 1cm2 and ≤ 12 16cm2 (post-debridement at time of 
randomization).
5.3.2. Exclusion Criteria – DFU Subjects; CRITERIA 2, 3, 5, 7, 8, 9, 10, 11, 
12, 13
PREVIOUS TEXT
2. Any unstable vascular syndromes (such as TIA, CVA, unstable angina, acute MI 
or ACS event) and/or any major changes (per investigator’s judgment) to related 
medications within 6 months prior to randomization.
3. History or malignancy within 5 years of screening or those with a strong family 
history of cancer (e.g. familial cancer disorders), with the exception of squamous 
cell or basal cell carcinoma of the skin that has been definitively treated.
5. Patients with active treatment for retinal neovascularization (e.g., diabetic 
proliferative retinopathy or age related macular degeneration) within 6 months of 
randomization.
7. History of venous thrombosis defined as deep vein thrombosis, pulmonary 
embolism or other venous thrombotic condition within 1 year prior to screening.
8. Active peptic, duodenal, or esophageal ulcer disease or any gastrointestinal 
bleeding, within 1 year prior to screening.
9. Subjects with a platelet count <100,000/mm3 at screening. 
10. Subjects with an International Normalized Ratio (INR) >1.1 at screening.  If on  
warfarin, then >2.5.
11. Subjects with a hemoglobin level above the gender-specific upper limit of normal 
at screening.


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12. Subjects with a history of non-traumatic joint inflammation (with the exception of 
inflammation due to osteoarthritis).
13. Patients with known pulmonary hypertension.
REVISED TEXT
2. Any unstable vascular syndromes (such as TIA, CVA, unstable angina, acute MI 
or ACS event) and/or any major changes (per investigator’s judgment) to related 
medications within 6 3 months prior to randomization.
3. History or mMalignancy within 5 2 years of screening or those with a strong 
family history of cancer (e.g. familial cancer disorders), with the exception of 
squamous cell or basal cell carcinoma of the skin that has been definitively 
treated.
5. Patients with active treatment for retinal neovascularization (e.g., diabetic 
proliferative retinopathy or age related macular degeneration) within 6 months of 
randomization.
7. History of venous thrombosis defined as deep vein thrombosis, pulmonary 
embolism or other venous thrombotic condition within 1 year prior to screening.
8. Active peptic, duodenal, or esophageal ulcer disease or any gastrointestinal 
bleeding, within 1 year prior to screening.
9. Subjects with a platelet count <100,000/mm3 at screening. 
10. Subjects with an International Normalized Ratio (INR) >1.1 at screening.  If on  
warfarin, then >2.5.
11. Subjects with a hemoglobin level above the gender-specific upper limit of normal 
at screening.
12. Subjects with a history of non-traumatic joint inflammation (with the exception of 
inflammation due to osteoarthritis).
13. Patients with known pulmonary hypertension.
7.3.2. Part B
PREVIOUS TEXT
Blood samples for HIF, (e.g., VEGF, EPO).
Biomarker Samples:  (e.g., for cytokines and bioburden)
Gene Expression (mRNA) and Macrophages (Immunohistochemistry)Tissue Samples
Heavy Water (Site involvement will depend on site feasibility – selected subjects (one cohort) 
based on emerging data) (Repeat Dosing only.)  Tissue samples via biopsy.
SensiLase (Dopplar blood flow)
Hyperspectral Imaging (oxygen dynamics) 


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Physical Indicators (e.g., photos and wound measurement). Silhouette for volume (record in eCRF)  
Digital photos (core) and acetate tracings (after screening scan and upload and send to core).
Clinical Indicators
Irritation/symptom Scale
REVISED TEXT
Blood samples for HIF, (e.g., VEGF, EPO).
Biomarker Samples:  (e.g., for cytokines and bioburden)
Gene Expression (mRNA) and Macrophages (Immunohistochemistry)Tissue Samples
Heavy Water (Site involvement will depend on site feasibility – selected subjects (one cohort) 
based on emerging data) (Repeat Dosing only.)  Tissue samples via biopsy.
SensiLase (Dopplar blood flow)
Hyperspectral Imaging (oxygen dynamics) – if the technique can be established/validated. (Site 
involvement will depend on site feasibility; selected subjects (one cohort) based on 
emerging data) (Repeat Dosing only.)  
Physical Indicators (e.g., photos and wound measurement). Silhouette for volume (record in eCRF)  
Digital photos (core) and acetate tracings (after screening scan and upload and send to core).
Clinical Indicators
Irritation/symptom Scale
7.8.1.1. Instructions for Assessing Vascular Perfusion with SensiLase
PREVIOUS TEXT
The subject is placed in a supine position.  The laser wand is placed in the guide and the 
guide is placed adjacent to the wound, as close to the peri-wound area as possible while 
remaining on completely epithelialized tissue.  A disposable cuff liner is placed on the 
cuff and the cuff is then placed snugly but not overly tight around the laser guide.  One or 
two readings are to be taken:  The first reading is to be taken at 12:00, with 12:00 being 
the most proximal edge of the wound.  The next reading is also to be taken at the 
proximal side of the wound but within the angiosome tissue block, if position one is not 
within the angiosome tissue block.  Angiosomes are designated locations found in the 
instruction manual for SensiLase.
REVISED TEXT
The subject is placed in a supine position.  The laser wand is placed in the guide and the 
guide is placed adjacent to the wound, as close to the peri-wound area as possible while 
remaining on completely epithelialized tissue.  A disposable cuff liner is placed on the 
cuff and the cuff is then placed snugly but not overly tight around the laser guide.  One or 
two readings are to be taken:  The first reading is to be taken at 12:00, with 12:00 being 
the most proximal edge of the wound.  The next reading is also to be taken at the 
proximal side of the wound but within the angiosome tissue block, if position one is not 


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within the angiosome tissue block.  All relevant angiosomes necessary for appropriate 
interpretation of blood flow should also be captured.  Angiosomes are designated 
locations found in the instruction manual for SensiLase.
7.8.2. Oxygen Dynamics/Angiogenesis
PREVIOUS TEXT
Oxygen dynamics and angiogenesis may be assessed by hyperspectral imaging as site 
feasibility allows.
REVISED TEXT
Oxygen dynamics and angiogenesis may be assessed by hyperspectral imaging as site 
feasibility allows and if the technique can be established/validated.
7.12.3.
PK Sampling Windows; BULLET POINT #4
PREVIOUS TEXT

Within 3 hours of target time for the 48 and 72 hour post-dose PK sample
REVISED TEXT

Within 3 hours of target time for the 48 and 72 hour post-dose PK sample
9.1.
Prohibited Medications; PARAGRAPH 2
PREVIOUS TEXT
Diabetic subjects must abstain from taking potent CYP2C8 inhibitors and inducers such 
as fluvoxamine, gemfibrozil, oral ketoconazole, trimethoprim, supplements containing 
quercetin and rifampin/rifampicin.  This is because the primary route of metabolism of 
GSK1278863 involves CYP2C8.  Data from a study (PHI113634) to assess the 
interaction potential between GSK1278863 and a CYP2C8 inhibitor (gemfibrozil) 
showed a clinically significant increase in GSK1278863 exposure following co 
administration.  Therefore, inhibitors of CYP2C8 are prohibited from 7 days prior to the 
first dose of investigational product until 7 days after the last dose of investigational 
product and inducers of CYP2C8 are prohibited from 14 days prior to the first dose of 
investigational product until 7 days after the last dose of investigational product.


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REVISED TEXT
Diabetic subjects must abstain from taking potent CYP2C8 inhibitors and inducers such 
as fluvoxamine, gemfibrozil, oral ketoconazole, trimethoprim, supplements containing 
quercetin and rifampin/rifampicin.  Diabetic subjects must abstain from taking potent 
CYP2C8 inhibitors and inducers such as gemfibrozil and rifampin/rifampicin . This 
is because the primary route of metabolism of GSK1278863 involves CYP2C8.  Data 
from a study (PHI113634) to assess the interaction potential between GSK1278863 and a 
CYP2C8 inhibitor (gemfibrozil) showed a clinically significant increase in GSK1278863 
exposure following co-administration.  Therefore, inhibitors of CYP2C8 are prohibited 
from 7 days prior to the first dose of investigational product until 7 days after the last 
dose of investigational product and inducers of CYP2C8 are prohibited from 14 days 
prior to the first dose of investigational product until 7 days after the last dose of 
investigational product.
7.13.1.   Time Period for Collecting Pregnancy Information
ADDED TEXT
Information on all pregnancies in female subjects will be collected after the start of 
dosing and through follow-up. 


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AMENDMENT 8
Where the Amendment Applies
This amendment applies to all sites participating in this study.
Summary of Amendment Changes with Rationale
This amendment contains the addition of an exclusion criterion for lactating or nursing 
females.  This change was necessary since data on prenatal and post natal development 
are currently not available.  The rationale for changes made in Amendment 7 was also 
updated due to omission in the previous amendment.
List of Specific Changes
5.3.2. Exclusion Criteria – DFU Subjects; CRITERIA 11
PREVIOUS TEXT
11.  Pregnant females as determined by positive urine hCG test at screening or prior to 
dosing.
REVISED TEXT
11.  Pregnant females as determined by positive urine hCG test at screening or prior to 
dosing or lactating/nursing females.
16.3 Appendix 3: Protocol Amendment Changes, Amendment 7, Summary 
of Changes with Rationale
PREVIOUS TEXT
This amendment contains modifications to inclusion criteria 3, 5 and 6 and exclusion 
criteria 2, 3.  Exclusion criteria 5 and 7 -13 were removed.  Other changes include 
updates to Part B that occurred in stream based on emerging data, but did not require a 
protocol amendment. Other minor edits for clarity.
REVISED TEXT
This amendment contains modifications to inclusion criteria 3, 5 and 6 and exclusion 
criteria 2, 3.  Exclusion criteria 5 and 7 -13 were removed.  
Rationale for Inclusion Criterion 3:  The results of a thorough QT study utilizing 
oral doses of GSK1278863 support the conclusion that there appears to be no 
clinically significant effect on ΔΔQTcF after administration of doses up to 500 mg in 
healthy subjects.  (GSK Document #2015N233454_00 PHI113635 14Dec 2015). 
These results, in addition to the limited systemic exposure demonstrated with topical 
application of GSK1278863, support the use of expanded QT enrolment criteria.


