Clinical trial NCT02723786
Conditions: Kidney Transplantation (Status Post)
Keywords: Delayed Graft Function Renal Transplantation Prevention GSK1070806
Sponsor: GlaxoSmithKline
Start date: 2016-08-27; Completion date: 2018-03-06
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase 2 study to evaluate the efficacy, safety, tolerability and pharmacokinetics of GSK1070806 in subjects undergoing renal transplantation. GSK1070806 is an anti-interleukin 18 (IL18) monoclonal antibody, which binds to IL-18 and inhibits signaling through the IL-18 receptor. Recipients of donor kidneys, retrieved after circulatory death of the donor, will be administered a single intravenous infusion of GSK1070806 to test whether inhibition of IL-18 can reduce the rate of Delayed Graft Function (DGF) and graft rejection. Subjects will be followed for 12 months post dose/transplant. Up to 40 adult subjects will be enrolled in this study.

Detailed description:

Arms: arm 1: Subjects received a single dose of 3 milligram per kilogram (mg/kg) intravenous (IV) infusion of GSK1070806 administered prior to kidney allograft reperfusion. Subjects also received a combination immunosuppression comprized of basiliximab; mycophenolate mofetil (MMF) or aziothioprine; tacrolimus; and corticosteroids based on the clinical judgment of the investigator.
Interventions: intervention 1: GSK1070806 intervention 2: 1) basiliximab 2) mycophenolate mofetil (MMF) OR azathioprine 3) tacrolimus 4) corticosteroids
Intervention descriptions: intervention 1: Injectable solution of 100 milligram/millilitre (mg/mL), administered as a single dose of 3 milligram/kilogram (mg/kg) (maximum of 10 mg/kg) diluted in 100 mL sterile IV infusion bag of 0.9% Sodium Chloride. intervention 2: This immunosuppressant regimen may be revised based on the clinical judgment of the investigator including titration of tacrolimus levels.

Protocol documents:
Prot_001.pdf: 
2015N240632_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
204824
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase 2 Pilot, Multicenter, Single Arm Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of 
GSK1070806 plus Standard of Care for the Prevention of 
Delayed Graft Function in Adult Subjects After Renal 
Transplantation
Compound Number:
GSK1070806
Development Phase:
IIA
Effective Date:
04-MAY-2017
Protocol Amendment Number:  03
Author (s):
Revision Chronology
GlaxoSmithKline Document 
Number
Date
Version
2015N240632_00
2015-NOV-30
Original
2015N240632_01
2016-FEB-03
Amendment No. 1
Updates to clarify select safety criteria; completion of abbreviations table.
2015N240632_02
2016-AUG-09
Amendment No. 2
Eligibility Criteria: Allowance of 2nd kidney transplant recipients for enrollment, removal of upper age 
limits, addition of definition for ‘surgical damage’ related to transplant organ retrieval; and clarifications to 
interim analysis and DCD categorization type.
2015N240632_03
2017-MAR-22
Amendment No. 3
Dose escalation: clarifications based on data from patients receiving 3mg/kg dose to escalate to higher 
dose.
2015N240632_04
2017-MAY-04
Re-Publishing
Eligibility Criteria: Additional exclusion criteria have been added to reduce the chance of enrolling  
patients with high cardiac risk profiles. Dose escalation: Based on emergent efficacy and PKPD data, the 
number of subjects required to be treated prior to a decision to escalate dose has been reduced, and stopping 
criteria following dose escalation have been amended. 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


2015N240632_04
CONFIDENTIAL
204824
2
SPONSOR SIGNATORY
Laura A Demopoulos, MD
Date
Director, Clinical Development


2015N240632_04
CONFIDENTIAL
204824
3
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site 
Address
Primary 
Medical 
Monitor 
GSK Upper 
Merion, 709 
Swedeland 
Road, King 
of Prussia,
PA 19406
Secondary 
Medical 
Monitor
GSK Upper 
Merion, 709 
Swedeland 
Road, King 
of Prussia,
PA 19406
Sponsor Legal 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):  2015-002812-33
PPD


2015N240632_04
CONFIDENTIAL
204824
4
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204824
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