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Rationale for Inclusion Criterion 5 and 6c: Systemic concentrations of GSK1278863 
measured from patients administered 1% w/w (at 100mg/cm2) have been below the 
LLOQ of the analytical assay (0.10 ng/mL). A larger upper limit of 
screening/randomization ulcer size results in maximum systemic exposure 
predictions (following once daily application of ointment strengths up to 10% w/w 
GSK1278863 (at 100 mg/cm2) for 14 days) well below this study’s intended systemic 
exposure limits (395 ng.h/mL and 198 ng/mL for AUC and Cmax, respectively). 
This prediction supports an increase in allowable ulcer size.
Rationale for Exclusion Criterion 2, 3, 5, 7-13: As of June 2016, GSK1278863 has 
been administered orally to over 1000 subjects, including those with chronic kidney 
disease (either not on dialysis or on dialysis), in single doses up to 500 mg, in repeat-
doses up to 100 mg daily for 4 weeks and up to 25 mg daily for 24 weeks.  Overall, 
the safety profile was consistent with the patient population and there were no 
adverse events that have been identified as related to treatment with GSK1278863.  
Planned phase 3 studies have thus adopted revised exclusion criteria consistent with 
those above in patients with anemia due to chronic kidney disease, a vulnerable 
population with respect to vascular events.
Systemic concentrations of GSK1278863 measured from DFU subjects administered 
1% w/w (at 100mg/cm2) have been below the LLOQ of the analytical assay (0.10 
ng/mL) and systemic exposures following once daily application of ointment 
strengths up to 10% w/w GSK1278863 (at 100 mg/cm2) in DFU subjects are 
predicted to be well below this study’s intended systemic exposure limits (395 
ng.h/mL and 198 ng/mL for AUC and Cmax, respectively).  
The decision to modify the exclusion criteria was therefore based on the safety 
profile demonstrated in the oral program in patients with a similar or greater risk 
profile who are exposed to systemic concentrations of GSK1278863 which are well 
above those in the topical program.  
Stopping and withdrawal criteria were also modified to align with the updated 
inclusion/exclusion criteria as appropriate.
Other changes include updates to Part B that occurred in stream based on emerging data, 
but did not require a protocol amendment. Other minor edits for clarity.

SAP_001.pdf: 
 
CONFIDENTIAL 
CM2009/00071/00  
The GlaxoSmithKline group of companies 
 
PWH115760 
 
1 
Division: Worldwide Development 
Retention Category: GRS019 
Information Type:  Clinical Pharmacology Reporting and Analysis Plan 
Title: 
Phase I Trial to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of Single Doses of 
Topical GSK1278863 in Healthy Volunteers and Diabetic 
Patients, and Repeat Doses of GSK1278863 in Diabetic 
Patients for the Treatment of Diabetic Foot Ulcer 
Compound 
Number: 
GSK1278863  
Effective Date: 
18-10-2017 
 
Description:  
The purpose of this reporting and analysis plan (RAP) is to describe the planned analyses 
and output to be included in the Clinical Pharmacology Study Report for Protocol 
PWH115760. This RAP is intended to describe the safety, pharmacokinetic, and 
pharmacodynamic analyses required for the study. This document will be provided to the 
study team members to convey the content of Statistical Analysis Complete (SAC) 
deliverables. 
Identifier/Version Number:  [CM2009/00071/00] 
Subject:   
 
Author’s Name and Functional Area:  
 
 
Clinical Statistics, MPC 
 
Approved by: 
The Clinical Statistics Director (or designee) will give final approval 
 
Senior Statistics Director 
PCPS, Statistics, Programming and 
Data Strategy 
DD-MMM-
YY 
 
PPD
PPD


 
CONFIDENTIAL 
CM2009/00071/00  
The GlaxoSmithKline group of companies 
 
PWH115760 
 
2 
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ................................................................................. 10 
2. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ....................................... 11 
2.1. 
Study Objectives ...................................................................... 11 
2.1.1. 
Primary Objectives .................................................... 11 
2.1.2. 
Exploratory Objectives ............................................... 12 
To evaluate the effect of single and repeated doses of GSK1278863 on:
 .................................................................................. 12 
• 
Gene expression for HIF targets and genes associated with 
wound healing in the DFU. ........................................... 12 
• 
Local levels of biomarkers (e.g., inflammatory panel for 
cytokines, proteases). ................................................... 12 
• 
Bioburden in the wound (e.g., rtPCR for bacterial load). ... 12 
• 
Physical characteristics of the wound (e.g., rate of healing, 
wound volume). ........................................................... 12 
• 
Clinical characteristics of the wound (e.g., exudate, 
granulation tissue, color). .............................................. 12 
To evaluate the effect of repeat doses of GSK1278863 on: ............... 12 
2.2. 
Study Endpoints ....................................................................... 13 
2.2.1. 
Primary Endpoints ..................................................... 13 
• 
Clinical safety and tolerability data including spontaneous 
AE reporting, ECGs, vital signs, nurse/physician observation 
and clinical laboratory values after single and/or repeat doses 
of GSK1278863. .......................................................... 13 
• 
Pharmacokinetic parameters of GSK1278863 and its 
metabolites:  SD: Cmax, tmax, terminal t½, tlag, AUC(0-∞), 
AUC(0-t), (AUC(0-∞) and RD: Cmax, tmax, terminal t½, 
AUC(0-t), (AUC(0-∞) and accumulation ratio), after single 
and/or repeat doses of GSK1278863, as data permit. ........ 13 
2.2.2. 
Exploratory Endpoints ............................................... 13 
After single doses of GSK1278863 (as data permit based on sampling 
feasibility): .................................................................. 13 
After repeat doses of GSK1278863 (as data permit based on sampling 
feasibility): ..................... Error! Bookmark not defined. 
3. 
STUDY DESIGN .................................................................................. 15 
3.1. 
Sample Size ............................................................................. 16 
4. 
PLANNED ANALYSES ........................................................................ 17 
4.1. 
Interim Analyses ....................................................................... 17 
4.2. 
Final Analyses .......................................................................... 17 
5. 
ANALYSIS POPULATIONS ................................................................. 17 
6. 
HYPOTHESES AND TREATMENT COMPARISONS .......................... 17 


 
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7. 
TREATMENT AND OTHER SUB-GROUP DESCRIPTIONS FOR DATA 
DISPLAYS ........................................................................................... 18 
8. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING .......................................................................................... 18 
8.1. 
Reporting Conventions ............................................................. 19 
8.2. 
Data Management .................................................................... 20 
8.3. 
Premature Withdrawal and Missing Data .................................. 20 
8.4. 
Baseline Definition .................................................................... 21 
8.5. 
Derived and Transformed Data ................................................ 22 
8.5.1. 
Change from Baseline ............................................... 22 
8.5.2. 
Multiple Measurements at One Time-point ................ 22 
8.5.3. 
Derived parameters for EPO ..................................... 22 
8.6. 
Values of Potential Clinical Importance..................................... 24 
9. 
STUDY POPULATION ......................................................................... 27 
10. SAFETY ANALYSES ........................................................................... 27 
11. PHARMACOKINETIC ANALYSES....................................................... 28 
11.1. 
Drug Concentration Measures .................................................. 28 
11.2. 
Deriving and Summarizing Pharmacokinetic Parameters ......... 29 
12. PHARMACODYNAMIC AND BIOMARKERS ANALYSES ................... 30 
12.1. 
Pharmacodynamic Analyses for DFU ....................................... 30 
12.1.1. 
Physical parameters of the wound ............................. 30 
12.1.2. 
Physical parameters of the wound: time to events Error! 
Bookmark not defined. 
12.1.3. 
Clinical parameters of the wound............................... 31 
12.2. 
Biomarker Analyses.................................................................. 31 
12.2.1. 
Wound fluid biomarkers: Cytokines ........................... 31 
12.2.2. 
Wound fluid biomarkers: Bioburden ........................... 31 
12.2.3. 
Gene expression in the DFU tissue ........................... 31 
12.2.4. 
Biomarkers of angiogenesis and blood flow and oxygen
 .................................................................................. 31 
12.2.5. 
Circulating biomarkers of systemic HIF activation ...... 32 
13. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES ....... ERROR! 
BOOKMARK NOT DEFINED. 
14. REFERENCES .................................................................................... 33 
15. ATTACHMENTS .................................................................................. 34 
15.1. 
Table of Contents for Data Display Specifications .................... 34 
15.1.1. 
Study Population ....................................................... 34 
15.1.2. 
Safety Figures & Tables ............................................ 35 
15.1.3. 
Pharmacokinetic Figures and Tables ......................... 37 
15.1.4. 
Pharmacodynamic Figures and Tables ..................... 38 
15.1.5. 
ICH Listings ............................................................... 40 
15.1.6. 
Other Listings ............................................................ 41 


 
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15.2 
Data Display Specifications (Example Shells)........................... 43 
 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine aminotransferase (SGPT) 
ANCOVA 
Analysis of Co-variance 
ANOVA 
Analysis of Variance 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under concentration-time curve 
AUC(0-) 
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time 
%AUCex 
Percentage of AUC(0-) obtained by extrapolation 
AUC(0-x) 
Area under the concentration-time curve from zero (pre-dose) to 
some fixed nominal time x 
AUC(0-t) 
Area under the concentration-time curve from time zero (pre-dose) 
to last time of quantifiable concentration within a subject across all 
treatments 
AUC(0-) 
Area under the concentration-time curve over the dosing interval 
-HCG 
Beta-Human Chorionic Gonadotropin 
BA 
Bioavailability 
BE 
Bioequivalence 
BMI 
Body mass index 
BP 
Blood pressure 
BPM 
Beat Per Minute 
BQL 
Below the quantification limit 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CIB 
Clinical Investigator’s Brochure 
CLr 
Renal clearance 
CL 
Systemic clearance of parent drug 
CL/F 
Apparent clearance following oral dosing 
Cmax 
Maximum observed concentration  
Cmin 
Minimum observed concentration 
Cτ 
Pre-dose (trough) concentration at the end of the dosing interval 
Ct 
Last observed quantifiable concentration 
CDMP 
Clinical Document Management and Publishing 
CO2 
Carbon dioxide 
CPDM 
Clinical Pharmacology and Discovery Medicine 
CPK 
Creatine phosphokinase 
CPKMS 
Clinical Pharmacokinetics Modelling & Simulation 
CPSR 
Clinical Pharmacology Study Report 
CP-RAP 
Clinical Pharmacology Reporting and Analysis Plan 


 
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CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRU 
Clinical Research Unit 
CV 
Coefficient of variance 
DBP 
Diastolic blood pressure 
DDS 
Drug Development Sciences 
DMPK 
Discovery Medicine Pharmacokinetics 
ECG 
Electrocardiogram 
ECP 
Endothelial Progenitor Cell 
EDC 
Electronic data capture 
EISR 
Expedited Investigator Safety Report 
EPO 
Erythropoietin 
Fabs 
Absolute bioavailability of drug determined following extravascular 
and intravascular dosing 
FDA 
Food and Drug Administration 
Frel 
Relative bioavailability of drug determined between two 
formulations of the same drug following similar or different 
extravascular route of administration 
FSH 
Follicle Stimulating Hormone 
FTIH 
First time in humans 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilence 
GGT 
Gamma glutamyltransferase 
GLS 
Geometric Least-Squares 
GSK 
GlaxoSmithKline 
HARP 
GSK system designed to aid the statistical analysis of clinical trials 
data (Phases I to IV). 
hCG 
Human chorionic gonadotropin 
HIV 
Human Immunodeficiency Virus 
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 
IDMC 
Independent Data Monitoring Committee 
IDSL 
Integrated Data Standards Library 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IU 
International Unit 
IV 
Intravenous 
Kg 
Kilogram 


 
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z 
Terminal phase rate constant 
L 
Liter 
LFTs 
Liver function tests 
Ln 
Naperian (natural) logarithm 
LOQ 
Limit of quantification 
LLQ 
Lower limit of quantification 
µg 
Microgram 
µL 
Microliter 
MAT 
Mean absorption time 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligrams 
mL 
Milliliter 
MRT 
Mean residence time 
MSDS 
Material Safety Data Sheet 
Msec 
Milliseconds 
NQ 
Non-quantifiable concentration measured as below LLQ 
PAH 
Pulmonary Artery Hypertension 
PASP 
Pulmonary Artery Systolic Pressure 
PHD 
HIF- proly hydroxylases 
PD 
Pharmacodynamic 
PGx 
Pharmacogenetics 
PK 
Pharmacokinetic 
PSRI 
Periodic Safety Reports for Investigators 
QC 
Quality control 
QD 
Once daily 
RAP 
Reporting and Analysis Plan 
RBA 
Relative Bioavailability 
RBC 
Red blood cells 
RV 
Right Ventricular 
SAE 
Serious adverse event(s) 
SAS 
Statistical Analysis Software 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operating Procedure 
SPM 
Study Procedures Manual 
SUSAR 
Suspected, Unexpected, Serious Adverse drug Reaction 
T 
Infusion duration 
T 
Time of last observed quantifiable concentration 
t½ 
Terminal phase half-life 
Τ 
Dosing interval 
Tlag 
Lag time before observation of drug concentrations in sampled 
matrix 
Tlast 
Time of last quantifiable concentration 


 
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Tmax 
Time of occurrence of Cmax 
ULN 
Upper limit of normal 
UK 
United Kingdom 
US 
United States 
Vd/F 
Apparent volume of distribution after extravascular (e.g., oral) 
administration 
WBC 
White blood cells 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
 
 
 
 
 
 
 
 
 


 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Pharmacology Study Report for Protocol: 
Revision Chronology: 
2011N121462_00 
2012-Mar-20 
Original 
2011N130130_01 
2012-NOV-21 
Amendment No.:01 This amendment 
reflects changes to the patient eligibility 
criteria, stopping criteria and sampling 
time points per regulatory feedback. 
2011N130130_02 
2013-FEB-14 
Amendment No.: 02 This amendment 
reflects changes to DFU patient 
eligibility criteria number 7 and 
screening procedures in Part A as well 
as minor edits for clarity. 
2011N130130_03 
2013-JUN-06 
Amendment No.: 03 This amendment 
clarifies an eligibility criterion and DFU 
clinical assessments as well as minor 
edits for clarity. 
2011N130130_04 
2014-JAN-29 
Amendment No.: 04 This amendment  
reflects changes in the container type 
used to supply the bulk ointment. Minor 
edits are also included for 
clarity. 
2011N130130_05 
2014-JUN-02 
Amendment No.: 05 This amendment 
reflects modifications to the DFU 
inclusion and exclusion criteria, 
hemoglobin stopping criteria and a 
change in biopsy collection 
expectations. Minor edits are also 
included for clarity. Amendment 5 was 
republished before distribution, with the 
DNG number of 2011N130130_06, in 
order to correct an error. 
2011N130130_07 
2014-NOV-19 
Amendment No. 06: Due to emerging 
data, specific areas of Part B of the 
protocol were redesigned to better meet 
the needs of the study. To date Part A 
GSK1278863 systemic exposure is 
below 
analytical limits of quantification and 
therefore the stand alone single dose 


 
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assessment in Part B is no longer 
required. Eclusion criteria number 10 
was adjusted to better reflect the patient 
population. Other minor edits were also 
included for clarity. 
PWH115760 
RAP_V11 
2017-SEP-19  
Amendment No. 07 Due to the 
termination of this indication some 
TLF’s were deleted in order to 
streamline outputs  
PWH115760 
RAP_V13 
2017-OCT-1  
Amendment No. 08 Text revisions to 
correspond with the TLF revisions in 
the prior amendments. Additional 
TLF’s added in order to comply with 
data disclosure.   
All decisions regarding final analysis, as defined in this RAP document, have been 
made prior to Database Freeze (unblinding) of the study data. 
 
2. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
• To evaluate the safety and tolerability of the topical application of 
GSK1278863 in healthy volunteers and patients with diabetic foot ulcer 
following single dose (SD) and repeat dose (RD) administration. 
• To determine the pharmacokinetics of single and repeat doses of GSK1278863 
and its metabolites following SD and RD administration. 


 
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2.1.2. 
Exploratory Objectives 
To evaluate the effect of single and repeated doses of GSK1278863 on: 
• Gene expression for HIF targets and genes associated with wound 
healing in the DFU.  
• Local levels of biomarkers (e.g. inflammatory panel for cytokines, 
proteases). 
• Bioburden in the wound (e.g. rtPCR for bacterial load). 
• Physical characteristics of the wound (e.g. rate of healing, wound 
volume). 
• Clinical characteristics of the wound (e.g., exudate, granulation tissue, 
color). 
To evaluate the effect of repeat doses of GSK1278863 on: 
• 
Gene expression for HIF targets and genes associated with wound 
healing in the DFU. 
• 
Local levels of biomarkers (e.g., inflammatory panel for cytokines, 
proteases, inflammatory cell counts, collagen turnover). 
• 
Bioburden in the wound (e.g., rtPCR for bacterial load). 
• 
Biomarkers of angiogenesis via blood flow and oxygen availability 
[e.g., skin perfusion pressure (SPP) and pulse volume (PV), 
hyperspectral imaging]. 
• 
Tissue concentrations of GSK1278863 after repeat dosing in selected 
subjects, as site capabilities to perform the assessment permit. 
• 
Circulating biomarkers for HIF activation (e.g., hemoglobin, hepcidin, 
EPO). 
• 
Physical characteristics of the wound (e.g. rate of healing, wound 
volume). 
• 
Clinical characteristics of the wound (e.g., exudate, granulation tissue, 
color) 
• 
The dose-response and/or exposure-response relationships of repeat 
doses of GSK1278863 using PK/PD modeling for selected primary 
and exploratory endpoints (as data permit). 


 
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2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoints 
• Clinical safety and tolerability data including spontaneous AE reporting, 
ECGs, vital signs, nurse/physician observation and clinical laboratory 
values after single and/or repeat doses of GSK1278863. 
• Pharmacokinetic parameters of GSK1278863:  SD: Cmax, tmax, terminal 
t½, tlag, AUC(0-∞), AUC(0-t), (AUC(0-∞) and RD: Cmax, tmax, terminal 
t½, AUC(0-t), (AUC(0-∞) and accumulation ratio), after single and/or 
repeat doses of GSK1278863, as data permit. 
2.2.2. 
Exploratory Endpoints 
After single doses of GSK1278863 (as data permit based on sampling 
feasibility): 
• Change from baseline in gene expression (mRNA) in the DFU tissue. 
• Change from baseline in biomarkers in the DFU (e.g., cytokine panel, 
protease panel). 
• Change from baseline on bioburden in the DFU (e.g., rtPCR for bacterial 
load). 
• Physical parameters of the wound (e.g., rate of healing, wound volume). 
• Clinical characteristics of the wound (e.g., exudate, granulation tissue, 
color). 
 
After repeat doses of GSK1278863 (as data permit based on sampling 
feasibility): 
• 
Change from baseline in gene expression (mRNA) in the DFU tissue. 
• 
Change from baseline in biomarkers of angiogenesis and blood flow and 
oxygen availability [e.g., skin perfusion pressure (SPP) and pulse volume 
(PV), hyperspectral imaging]. 
• 
Change from baseline in biomarkers in the DFU (e.g., cytokine panel, 
protease panel, macrophage quantification) 
a. 
If the methodology can be validated at the site(s) cell proliferation and 
collagen turnover will be assessed. 
• 
Change from baseline on bioburden in the DFU (e.g., rtPCR for bacterial 
load). 