2015N240632_04
CONFIDENTIAL
204824
5
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 204824........................................................8
2.
INTRODUCTION....................................................................................................10
2.1.
Overview.....................................................................................................10
2.2.
Background ................................................................................................10
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................12
4.
STUDY DESIGN ....................................................................................................14
4.1.
Overall Design ............................................................................................14
4.2.
Treatment Arms and Duration.....................................................................14
4.3.
Type and Number of Subjects.....................................................................15
4.4.
Design Justification.....................................................................................15
4.5.
Dose Justification........................................................................................15
4.6.
Benefit:Risk Assessment ............................................................................16
4.6.1.
Risk Assessment .........................................................................17
4.6.2.
Benefit Assessment.....................................................................22
4.6.3.
Overall Benefit/Risk Conclusion...................................................22
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............22
5.1.
Inclusion Criteria.........................................................................................22
5.2.
Exclusion Criteria........................................................................................24
5.3.
Screening/Baseline/Run-in Failures............................................................27
5.4.
Withdrawal/Stopping Criteria.......................................................................27
5.4.1.
Liver Chemistry Management ......................................................28
5.4.2.
QTc Evaluation Criteria................................................................28
5.5.
Safety Interim Analysis ...............................................................................29
5.6.
Subject and Study Completion....................................................................29
6.
STUDY TREATMENT ............................................................................................29
6.1.
Investigational Product and Other Study Treatment....................................29
6.2.
Treatment Assignment................................................................................30
6.3.
Blinding.......................................................................................................30
6.4.
Packaging and Labeling..............................................................................30
6.5.
Preparation/Handling/Storage/Accountability..............................................30
6.6.
Compliance with Study Treatment Administration.......................................31
6.7.
Treatment of Study Treatment Overdose....................................................31
6.8.
Treatment after the End of the Study ..........................................................31
6.9.
Lifestyle and/or Dietary Restrictions............................................................31
6.10.
Concomitant Medications and Non-Drug Therapies....................................31
6.10.1.
Standard Immunosuppressive Therapy .......................................32
6.10.2.
Management of low white cell count ............................................32
6.10.3.
Graft Dysfunction/Graft rejection..................................................32
6.10.4.
Prophylaxis and Surveillance for Infection....................................32
6.10.4.1.
Pneumocystis and Fungal Infection
Prophylaxis.................................................................32
6.10.4.2.
Cytomegalovirus Infection ..........................................32
6.10.4.3.
BK virus......................................................................33


2015N240632_04
CONFIDENTIAL
204824
6
6.11.
Prohibited Medications and Non-Drug Therapies........................................33
6.11.1.
Vaccines......................................................................................33
6.11.2.
Concomitant Medications.............................................................33
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................34
7.1.
Time and Events Table...............................................................................35
7.2.
Screening and Critical Baseline Assessments ............................................37
7.3.
Efficacy.......................................................................................................37
7.4.
Safety .........................................................................................................37
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........37
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................38
7.4.1.2.
Method of Detecting AEs and SAEs ...........................38
7.4.1.3.
Follow-up of AEs and SAEs........................................38
7.4.1.4.
Cardiovascular and Death Events ..............................39
7.4.1.5.
Regulatory Reporting Requirements for SAEs............39
7.4.2.
Pregnancy ...................................................................................39
7.4.3.
Physical Exams ...........................................................................40
7.4.4.
Vital Signs....................................................................................40
7.4.5.
Electrocardiogram (ECG).............................................................40
7.4.6.
Clinical Safety Laboratory Assessments ......................................40
7.4.7.
Immunogenicity............................................................................41
7.5.
Pharmacokinetics .......................................................................................42
7.5.1.
Blood Sample Collection and Analysis.........................................42
7.5.2.
Renal Graft Biopsies....................................................................42
7.6.
Mechanistic Biomarker(s)/Pharmacodynamic Markers................................43
7.6.1.
Cytokines.....................................................................................43
7.6.2.
Renal Graft Biopsies....................................................................43
7.6.3.
Biomarkers relating to acute rejection..........................................43
7.6.4.
Clinical Biomarkers......................................................................43
7.6.4.1.
Urinary biomarkers of injury........................................43
7.6.4.2.
Renal preservation fluid sampling...............................44
7.6.5.
Circulating cellular phenotype (Cambridge only)..........................44
8.
DATA MANAGEMENT ...........................................................................................44
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................45
9.1.
Hypotheses.................................................................................................45
9.2.
Sample Size Considerations.......................................................................45
9.2.1.
Sample Size Assumptions ...........................................................45
9.2.2.
Sample Size Sensitivity................................................................46
9.2.3.
Sample Size Re-estimation or Adjustment...................................47
9.3.
Data Analysis Considerations .....................................................................47
9.3.1.
Analysis Populations....................................................................47
9.3.2.
Interim Analysis ...........................................................................48
9.4.
Key Elements of Analysis Plan ...................................................................50
9.4.1.
Primary Analyses.........................................................................50
9.4.2.
Secondary Analyses ....................................................................50
9.4.3.
Other Analyses ............................................................................50
9.4.4.
Safety Analyses...........................................................................50
9.4.5.
Pharmacokinetic Analyses...........................................................50