 
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• 
Tissue concentrations of GSK1278863 in selected subjects as determined 
from micro-dialysis during RD, if feasible to conduct the assessment. 
• 
Change from baseline on circulating biomarkers of systemic HIF 
activation in the blood (e.g., hemoglobin, hepcidin, EPO). 
• 
Physical parameters of the wound following repeat doses of GSK1278863, 
for example:  
a. 
Rate of wound healing (via planimetry). 
b. Change in wound volume (Silhouette software). 
c. 
Percentage of subjects with closure of the study DFU. 
d. Time to DFU closure. 
e. 
Time required to achieve a certain percent of wound closure. 
f.     Incidence of DFU closure. 
• 
Clinical characteristics of the wound (e.g., exudate, granulation tissue, 
color). 
• 
Correlation between GSK1278863 dose and/or exposure and parameters of 
pharmacodynamic activity, safety, and tolerability, as data permit. 
Due to the termination of this project and the limitations of the data some of the 
exploratory endpoints have been modified for reporting as follows:  
• Gene expression and qPCR data will be analysed by Target Sciences and 
the results will be summarized in a separate report. 
• Instead of change from baseline, descriptive summaries will be created for 
the angiogenesis and blood flow and oxygen availability, the biomarkers in 
the DFU, the bioburden in the DFU, and biomarkers of systemic HIF 
activation in the blood.  
• The only physical parameter to be evaluated is change in wound volume 
and area  
• Correlation between GSK1278863 and PD and safety will not investigated 
further, unless multiple safety issues make is necessary  
  
Given the time it takes to process the assay, the histology data will not be available for 
inclusion in the final data base at the time of database freeze.  Therefore, this data will 
be analysed when it becomes available.  If the results are available before CSR, then 
they will be included in the study report; otherwise, they will be included in an 
addendum to the study report or separate study report. 
 


 
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3. 
STUDY DESIGN 
This first-time-in-human study of the topical formulation of GSK1278863 is designed 
as an initial exploration of the safety, tolerability, pharmacokinetic and 
pharmacodynamic effects.  The study will be performed in a cohort of healthy 
volunteers and then in diabetics, including application both to healthy, intact skin, as 
well as to diabetic foot ulcers directly. This study includes two parts (Part A and Part 
B). Part A is designed to evaluate single applications of GSK1278863. Part A will 
include one cohort of healthy volunteers (intact skin) and approximately 3 cohorts of 
diabetic subjects with foot ulcer. Part B is designed to evaluate repeat applications of 
GSK1278863 in diabetics, both in the clinic and by subjects at home. Part B will 
include approximately 3 cohorts in which the concentration of drug applied will be 
determined by pharmacokinetic data from Part A and earlier cohorts in Part B.  For 
both parts of the protocol, additional cohorts may be added as necessary to obtain 
relevant safety, pharmacokinetic or pharmacodynamic data. 
 
 Furthermore, for both Parts A and B, there will be at least one week between cohorts 
for review of safety, tolerability and PK data by the GSK study team (unblinded) and 
the Investigator (blinded). Pharmacodynamic data, where available, may be obtained 
for review. Enrollment to each cohort may be staggered (i.e., cohorts do not have to be 
enrolled as one group). However, all enrollments should occur within ~4 weeks for 
each cohort. Diabetic subjects, in either Part A or B, will require a two week run in 
period in which standard of care is given before treatment of the DFU with 
GSK1278863 or placebo in order to ensure the wound does not show a greater than 
30% reduction in size. 
 
 


 
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Figure 1 
Study Design/Schematic 
 
 
 
Subjects will be assigned to receive GSK1278863A or vehicle (placebo) in Part A and 
GSK1278863A or vehicle or SOC only (moist occlusion) in Part B in accordance with 
the randomization schedule generated by GSK, prior to the start of the study, using 
validated internal software. 
 
Based on data from Part A it was decided that there would only be one cohort in part 
B.   
3.1. 
Sample Size 
There is no formal calculation of power or sample size in this study. Sample sizes are 
based on feasibility. A sample size of six subjects per active single dose (Part A), and 
twelve subjects per active repeated dose (Part B) completing the study are feasible 
sample sizes to provide sufficient safety and PK data for this FTIH study. The target 
sample size is set at 8 subjects per cohort in Part A, (6 on active treatment and 2 on 
placebo), and 16 per cohort in Part B, (12 on active treatment, 2 on placebo and 2 
receiving standard of care). The sample size for the placebo at each dose level is set at 
two to avoid subject bias in safety assessment. 
 
 


 
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4. 
PLANNED ANALYSES 
4.1. 
Interim Analyses 
There will be no formal interim analysis; however, all preliminary safety, tolerability, 
and available pharmacokinetic data will be reviewed internally at GSK prior to each 
dose escalation (GSK study staff are unblinded). 
4.2. 
Final Analyses 
The final planned SAC analyses will be performed after all subjects have completed or 
withdrawn from the study and after the database freeze/unblinding is declared. 
 
5. 
ANALYSIS POPULATIONS 
All Subject Population: All subjects who receive at least one dose of study drug 
(including GSK1278863, placebo and standard care) will be included in the All 
Subject Population.  Randomized subjects will only be excluded if there is clear 
documented evidence of failure to take any study medication.  Subjects in the All 
Subject Population will be analyzed according to the treatment received and will be 
used for the reporting of safety and study population. 
Enrolled: All participants who sign informed consent and for whom a record exists on 
the study database.  This population will be used for the tables/listings of reasons for 
withdrawal before randomization and listings of AEs and SAEs for non-randomized 
participants. 
Pharmacodynamic (PD) Population: All subjects who provide pharmacodynamic 
(PD) data will be included in the PD population. This population will be used in the 
evaluation of PD.  For the change from baseline assessment, only those providing both 
evaluable baseline and post-dose values (so that the change can be calculated) will be 
included in the analysis. All subjects in the PD Population will be analyzed according 
to the treatment they actually received.   
Pharmacokinetic (PK) Population: All subjects from whom a pharmacokinetic (PK) 
sample has been obtained and analyzed will be included in the PK population. This 
population will be used for reporting of PK concentration and the PK parameters. 
6. 
HYPOTHESES AND TREATMENT COMPARISONS 
This study is designed to evaluate the safety and tolerability of topical application of 
GSK1278863 in healthy volunteers and patients with diabetic foot ulcer following 
single dose (SD) and repeat dose (RD) administration. No formal hypothesis will be 
tested. For each primary pharmacokinetic endpoint, point estimates and corresponding 


 
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95% confidence intervals will be constructed for GSK1278863 and it metabolites for 
SD and RD respectively. Comparison of PD endpoints, including physical parameters 
of the wound, clinical characteristics of the wound, gene expression, biomarkers, 
bioburden, etc, will be performed with GSK1278863 versus placebo or standard care 
as data permit.   
   
7. 
TREATMENT AND OTHER SUB-GROUP 
DESCRIPTIONS FOR DATA DISPLAYS 
Randomisation 
Final Data Display 
 (i.e. HARP / other) 
Code 
Treatment Description 
Treatment Description* 
A 
0.3 mg GSK1278863 
300mg of 0.1% ointment to deliver 
300µg of GSK1278863- SD 
B 
GSK1278863 Single Dose B 
300mg of 1% ointment to 
deliver 3000µg of 
GSK1278863- SD 
C 
GSK1278863 Single Dose C 
0.1% of GSK1278863 ointment  
at 25 mg/cm2 SD 
D 
GSK1278863 Single Dose D 
1% of GSK1278863 ointment 
at 25 mg/cm2 SD 
E 
GSK1278863 Single Dose E 
1% of GSK1278863 ointment 
at 100 mg/cm2 SD 
R1r            GSK1278863 Repeat Dose R1r 
1% of GSK1278863 ointment 
at 100 mg/cm2 RD 
PR1r 
Placebo  
Placebo RD 
P 
Placebo 
Placebo SD 
Sr 
Standard of Care 
Standard of Care RD 
* for dose applies to DFU patients, since the actual dose depends on the size of the 
wound, the treatment description should use a volume measure similar as used for 
Doses C and D once the actual dose formulation becomes available.   
 
8. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
AND HANDLING 
Data will be listed and summarized according to GlaxoSmithKline reporting standards, 
where applicable. 


 
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8.1. 
Reporting Conventions 
• All the data will be listed for clinical safety and tolerability evaluation.  
• Missing data will not be imputed.  
• Actual times relative to study drug dosing will be used in data listings. Planned 
times relative to study drug dosing will be used in data summaries. 
• Any changes from the analyses within this reporting and analysis plan will be 
stated in the final study report 
• Analyses are performed using the SAS/STAT® module of the SAS® System, 
Version 9.3 (SAS and SAS/STAT are registered trademarks of the SAS 
Institute Inc., Cary, NC, USA). Programs will be imported into HARP and the 
final output will be produced by running drivers in HARP. 
• Sections 10 to 13 contain the details regarding the planned analyses and see 
Section 15.2 for the data displays for decision critical results. 
• For subjects who entered multiple cohorts, the subject number of the very first 
entry will be used as the subject ID for reporting purpose.    
 
 


 
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8.2. 
Data Management 
The data collection tool for this study will be GSK-defined electronic case report 
forms (CRFs). In all cases, subject initials will not be collected nor transmitted to 
GSK. Subject data necessary for analysis and reporting will be entered/transmitted into 
a validated database or data system. Clinical data management will be performed in 
accordance with applicable GSK standards and data cleaning procedures. Original 
CRFs will be retained by GSK, while the investigator will retain a copy. 
 