2015N240632_04
CONFIDENTIAL
204824
7
10. STUDY GOVERNANCE CONSIDERATIONS........................................................51
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............51
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................51
10.3.
Quality Control (Study Monitoring) ..............................................................52
10.4.
Quality Assurance.......................................................................................52
10.5.
Study and Site Closure ...............................................................................52
10.6.
Records Retention......................................................................................53
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................53
11. REFERENCES.......................................................................................................55
12. APPENDICES........................................................................................................60
12.1.
Appendix 1:  Abbreviations and Trademarks...............................................60
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................63
12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................66
12.3.1.
Definition of Adverse Events........................................................66
12.3.2.
Definition of Serious Adverse Events...........................................67
12.3.3.
Definition of Cardiovascular Events .............................................69
12.3.4.
Recording of AEs and SAEs ........................................................69
12.3.5.
Evaluating AEs and SAEs............................................................70
12.3.6.
Reporting of SAEs to GSK...........................................................71
12.4.
Appendix 4: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................72
12.4.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............72
12.4.2.
Collection of Pregnancy Information ............................................72
12.5.
Appendix 5: Protocol Amendment 1............................................................74
12.6.
Appendix 6: Protocol Amendment 2............................................................80
12.7.
Appendix 7: Protocol Amendment 3............................................................85


2015N240632_04
CONFIDENTIAL
204824
8
1.
PROTOCOL SYNOPSIS FOR STUDY 204824
Rationale
GSK1070806 is an anti-IL18 IgG1 monoclonal antibody, which binds to the IL-18 
cytokine and thereby inhibits signalling through the IL-18 receptor. In post renal 
transplantation patients urinary IL-18 levels are elevated, correlating with the incidence 
of delayed graft function (DGF). Signalling downstream of IL-18 has also been 
implicated in renal transplant rejection. 
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To assess the frequency of delayed graft 
function (DGF) in donation after circulatory 
death (DCD) renal transplant recipients 
treated with GSK1070806.

Proportion of subjects requiring dialysis 
during the first 7 days post transplant, 
(excluding requirement for dialysis due to 
hyperkalemia within first 24 post-operative 
hours).
Secondary

To assess graft function in DCD renal 
transplant recipients treated with 
GSK1070806.

Serum creatinine at baseline and over time 
post transplant.

Urine output at baseline and over time post 
transplant.

Proportion of subjects in the first 7 days 
with: 
-
Primary Non Function
-
Functional DGF
-
Intermediate Graft Function
-
Immediate Graft Function

To assess the effect of GSK1070806 on 
acute rejection risk, and rejection/PD 
biomarkers.

Proportion of subjects with episodes of 
biopsy-proven acute rejection.

Rejection biomarkers/ PD markers 
(including serum IP-10 and Mig) at 
baseline and over time post transplant.

To assess the effect of GSK1070806 on 
dialysis dependency and graft survival.

Number of dialysis events per patient in the 
first 30 days post transplant.

Proportion of subjects who are dialysis-
independent at visits up to 12 months post 
transplant.

To assess the safety and tolerability of 
GSK1070806 in renal transplant recipients.

AEs and SAEs
-
Clinical laboratory values
-
Vital signs


2015N240632_04
CONFIDENTIAL
204824
9
Objectives
Endpoints
-
Frequency, type and severity of 
infections

To assess the pharmacokinetics of 
GSK1070806 in renal transplant recipients.

Serum concentrations of GSK1070806 
over time, and derived pharmacokinetic 
parameters if feasible (AUC, Cmax). 

To assess the effect of GSK1070806 
administration on serum IL-18 levels.

Free, total, and GSK1070806 bound IL-18 
at baseline and over time post transplant.

To determine immunogenicity of 
GSK1070806 in renal transplant recipients.

Frequency of anti-drug antibodies (ADAs) 
before and after GSK1070806 
administration.