Data Type 
Source  
Format of 
Data 
Planned Date 
of Final File1 
Responsibility 
Study 
population, 
Safety, PD 
sampling 
Inform Database 
IDSL data 
DBR 
CPSSO  
Safety 
Laboratory 
Data  
Quest Central 
Laboratory  
IDSL data 
DBR 
CPSSO/Extern
al Vendor  
PK 
Concentration 
SMS2000 data files 
data file 
DBR 
DMPK 
Biomarker/bio
burden 
External Vendor 
Forsyth files 
through external 
alliance portal 
.xlsx and. cel 
files 
DBR 
CPSSO/ 
External 
Vendor/Target 
Sciences 
PD 
CRO CPC – files 
through external 
alliance portal 
IDSL data 
DBR 
CPSSO/Extern
al Vendor 
1This is for study teams to determine upfront if there is a possibility of not meeting the completion of the 
CPSR within 6 months of LSLV (i.e. novel data that may not be available until several months after LSLV). 
8.3. 
Premature Withdrawal and Missing Data 
All subjects who withdraw prematurely from the study/study drug will be documented 
and the reason for their withdrawal recorded in the final Clinical Pharmacology Study 
Report (CPSR).  All available data from subjects who withdraw will be listed and all 
available planned data will be included in the summaries according to the populations 
defined in Section 5. 
In the event that the study is prematurely discontinued, all available data will be listed 
and a review carried out by the study team to assess which statistical analyses are still 
considered appropriate. 
No imputations will be made for missing data. 
 


 
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8.4. 
Protocol Deviations 
Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be listed.  
Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with.  Data will be reviewed prior to unblinding and freezing the 
database to ensure all important deviations are captured and categorized on the 
protocol deviations dataset. This dataset will be the basis for listings of protocol 
deviations. 
A separate listing of all inclusion/exclusion deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF. 
 
8.5. 
Baseline Definition 
Baseline values for safety and PD parameters will be calculated for each subject as 
defined in the following table: 
The following table indicates the baseline observations to be used in the analyses: 
Parameter 
Visit of Baseline 
Observation  
Safety: 
 
ECG 
Day 1 pre-dose  
Laboratory 
Day 1 pre-dose 
Vital Signs 
Day1 pre-dose 
(weight/height at 
screening) 
Demographics  
Screening 
PD: 
 
Gene expression 
Day 1 pre-dose 
Biomarkers 
Day 1 pre-dose 
Physical 
characteristics  
Day 1 pre-dose 
Clinical 
characteristics  
Day 1 pre-dose 
PK parameters 
 Day 1 
Note for cohort 2, baseline should be Day1 predose on Period 2. 
For those without baseline run in, screening visit  should come from baseline run in for 
reporting purpose.   


 
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If, for any parameter, the baseline has a missing value or blow LLQ, then the most-
recent non-missing value obtained before dosing will be used as the baseline value for 
that parameter. 
8.6. 
Derived and Transformed Data 
8.6.1. 
Change from Baseline 
The change from baseline will be calculated for each post-baseline time-point by 
subtracting the baseline values from the individual post-baseline values.  If either the 
baseline or post-baseline value is missing, the change from baseline will be set to 
missing as well. 
8.6.2. 
Multiple Measurements at One Time-point 
Where planned multiple measurements are recorded for a particular time point, the 
mean of the measurements will be calculated and used in any derivation of summary 
statistics.  However all available data will be listed.     
8.6.3. 
Derived parameters for EPO   
Cmax, tmax and AUC of EPO concentration will be derived for each subject by the 
study day (Part A: Day 1; Part B: Day 1, Day 8, Day14 or Day21) .   
The maximum observed concentration (Cmax) and the first time of its occurrence 
(tmax) will be obtained directly from the EPO concentration-time data for each subject 
by study day. 
AUC will be calculated using linear trapezoidal rules. Let C1 and C2 be two adjacent 
concentration point and T1 and T2 be corresponding two adjacent time points, then  
according to the trapezoidal rule, the partial AUC between T1 and T2,  AUC[T1, T2]= 
(C1+C2)*(T2-T1)/2, and total AUC is the sum of all partial AUC’s within the defined 
time window.   
8.6.4. 
Derived parameters for time to event measures   
   Time to events for wound healing will be derived using a first occurrence approach 
as follows:  
x% healed: the x% healing event is recorded when percent change from baseline of 
area of wound (or volume of wound) is -x% or lower; the time of first occurrence is 
the event time, x can be 30, 50 or 75; 
The full closure event is recorded when the wound is fully healed, the event time is the 
first occurrence time of the event.  


 
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The event time (number of days) = date of event occurrence – date of Randomization 
+1 
 
8.6.5. 
Derived Parameters for Metabolite:Plasma Exposure Ratios 
If data permit, Metabolite : Parent drug systemic exposure ratios (corrected for 
molecular weight) will be calculated for plasma AUC and Cmax parameters as 
follows:  
M: P AUC ratio =
Metabolite AUC Metabolite MW
⁄
GSK1278863 AUC GSK1278863 MW
⁄
 
M: P Cmax ratio =
Metabolite Cmax Metabolite MW
⁄
GSK1278863 Cmax GSK1278863 MW
⁄
 
 
Compound 
Molecular Weight 
(MW) 
GSK1278863   
(parent) 
393.442 
GSK2391220 
(metabolite) 
425.442 
GSK2531403 
(metabolite) 
425.442 
GSK2487818 
(metabolite) 
425.442 
GSK2506102 
(metabolite) 
425.442 
GSK2531398 
(metabolite) 
425.442 
GSK2531401 
(metabolite) 
441.442 
 


 
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8.6.6. 
Derived Parameters for Actual Drug Administered 
In Part A, the difference of syringe weights will be calculated for determination of 
amount of dose administered.  Predose syringe weight will reflect the empty syringe 
weight plus amount of drug to be administered; postdose syringe weight will reflect 
the empty syringe weight plus any residual drug remaining in syringe after dosing. 
Amount of Dose Administered
= Syringe weight predose – Syringe weight postdose 
In Part B, the difference in ointment tube weights will be calculated for a general 
assessment of patient compliance by determining the average amount of dose 
administered in the repeat dose portion of the study. Predose tube weight will reflect 
the tube weight prior to dosing; postdose tube weight will reflect the tube weight when 
the patient returns for their office visits throughout the repeat dose portion of the 
study. 
Average Amount of Dose Administered
= Tube weight predose −Tube weight postdose
Number of days
 
 
8.7. 
Values of Potential Clinical Importance 
 
Laboratory Values of Potential Clinical Importance (Healthy Volunteers) 
Hematology Analyte 
Effect 
Relative – Low 
(Multipliers of LLN) 
Relative – High 
(Multipliers of ULN) 
White Blood Cell Count 
(x109/ L) 
 
0.5 
2 
Neutrophil Count (x109/ L) 
 
0.75 
 
Hemoglobin (g/L) 
Low 
< -25 decrease from baseline 
Male 
 
1.1 
Female 
 
1.1 
Hematocrit (Ratio of 1) 
Low 
< -0.1 decrease from baseline 
Male 
 
1.1 
Female 
 
1.1 
Platelet Count (x109/ L) 
 
0.5 
1.75 
Lymphocytes (x109/ L) 
 
0.75 
 
 


 
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Chemistry Analyte 
Effect 
Relative – Low 
(Multipliers of LLN) 
Relative – High 
(Multipliers of ULN) 
Albumin (g/L) 
 
 
 
Calcium (mmol/L) 
 
0.85 
1.1 
Creatinine (mol/L) 
 
 
 
High 
≥ 22 increase from baseline 
(Note 22 mol/L ≈ 0.25 mg/dL) 
Glucose (mmol/L) 
 
0.71 
1.41 
Potassium (mmol/L) 
 
0.86 
1.1 
 
Liver Function Test 
Analyte 
Effect 
Potential Clinical Importance (PCI) 
Range 
Unit 
ALT/SGPT 
High 
 2x ULN 
U/L 
AST/SGOT 
High 
 2x ULN 
U/L 
AlkPhos 
High 
 2x ULN 
U/L 
T Bilirubin 
High 
 1.5xULN 
µmol/L 
T. Bilirubin + ALT 
High 
 1.5xULN T. Bilirubin 
+ 
 2x ULN ALT 
µmol/L 
 
U/L 
 
ECG Values of Potential Clinical Importance (Healthy Volunteers) 
ECG Parameter 
Potential Clinical Importance Range (PCI) 
Unit 
Absolute QTc interval 
>450  
msec 
Increase from baseline QTc 
>60 
msec 
QRS interval 
 >110 
msec 
 
 
Vital Sign Values of Potential Clinical Importance (Healthy Volunteers) 
Vital Sign Parameter 
Potential Clinical Importance Range (PCI) 
Unit 
Systolic Blood Pressure 
< 85 or > 160 
mmHg 
Diastolic Blood Pressure 
< 45 or > 100 
mmHg 
Heart Rate 
< 40 or > 110 
bpm 
 
PCI for patients 


 
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Hematology Analyte 
Effect 
Relative – Low 
(Multipliers of LLN) 
Relative – High 
(Multipliers of ULN) 
White Blood Cell Count 
(x109/ L) 
 
0.5 
2 
Neutrophil Count (x109/ L) 
 
0.75 
 
Hemoglobin (g/L) 
Low 
< -25 decrease from baseline 
Male 
 
1.1 
Female 
 
1.1 
Hematocrit (Ratio of 1) 
Low 
< -0.1 decrease from baseline 
Male 
 
1.1 
Female 
 
1.1 
Platelet Count (x109/ L) 
 
0.5 
1.75 
Lymphocytes (x109/ L) 
 
0.75 
 
 
Chemistry Analyte 
Effect 
Relative – Low 
(Multipliers of LLN) 
Relative – High 
(Multipliers of ULN) 
Calcium (mmol/L) 
 
0.85 
1.1 
Creatinine (mol/L) 
 
 
 
High 
≥ 22 increase from baseline 
(Note 22 mol/L ≈ 0.25 mg/dL) 
Glucose (mmol/L) 
 
0.5 
2 
Potassium (mmol/L) 
 
.75 
1.25 
Sodium (mmol/L) 
 
.9 
1.1 
 
Liver Function Test 
Analyte 
Effect 
Potential Clinical Importance (PCI) 
Range 
Unit 
ALT/SGPT 
High 
 2x ULN 
U/L 
AST/SGOT 
High 
 2x ULN 
U/L 
AlkPhos 
High 
 2x ULN 
U/L 
T Bilirubin 
High 
 1.5xULN 
µmol/L 
T. Bilirubin + ALT 
High 
 1.5xULN T. Bilirubin 
+ 
 2x ULN ALT 
µmol/L 
 
U/L 
 


 
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ECG Values of Potential Clinical Importance (DFU Patients) 
ECG Parameter 
Potential Clinical Importance Range (PCI) 
Unit 
Absolute QTc interval 
>500 for patients with baseline bundle branch block 
(BBB) and >450 for patient without a baseline BBB 
msec 
Increase from baseline QTc 
>60 
msec 
QRS interval 
 >110 
msec 
 
 
Vital Sign Values of Potential Clinical Importance (DFU Patients) 
Vital Sign Parameter 
Potential Clinical Importance Range (PCI) 
Unit 
Systolic Blood Pressure 
< 85 or > 160 
mmHg 
Diastolic Blood Pressure 
< 45 or > 100 
mmHg 
Heart Rate 
< 40 or > 110 
bpm 
 
 
 
9. 
STUDY POPULATION 
Study population data will be summarised by, or under the direct auspices of Clinical 
Statistics GlaxoSmithKline. 
The precise format and content of Study Population tables are shown in Section 15.1.1 
of this RAP. 
The study population tables will use the “All Subjects” population unless otherwise 
specified. 
 
 
10. 
SAFETY ANALYSES 
Safety analysis will be based on the All Subject Population. Safety parameters include 
adverse events, clinical laboratory evaluations, vital signs, ECGs, and physical 
examinations if data permit. 
 
Clinical monitoring and laboratory safety will be reviewed by the Investigator but will 
not be formally analyzed. Vital signs and ECG data will be summarized by dose and 
time point. 
 
The following safety data will be presented in tabular and/or graphical format and 
summarized descriptively according to GSK’s IDSL standards by, or under the direct 
auspices of Clinical Statistics, Quantitative Science, GSK. 


 
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• Exposure data 
• Adverse events (AEs) 
• Laboratory data, including hematology, clinical chemistry, routine urinalysis, 
lipase, amylase,  
• Vital signs (systolic BP, diastolic BP,and pulse rate), weight/height 
• ECG data 
 
 
11. 
PHARMACOKINETIC ANALYSES 
The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be 
performed by, or under the direct auspices of, Clinical Pharmacology Science and 
Study Operations (CPSSO), GlaxoSmithKline. 
The merge of PK concentration data, randomisation and CRF data will be performed 
by, or under the direct auspices of, Clinical Statistics (programmer), GlaxoSmithKline.   
Derivation of pharmacokinetic parameters will be performed by, or under the direct 
auspices of, Clinical Pharmacology Modelling and Simulation (CPMS), 
GlaxoSmithKline. 
Statistical analysis of pharmacokinetic parameters will be performed by, or under the 
direct auspices of, Clinical Statistics (Statistician), GlaxoSmithKline. 
Listings will be generated and summary statistics (n, arithmetic mean, standard 
deviation, minimum, median, maximum) will be calculated for each derived plasma 
pharmacokinetic (PK) parameter by regimen and time. PK parameters are listed in 
Section 2.1.1.  
 
11.1. 
Drug Concentration Measures  
Concentrations of GSK1278863 in plasma and its metabolites [M2, M3, M4, M5, M6 
and M13] will be listed and summarised by treatment group and nominal time.  
Standard summary statistics will be calculated (i.e. mean and associated 95% 
confidence interval, standard deviation, median, minimum and maximum).  Refer to 
the standard operating procedure, SOP-CPK-0001, and the guidance document, GUI-
CPK-3001, for more information regarding the treatment of plasma concentrations 
below the assay’s lower limit of quantification (NQ).  For this study, when there is 


 
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more than one embedded NQ, NQ will be treated as zero rather than missing or 
truncated.  Leading and tailing NQ will be treated per SOP. 
Individual plasma concentration-time profiles and median/mean profiles by treatment 
group will be plotted.  Each of the figures will contain one plot on the untransformed 
scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. log-linear plot).  
Plasma drug concentrations excluded from the PK analysis (i.e. PK parameter 
calculation) will be excluded from the summaries and figures.  These concentrations 
will be flagged in the listing of PK concentration data. 
11.2. 
Deriving and Summarizing Pharmacokinetic Parameters 
For subjects in each active treatment group the following pharmacokinetic parameters 
will be determined from the plasma concentration-time data for GSK1278863 and its 
metabolites [M2, M3, M4, M5, M6 and M13]. The pharmacokinetic parameters will 
be calculated by standard non-compartmental analysis according to current working 
practices and using WinNonlin Version 5.2 or higher.  All calculations of non-
compartmental parameters will be based on actual sampling times. 
1. The first occurrence of the maximum observed plasma concentration determined 
directly from the raw concentration-time data (Cmax). 
2. The time at which Cmax is observed will be determined directly from the raw 
concentration-time data (tmax).  
3. The area under the plasma concentration-time curve to the last quantifiable 
concentration (AUC(0-t)), will be determined using the linear trapezoidal rule for 
increasing concentrations and the logarithmic trapezoidal rule for decreasing 
concentrations. 
4. The AUC extrapolated to infinity (AUC(0-)) will be calculated, where data 
permit, as the sum of AUC(0-t) and Ct/z, where Ct is the observed plasma 
concentration obtained from the log-linear regression analysis of the last 
quantifiable time-point and z is the terminal phase rate constant.  The percentage 
of the AUC(0-) that is extrapolated will be calculated as the ratio of [AUC(0-) 
minus AUC(0-t)] to AUC(0-). 
5. The apparent terminal elimination half-life (t1/2) obtained as the ratio of ln2/z, 
where z is the terminal elimination phase rate constant estimated by linear 
regression analysis of the log transformed concentration-time data (if data 
permits) 
6. Trough concentration (Cτ) will be measured as the lowest concentration prior to  
dosing  on Day 18 in Part B.  Summary statistics of trough concentration will be 
used as an informal assessment of the attainment of steady state. 
 


 
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7. If data permit, the metabolite:parent AUC and Cmax ratios (corrected for 
molecular weight) will be calculated.  
Time profile for PK concentration for individual subjects will be plotted by dose 
regimen and study day.  Mean (SD) plot for PK concentration will be generated by 
dose regimen and day.      
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D. Statistical analyses of the pharmacokinetic 
parameter data will be the responsibility of Clinical Statistics, Quantitative Science, 
GlaxoSmithKline. 
 
 
12. 
PHARMACODYNAMIC AND BIOMARKERS 
ANALYSES 
 
12.1. 
Pharmacodynamic Analyses for DFU  
12.1.1. 
Physical parameters of the wound  
Wound volume/area, after log-e transformation if appropriate, will be analyzed using a 
repeat measures ANOVA model, fitting terms for regimen, visit,  interaction of 
regimen and visit,  and with compound symmetry variance-covariance structure, for 
Part B as data permit. The repeat measures ANOVA  model will be used to produce 
least squares means, point estimates, and 95% confidence intervals for each post-dose 
time point vs Day 1 predose, , each post-repeat-dose time point vs Day 8 predose, as 
well as for the baseline corrected active versus placebo  and active vs standard care 
(Part B)  for each post-dose visiting time point(see Exhibit A) 
Physical parameters of the wound will be summarized (for continuous measures) or 
tabulated (for categorical measures) by regimen and visit for Part A and Part B 
respectively.  Descriptive summary stats include n, arithmetic mean and corresponding 
95% confidence interval, standard deviation, minimum, median, maximum.  
Mean (SE) plots will be produced by regimen, including part A  and part B across 
study day (day 1, day 4 and follow-up for part A, Day 1 and Day 8 for part B), as well 
as for Part B alone, by  regimen and study days  (Exhibit H) 
Physical parameters of the wound will be analyzed and summarized separately by 
methods (Acetate or photo). 
 


 
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12.1.2. 
Clinical parameters of the wound  
Clinical parameters of the wound will be summarized (for continuous measures) or 
tabulated (for categorical measures) by regimen and visit for Part A and Part B 
respectively.  Descriptive summary stats include n, arithmetic mean and corresponding 
95% confidence interval, standard deviation, minimum, median, maximum. Tabulation 
for categorical endpoints will be presented in a frequency table (n, % by regimen and 
visiting time). 
Similar ANCOVA model as 12.1.1, as well as Mean (SE) plot, may apply to 
(continuous) clinical parameters of the wound as data permit.   
12.2. 
Biomarker Analyses 
12.2.1. 
Wound fluid biomarkers: Cytokines 
Change from baseline wound fluid biomarkers, including cytokines, growth factors 
and proteases, after log-e transformation if appropriate (i.e. change from baseline 
becomes log ratio on the loge transformed data), will be analyzed separately for Part A 
DFU and Part B. 
Descriptive statistics (n, arithmetic mean and corresponding 95% confidence interval, 
standard deviation, minimum, median, maximum) will be calculated by regimen and 
visiting time points. In addition, in cases that loge transformed data are used in the 
analysis, geometric means (and corresponding 95% confidence interval) and between 
subject coefficients of variation (CVb) will be calculated by regimen and visit time 
points, where Geometric mean = exp (mean on loge-scale) CVb(%) = sqrt[exp(sd2)-
1]x100 where sd is the standard deviation of the loge-transformed data. 
Mean (SE) plots will be produced by regimen agent across visit.  
12.2.2. 
Wound fluid biomarkers: Bioburden  
Similar summary descriptive statistics and mean SE plot by regimen and visit will be 
produced (see Section 12.2.1). 
 
12.2.3. 
Gene expression in the DFU tissue  
The qPCR data from the forsyth vendor will be analysed by target science and the 
finding will be summarized in a separate report. 
12.2.4. 
Biomarkers of angiogenesis and blood flow and oxygen 
Similar summary descriptive statistics and mean SE plot by regimen and visit will be 
produced (see Section 12.2.1). 


 
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12.2.5. 
Circulating biomarkers of systemic HIF activation 
Summary descriptive statistics and mean SE plot by regimen and visit will be 
produced (see Section 12.2.1). 