ADA titers.
Overall Design
Study 204824 is a phase 2, pilot, multicenter, single arm Bayesian sequential design 
study to evaluate the efficacy, safety, tolerability and pharmacokinetics of GSK1070806 
in patients undergoing renal transplantation. 
The primary endpoint is frequency of DGF defined by a requirement for dialysis (except 
as needed for hyperkalaemia during the first 24 hours) within the first 7 days post 
transplantation. The trial utilizes a Bayesian sequential design to test whether 
GSK1070806 lowers the frequency of DGF. As secondary objectives the protocol 
assesses the safety and tolerability of GSK1070806 in renal transplantation, graft 
function/survival (serum creatinine, urine output, dialysis events), the impact on 
indicators of acute rejection, as well as GSK1070806 pharmacokinetics, 
pharmacodynamics and immunogenicity. 
Treatment Arms and Duration
Participants will receive a single intravenous (IV) infusion of GSK1070806 administered 
prior to kidney allograft reperfusion, and will be followed for 12 months post dose. 
Type and Number of Subjects
Adult subjects (18 years of age and older). Dialysis-dependent, recipient of first or 
second time, single kidney-only, Donation after Circulatory Death (DCD) transplants, 
receiving a planned immunosuppressive standard of care comprised of basiliximab, 
mycophenolate mofetil (MMF) or azathioprine, tacrolimus and corticosteroids. DCD 
donor kidneys must be ‘controlled’ meeting either Maastricht Category 3 or 4 criteria. 
The number of subjects to be enrolled will be up to approximately 40. 


2015N240632_04
CONFIDENTIAL
204824
10
2.
INTRODUCTION
2.1.
Overview
GSK1070806 is an anti-IL18 IgG1 monoclonal antibody, which binds to the IL-18 
cytokine and thereby inhibits signalling through the IL-18 receptor. In patients post renal 
transplantation, urinary IL-18 levels may be elevated, correlating with the incidence of 
delayed graft function (DGF). Signalling downstream of IL-18 has also been implicated 
in renal allograft rejection. 
Recipients of DCD renal allografts will be administered a single infusion of 
GSK1070806 prior to reperfusion of the transplanted kidney, to test the hypothesis that 
inhibition of IL-18 can reduce the rate of DGF (primary endpoint) and episodes of graft 
rejection (secondary endpoints). Historic DGF rates and a Bayesian statistical approach 
have enabled this single arm interventional approach.
2.2.
Background
Acute kidney injury (AKI) complicates 5-10% of hospital admissions, and an increasing 
body of evidence shows that these acute insults are associated with short- and long-term 
increases in healthcare cost, morbidity and mortality [Rewa, 2014, Ryden, 2014, 
Lewington, 2013]. Survivors of AKI experience a risk of new chronic kidney disease of 
25.8 cases per 100 patient years, and a risk of end stage renal disease of 8.6 cases per 100 
patient years, which is also proportional to the severity of the AKI [Coca, 2014]. 
Accordingly, treatments affording renal protection in the acute setting are of significant 
interest.
Delayed graft function (DGF) after renal transplantation is a niche manifestation of AKI, 
defined as the failure of a transplanted kidney to function immediately in the wake of 
transplantation. Patients affected by DGF require dialysis pending the onset of renal 
function, and compared to those without DGF are at increased risk of graft failure at one 
year [Moers, 2009, Tapiawala, 2010]. Depending upon known risk factors (principally 
donor age, cold ischemic time, and whether organ donation follows brain death (DBD) or 
circulatory death (DCD)) the risk of DGF is between 25 and 50% [Summers, 2013]. 
Ischemic renal injury is the consequence of processes that result directly from cellular 
hypoxia (depletion of ATP, mitochondrial leakage, free radical toxicity, loss of 
membrane potentials) and from immune amplification of injury (stimulation of TLRs 
[toll-like receptors], cytokine release, complement activation, neutrophil and monocyte 
chemotaxis).
IL-18 is an inflammatory cytokine secreted in response to cellular injury or inflammatory 
stimulus [Gu, 1997].  Transcriptional control of IL-18 is uniquely regulated such that 
stores are available at rest for immediate release, which is dependent on cleavage from 
pro-IL-18 by caspase-1 [Puren, 1999, Tone, 1997]. IL-18 release then signals proximally 
in the pro-inflammatory cascade, inducing synthesis of IFN, TNFα, IL-6, IL-8, and IL-1 
amongst other cytokines [Puren, 1999, Fortin, 2009]. In addition to a role in activation of 
innate and adaptive immunity, IL-18 has been shown to be directly cytotoxic to renal 
tubular epithelial cells in vitro [Zhang, 2011]. 