 
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13. 
REFERENCES 


 
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14. 
ATTACHMENTS 
14.1. 
Table of Contents for Data Display Specifications 
14.1.1. 
Study Population 
Table 
No. 
Population 
IDSL No. / 
Example 
Shell 
Title  
Additional 
Programming Notes 
Deliverable 
Priority 
1.01  
All Subjects 
DM1 
Summary of Demographic Characteristics 
 
SAC, in stream  
1.02  
Enrolled 
DM11 
Summary of Age Ranges 
 
 
1.03  
All Subjects 
IE1 
Summary of Inclusion/Exclusion Criteria Deviations 
 
SAC 
1.04  
All Subjects 
DM5 
Summary of  Race and Racial Combinations 
 
SAC 
1.05  
All Subjects 
ES1 
Summary of Subject Disposition 
 
SAC, in stream 
1.06  
All Subjects 
ES6 
Summary of Reasons for Run-In Failure 
 
SAC, in stream 
1.07 
Enrolled 
NS1  
Summary of Number of Subjects by Country and Site 
ID  
 
SAC 


 
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14.1.2. 
Safety Figures & Tables 
Tables  
Table 
No. 
Population 
IDSL No. / 
Example Shell  
Title  
Programming Notes 
Deliverable 
Priority 
10.xx 
All Subjects 
Ex1 
Summary of Exposure data for Part A 
 
SAC, in stream 
10.xx 
All Subjects 
Ex1 
Summary of Exposure data for Part B 
 
SAC, in stream 
10.xx 
All Subjects 
AE1 
Summary of All Adverse Events  
 
SAC, in stream 
10.xx 
All Subjects 
AE1 
Summary of Drug Related Adverse Events  
 
SAC, in stream 
10.xx 
All Subjects 
AE1 
Summary of AEs Leading to Withdrawal  
 
SAC, in stream 
10.xx 
All Subjects 
AE5 
Summary of Adverse Events by Maximum Intensity 
 
SAC, in stream 
10.xx 
All Subjects 
LB1 
Summary of Chemistry Data 
 
SAC 
10.xx 
All Subjects 
LB1 
Summary of Hematology Data 
 
SAC 
10.xx 
All Subjects 
VS1 
Summary of Vital Signs 
 
SAC, in stream 
10.xx 
All Subjects 
EG2 
Summary of ECG Values  
 
SAC, in stream 
10.xx 
All Subjects 
LB2 
Summary of Hematology Data Outside the Reference 
Range 
 
SAC 
10.xx 
All Subjects 
LB2 
Summary of Chemistry Data Outside the Reference 
Range 
 
SAC 
10.xx 
All Subjects 
VS2  
Summary of Vital Sign Data Outside Clinical Concern 
Range 
 
SAC 
10.xx 
All Subjects 
EG2 
Summary of Change from baseline ECG Values  
 
SAC, in stream 
10.xx 
All Subjects 
EG1 
Summary of ECG Findings  
 
SAC, in stream 
10.xx 
All Subjects 
Exhibit F 
Summary of raw EPO data by treatment 
 
SAC, in stream 
10.xx 
All Subjects 
AE15 
Summary of Common Non-Serious Adverse Events by 
System Organ Class and Preferred Term 
AE is considered 
common if more than 
one subject experiences 
it regardless of treatment 
SAC 
10.xx 
All Subjects 
AE16 
Summary of Serious Events by System Organ Class 
and Preferred Term (Number of Subjects and 
Occurrences)  
 
SAC 


 
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Figures 
Figure 
No. 
Population 
IDSL  No. / 
Example Shell 
Title  
Programming 
Notes 
Deliverable 
Priority 
10.xx 
All Subjects 
Exhibit E 
The Time course of EPO values of treatment period  
 
SAC, in stream 
 


 
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14.1.3. 
Pharmacokinetic Figures and Tables 
 
Tables 
Table 
No. 
Population 
IDSL No. / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Priority 
11.xx 
PK 
PKCT1 
Summary of {Matrix} GSK1278863 Pharmacokinetic 
Concentration-Time Data   
By treatment and visit time 
SAC, in stream 
11.xx 
PK 
PKCF6  
Individual Subject Plasma GSK1278863A Concentration-
Time Plots – by Treatment Regimen  
1. X-axis displays actual 
relative time. 
2.  Include line for LLQ along 
with footnote defining LLQ 
value. 
SAC 
 


 
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14.1.4. 
Pharmacodynamic Figures and Tables 
 
Figures 
Figure 
No. 
Population 
IDSL No. / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
Priority 
12.xx 
PD 
Exhibit H 
Plot of Mean(SE) PD Endpoints - Skin Perfusion 
Pressure(mmHg) and Pulse Volume Recording(mmHg) 
 
SAC, in stream 
12.xx 
PD 
Exhibit H 
Plot of Mean(SE) PD Endpoints - Wound Area(cm2) 
 
SAC, in stream 
12.xx 
PD 
Exhibit H 
Plot of Mean(SE) PD Endpoints - Wound Depth(mm) 
 
SAC, in stream 
12.xx 
PD 
Exhibit H 
Plot of Mean(SE) PD Endpoints - Wound Volume(mm3) 
 
SAC, in stream 
12.xx 
PD 
Exhibit H 
Plot of Mean(SE) Exploratory Biomarker Parameters  
One plot per endpoint.  
SAC 
12.xx 
PD 
Exhibit Y 
Spline Plot of Percent Change from Baseline of Wound 
Area  
A plot for photo and for acetate 
SAC 
Tables 
Table 
No. 
Population 
IDSL No. / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
Priority 
12.xx 
PD 
Exhibit A 
Point Estimate and 95% Confidence Interval for 
the Comparison of wound size changes in part 
B (unit) 
Results may report in one single table for 
all the physical parameters of wound 
SAC, in stream 
12.xx 
PD 
Exhibit G 
Summary Statistics of PD Endpoints - Skin 
Perfusion Pressure(mmHg) and Pulse Volume 
Recording(mmHg) 
 
SAC, in stream 
12.xx 
PD 
Exhibit G 
Summary Statistics of PD Endpoints - Wound 
Area(cm2) 
for wound area and wound volume. 
Wound area is done by photo and 
acetate 
SAC, in stream 
12.xx 
PD 
Exhibit G 
Summary Statistics of PD Endpoints - Wound 
Depth(mm) 
 
SAC, in stream 


 
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Table 
No. 
Population 
IDSL No. / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
Priority 
12.xx 
PD 
Exhibit G 
Summary Statistics of PD Endpoints - Wound 
Volume(mm3) 
for wound area and wound volume. 
Wound area is done by photo and 
acetate 
SAC, in stream 
12.xx 
PD 
Exhibit Z 
Summary of Exploratory Biomarker Parameters 
 
SAC 


 
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14.1.5. 
ICH Listings 
Table 
No. 
Population 
IDSL No. / 
Example 
Shell  
Title  
Programming Notes 
Deliverable 
Priority 
1 
 
All Subjects 
DM4 
Listing of Demographic Characteristics 
 
SAC, in stream 
2 
 
All Subjects 
 
Listing of all Clinical Chemistry Laboratory Data for Subjects 
with Abnormalities of Potential Clinical Importance 
 
SAC 
3 
 
All Subjects 
IE3 
Listing of Subjects with Inclusion/exclusion Criteria 
Deviations 
 
SAC 
4 
 
All Subjects 
DM10 
Listing of Race 
 
SAC 
5 
 
All Subjects 
CM3 
Listing of Concomitant Medications by Generic Term 
 
SAC 
6 
 
All Subjects 
ES3 
Listing of Reason for Withdrawal 
 
SAC, in stream 
7 
 
All Subjects 
DV1A 
Listing of Subjects with study protocol Deviations 
 
SAC 
8 
 
All Subjects 
EX3 
Listing of Exposure Data 
 
SAC 
9 
 
All Subjects 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
 
SAC 
10  
All Subjects 
AE8 
Listing of all Adverse Events 
 
SAC 
11  
All Subjects 
AE9a 
Listing of AEs with No Resolution Date 
 
SAC 
12  
All Subjects 
LB5 
Listing of Clinical Chemistry of Potential Clinical Importance 
 
SAC 
13  
All Subjects 
LB12 
Listing of all Clinical Hematology Laboratory Data for 
Subjects with Abnormalities of Potential Clinical Importance 
 
SAC 
14  
All Subjects 
CP_VS4 
Listing of All Vital Signs for Subjects with Values of Potential 
Clinical Importance 
 
SAC 


 
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Table 
No. 
Population 
IDSL No. / 
Example 
Shell  
Title  
Programming Notes 
Deliverable 
Priority 
15  
All Subjects 
CP_VS4 
Listing of Vital Signs of Potential Clinical Importance 
 
SAC 
16  
All Subjects 
CP_EG6a 
Listing of All ECG Values for Subjects with a Value of 
Potential Clinical Importance  
 
SAC 
17  
All Subjects 
CP_EG3 
Listing of ECG Values of Potential Clinical Importance 
 
SAC 
18  
All Subjects 
CP_EG5 
Listing of Abnormal ECG Findings 
 
SAC 
19  
All Subjects 
IE4 (XO) 
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations 
 
SAC 
20  
Enrolled 
ES7 
Listing of Reasons for Run-In Failure 
 
SAC 
21  
All Subjects 
Exhibit Q 
Listing of prior Medications 
 
SAC 
22  
All Subjects 
AE8 
Listing of Serious Adverse Events 
 
SAC, in stream 


 
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14.1.6. 
 Other Listings 
Table 
No. 
Population 
IDSL No. / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Priority 
1 
 
PD 
Exhibit N 
Listing PD Endpoints by Treatment and Time Points for Part 
A and Part B Respectively - Skin Perfusion Pressure and 
Pulse Volume Recording 
 
SAC 
2 
 
PD 
Exhibit N 
Listing PD Endpoints by Treatment and Time Points for Part 
A and Part B Respectively - Wound Area(cm2) 
 