2015N240632_04
CONFIDENTIAL
204824
11
Role of IL-18 in DGF: In large clinical cohorts, early rises in urinary IL-18 levels in the 
first few hours after renal insults correlate closely with the subsequent development of 
AKI both in native [Parikh, 2011] and transplanted [Hall, 2010] kidneys, and predict long 
term dysfunction [Hall, 2012, Coca, 2014]. Furthermore, emerging data has correlated 
IL-18 levels measured in organ preservation fluids with post-operative graft dysfunction. 
More direct evidence of a role in pathogenesis is derived from rodent models of 
experimental ischemic renal injury, in which disruption of IL-18 signalling by gene 
deletion, exogenous administration of neutralizing antiserum, genetic knock-in or 
exogenous administration of the IL-18 binding protein (IL-18BP, a neutralizing decoy 
receptor) are all protective [Melnikov, 2001, Melnikov, 2002, He, 2008, Wu, 2008]. 
However, some rodent studies have demonstrated no, or non-statistically significant, 
benefit of inhibiting IL-18 [Daemen, 2001; Shigeoka, 2010].
Role of IL-18 in allograft rejection: Renal biopsy samples from patients experiencing 
acute rejection have demonstrated strong staining for IL-18, and serum IL-18 levels are 
highly elevated compared with controls [Striz, 2005]. Furthermore, rodent studies using a 
mismatched cardiac allograft model demonstrated enhanced graft survival when subject 
to IL-18 neutralization [Dudler, 2007]. IL-18 was originally identified for its role in 
inducing IFN[Okamura, 1995], which is strongly implicated in Th1 polarization. Acute 
cell-mediated rejection has been defined as a CD4+ Th1 mediated process [Issa, 2010], 
where elevated levels of the downstream Th1 chemokine IP-10 have been shown to 
predict acute rejection episodes [Field, 2014, Zhang, 2014, Rabant, 2015]. IP-10 
inhibition was capable of prolonging graft survival in mismatched rodent transplantation 
models [Hancock, 2001], and in GSK1070806 clinical studies a reduction in IP-10 has 
been a key pharmacodynamic readout [see Investigators Brochure, GlaxoSmithKline 
Document Number WM2009/00047/04]. Thus, it is reasonable to hypothesize that 
neutralization of IL-18 causing downstream reductions in IP-10 levels may protect 
allografts from rejection. 
Clinical experience with IL-18 inhibitors: Recognition that IL-18 may play an important 
role in various diseases has led to the development of investigational therapies targeting 
IL-18 or its signalling pathways, which have been well tolerated in healthy subjects and 
patients with RA, Crohn’s disease, and plaque psoriasis [Tak, 2006; Mistry, 2014].  
In volunteers, single intravenous infusion doses of the anti-IL18 monoclonal antibody, 
GSK1070806, were well tolerated in both healthy and obese subjects. No differences in 
infections, immune system disorders or haematologic abnormalities were observed 
following single intravenous GSK1070806 infusions up to 10 mg/kg in 57 subjects when 
compared with placebo. Four subjects had SAEs (head injury, mild pericarditis [placebo 
group], kidney stones, pneumothorax) that were all considered unrelated to study 
treatment by the Investigator [Mistry, 2014]. 
GSK1070806 was also evaluated in subjects with type 2 diabetes, in which two repeat 
doses of GSK1070806, administered 28 days apart, were well-tolerated. The most 
frequently reported AE was nasopharyngitis which occurred in 11 subjects. Headache, 
diarrhea and hypertension were the second most frequently reported AEs, which occurred 
in 5 subjects each. None of the reported AEs was considered related to GSK1070806. 
The most frequently reported MedDRA system organ class was ‘Infections and 


2015N240632_04
CONFIDENTIAL
204824
12
Infestations’. Adverse events in this category were reported in 15 subjects (N=37 subjects 
total), 6/12 on placebo, 4/13 following 0.25 mg/kg GSK1070806 administration, and 5/12 
following 5.0 mg/kg GSK1070806 administration. 
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To assess the frequency of delayed graft 
function (DGF) in donation after circulatory 
death (DCD) renal transplant recipients 
treated with GSK1070806.

Proportion of subjects requiring dialysis 
during the first 7 days post transplant, 
(excluding requirement for dialysis due to 
hyperkalemia within first 24 post-operative 
hours).
Secondary

To assess graft function in DCD renal 
transplant recipients treated with 
GSK1070806.