SAC 
3 
 
PD 
Exhibit N 
Listing PD Endpoints by Treatment and Time Points for Part 
A and Part B Respectively - Wound Depth(mm) 
 
SAC 
4 
 
PD 
Exhibit N 
Listing PD Endpoints by Treatment and Time Points for Part 
A and Part B Respectively - Wound Volume(mm3)   
 
SAC 
5 
 
PD 
 
SAS output for mixed effects models Analysis of physical 
characteristics of wound healing  
 
SAC, in stream 
6 
 
All Subjects 
AE2 
Listing of Relationship Between System Organ Class 
and Verbatim Text 
 
SAC, in stream 
7 
 
PD  
LB12 
Listing of Exploratory Biomarker Parameters 
List all data, flag if out of range  
SAC 
 
 


 
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15.2 Data Display Specifications (Example Shells) 
Exhibit A  Point Estimate and 95% Confidence Interval for the Comparison of change  of wound volume/Area (unit) in Part B   
Parameter 
Comparison 
Group 
Estimates (units)  
95% CI 
P value 
Wound volume (unit) 
Day 7 vs Day 1 
Active  
xx.xx 
(xx.xx, xx.xx) 
0.xxx 
Placebo / Standard of Care 
xx.xx 
(xx.xx, xx.xx) 
0.xxx 
Day 15 vs Day 1  
Active 
xx.xx 
(xx.xx, xx.xx) 
0.xxx 
Placebo / Standard of Care 
xx.xx 
(xx.xx, xx.xx) 
0.xxx 
Follow-Up vs Day 1  
Active 
xx.xx 
(xx.xx, xx.xx) 
0.xxx 
Placebo / Standard of Care 
xx.xx 
(xx.xx, xx.xx) 
0.xxx 
Active vs Placebo/SoC 
Day 7–Day 1 
xx.xx 
(xx.xx, xx.xx) 
0.xxx 
Day 15–Day 1 
xx.xx 
(xx.xx, xx.xx) 
0.xxx 
Follow-Up– Day 1 
xx.xx 
(xx.xx, xx.xx) 
0.xxx 
This is a mock-up table, in addition to the end of treatment, estimates of other visits vs day 1 should also be produced in this analysis. 
Similar table will be generated for other physical and clinical characteristics including healing rate, as data permit  
 
Protocol 
: [PWH115760] 
Population 
: [PD Population] 
 
 


 
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Exhibit H 
 
Note: This is a mock up, visiting time schedule will vary for different pd endpoints. One endpoint per plot.    
 


 
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Exhibit I 
 
 
 
0
0.2
0.4
0.6
0.8
1
Day21
Follow-up
Bar-Chart  of Mean Healing Rates (+SE) by 
Regiment at The End of Treatment and 
Follow-up 
PBO
SOC
PHI Dose1
PHI Dose3
PHI Dose1
NIHSS Scores


 
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Exhibit J Kaplan-Meier of comparisons of probability of wound healing 
 
  
 
 
 
Note: this is a mock-up, this plot may be produced with individual active (GSK1278863) regimen vs placebo and soc or combined active 
doses vs placebo and soc as data permit and appropriate to the data. 


 
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Summary of Chemistry and PD Data 
 
 
Parameter 
 
Time points  
 
Summary 
Statistics 
 
 
GSK 1278863 
 
 
Placebo 
 
 
 
 
 
 
 
 PD endpoint 
(units) 
Day 1 predose  
N 
xxx 
Xxx 
 
 
 
n 
xxx 
Xxx 
 
 
 
Arith. Mean 
xxx.x 
xxx.x 
 
 
 
95% CI 
(xxx.x,xxx.x) 
(xxx.x,xxx.x) 
 
 
 
SD(arith) 
xxx.x 
xxx.x 
 
 
 
Geo. Mean* 
xxx.x 
xxx.x 
 
 
 
95% CI* 
(xxx.x,xxx.x) 
(xxx.x,xxx.x) 
 
 
 
SD(log)* 
xxx.x 
xxx.x 
 
 
 
%CVb 
xxx.x 
xxx.x 
 
 
 
Median 
xxx.x 
xxx.x 
 
 
 
Min 
xxx.x 
xxx.x 
 
 
 
Max 
xxx.x 
xxx.x 
 
 
 
:::::::::::::::::::::::::::: 
 
 
 
 
 
 
 
 
 
* Only for the endpoints which are log transformed in statistical analysis. 
 
 
 
 


 
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Exhibit J 
Figure 11.xx 
Individual Plasma GSK1278863 concentration by dose regimen and Day 
 
 
 
   
 
 
 
P
P
D


 
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Exhibit G 
Summary of Chemistry and PD Data 
Period Treatment 
Wound 
method 
N 
Visit 
Planned 
Time point 
n 
Mean 
SD 
Median 
Min. 
Max. 
Placebo DFU 
Acetate 
3 
PART A PERIOD 1 
DAY 1 
PREDOSE 
3 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
72 H 
2 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
PART A PERIOD 1 
DAY 2 
PREDOSE 
3 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
72 H 
2 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
Photo 
3 
PART A PERIOD 1 
DAY 1 
PREDOSE 
3 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
72 H 
2 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
PART A PERIOD 1 
DAY 2 
PREDOSE 
3 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
72 H 
2 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
0.1% of 25 mg/cm2  
Active 
Acetate 
3 
PART A PERIOD 1 
DAY 1 
PREDOSE 
3 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
72 H 
2 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
PART A PERIOD 1 
DAY 2 
PREDOSE 
3 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
72 H 
2 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
Photo 
3 
PART A PERIOD 1 
DAY 1 
PREDOSE 
3 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
72 H 
2 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
PART A PERIOD 1 
DAY 2 
PREDOSE 
3 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
72 H 
2 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
 
 


 
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Note: X-axis will include visit2 predose and visit6 end of treatment; label drug A as: GSK 1278863 and drug B as placebo; one box plot 
will generated for each PD protein marker (HIF-1, PDK4, COX4,  etc. )    
 
 
Exhibit K 
Figure 11.xx 
Mean (+SD) plasma GSK1278863 concentration by dose regimen and day 


 
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Exhibit L 


 
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Summary of Chemistry and PD Data 
 
 
 
Parameter 
Visit 
Time 
 
Summary 
Statistics 
 
 
5 mg GSK1278863 
 
 
Placebo 
 
 
 
 
 
PD parameter (unit) 
Screening  
n 
Xxx 
Xxx 
 
 
Arith. mean 
xxx.x 
xxx.x 
 
 
95% CI 
(xxx.x,xxx.x) 
(xxx.x,xxx.x) 
 
 
SD(arith) 
xxx.x 
xxx.x 
 
 
Geo. Mean* 
xxx.x 
xxx.x 
 
 
95% CI* 
(xxx.x,xxx.x) 
(xxx.x,xxx.x) 
 
 
SD(log)* 
xxx.x 
xxx.x 
 
 
%CVb 
xxx.x 
xxx.x 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min 
xxx.x 
xxx.x 
 
 
Max 
xxx.x 
xxx.x 
 
 
::::::::: 
::::::::: 
::::::::; 
 
 
 
:::::::::: 
:::::::::: 
:::::::::: 
n 
Xxx 
Xxx 
 
Day 6 
Arith. mean 
xxx.x 
xxx.x 
 
 
95% CI 
(xxx.x,xxx.x) 
(xxx.x,xxx.x) 
 
 
SD(arith) 
xxx.x 
xxx.x 
 
 
Geo. Mean* 
xxx.x 
xxx.x 
 
 
95% CI* 
(xxx.x,xxx.x) 
(xxx.x,xxx.x) 
 
 
SD(log)* 
xxx.x 
xxx.x 
 
 
%CVb 
xxx.x 
xxx.x 
 
 
Median 
xxx.x 
xxx.x 


 
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Min 
xxx.x 
xxx.x 
 
 
Max 
xxx.x 
xxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note :This is just a mock-up, The same type of summary table will be generated for other PD endpoints, LAB 
parameters and other Blood/Urine Biomarkers, protein transcriptional biomarkers. Parameters from the same type 
of test (e.g. physical characteristics of wound) may be summarized and reported in one table. 
Change from baseline data will be summarized similarly by treatment and visiting timepoints (and simulation 
conditions if apply). GeoMean and 95% for the difference of log transformed should also be included in the 
change from baseline summary table, where Geomean will be a ratio estimate, i.e. exp[log(post) –log(baseline)]  
No other statistics (SD(log), %CVb, Median, Min and max) for log-transformed are needed in the change from 
baseline summary table. 
* Only for the endpoints which are log transformed in statistical analysis. 
 
 
 
 
 
 
 
 
 
 


 
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Exhibit Q List of Prior Medication  
 
PVD114272 
9.xxx 
PPD
PPD - This section has been excluded to protect patient privacy.


 
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Exhibit Y Percent Area Change from Baseline of Wound Area  
 
 
 


 
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Exhibit Z Table of Forsyth Endpoints  
 
Biomaker 
Treatment 
Day 1 
Day 7 
Day 15 
Change from Day 1 to Day 
15 
Mean 
SE 
Mean 
SE 
Mean 
SE 
Mean 
SE 
Angiopoietin-2 
Active  
x.x 
x.xx 
x.x 
x.xx 
x.x 
x.xx 
x.x 
x.xx 
 
Placebo/SoC x.x 
x.xx 
x.x 
x.xx 
x.x 
x.xx 
x.x 
x.xx 
 
 
 


 
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Exhibit R 
Listing of subjects who entered multiple cohorts in the study 
Subseqent  
Initial 
subjid/ 
Sex/ 
# of  
Rand #/ 
Rand #/ 
Initial 
Age/ 
cohorts  
cohort/ 
cohort/ 
Inv 
Subjid  
Race 
Entered 
trt seq 
trt seq 
Note: for those with multi-cohort entrances, the initial subject number, i.e. the very first number assigned to the subject when he/she first 
entered the study, will be used as the subject ID  for the subject.    
PPD - This section has been excluded to protect patient privacy.