Serum creatinine at baseline and over time 
post transplant.

Urine output at baseline and over time post 
transplant.

Proportion of subjects in the first 7 days 
with: 
-
Primary Non Function
-
Functional DGF
-
Intermediate Graft Function
-
Immediate Graft Function

To assess the effect of GSK1070806 on 
acute rejection risk, and rejection/PD 
biomarkers.

Proportion of subjects with episodes of 
biopsy-proven acute rejection.

Rejection biomarkers/ PD markers 
(including serum IP-10 and Mig) at 
baseline and over time post transplant.

To assess the effect of GSK1070806 on 
dialysis dependency and graft survival.

Number of dialysis events per patient in the 
first 30 days post transplant.

Proportion of subjects who are dialysis-
independent at visits up to 12 months post 
transplant.

To assess the safety and tolerability of 
GSK1070806 in renal transplant recipients.

AEs and SAEs
-
Clinical laboratory values
-
Vital signs
-
Frequency, type and severity of 
infections

To assess the pharmacokinetics of 
GSK1070806 in renal transplant recipients.

Serum concentrations of GSK1070806 
over time, and derived pharmacokinetic 
parameters if feasible (AUC, Cmax). 


2015N240632_04
CONFIDENTIAL
204824
13
Objectives
Endpoints

To assess the effect of GSK1070806 
administration on serum IL-18 levels.

Free, total, and GSK1070806 bound IL-18 
at baseline and over time post transplant.

To determine immunogenicity of 
GSK1070806 in renal transplant recipients.

Frequency of anti-drug antibodies (ADAs) 
before and after GSK1070806 
administration.

ADA titers.
Exploratory

To assess the impact of GSK1070806 on 
urine biomarkers of renal injury.

Serial measurements of urinary 
biomarkers, including KIM-1, NGAL and IL-
18, at baseline and over time post 
transplant.

To assess IL-18 target engagement in the 
kidney.

GSK1070806 and IL-18 levels within renal 
graft biopsies, as assessed by 
immunohistochemistry.

To assess the relation between IL-18 levels 
in renal preservation fluid and graft function.

Level of IL-18 in renal preservation fluid.

To assess the impact of GSK1070806 
administration on IL-18 binding protein 
levels.

Serum IL-18 binding protein at baseline 
and over time post transplant.

To assess the humoral and cellular 
response to the transplanted organ in the 
presence of GSK1070806.

Serum cytokine levels at baseline and over 
time post transplant.

Histological analysis of biopsies with 
respect to cellular infiltrate.

To assess health outcomes in renal 
transplant recipients following 
GSK1070806 administration.

Length of hospital stay

Re-hospitalization


2015N240632_04
CONFIDENTIAL
204824
14
4.
STUDY DESIGN
4.1.
Overall Design
Figure 1
Study Design
Study 204824 is a phase 2, pilot, multicenter, single arm Bayesian sequential design 
study to evaluate the efficacy, safety, tolerability and pharmacokinetics of GSK1070806 
in patients undergoing renal transplantation. 
The primary endpoint is frequency of DGF defined by a requirement for dialysis (except 
as needed for hyperkalaemia during the first 24 hours) within the first 7 days post 
transplantation. The trial utilizes a Bayesian sequential design [Section 9] to test whether 
GSK1070806 lowers the frequency of DGF. As secondary objectives the protocol 
assesses the safety and tolerability of GSK1070806 in renal transplantation, graft 
function/survival (serum creatinine, urine output, dialysis events), the impact on 
indicators of acute rejection, as well as GSK1070806 pharmacokinetics, 
pharmacodynamics and immunogenicity.
All subjects enrolled will have been evaluated by the investigative site’s transplant 
program, and be considered suitable for transplantation by the institution’s eligibility 
criteria.  Informed consent will be obtained from all subjects before screening.  Donation 
after circulatory death (DCD) transplantation is an unplanned activity, thus screening will 
occur on an emergency basis in the hours before transplantation using available clinical 
data.
Inclusion/exclusion criteria have been designed to exclude patients with heightened risk 
of infection, given that GSK1070806 (anti-IL18 monoclonal antibody) in this protocol 
amounts to an additional immunosuppressive on top of the standard of care 
immunosuppressive regimen. Furthermore, anti-infective prophylaxis therapy and viral 
testing has been implemented to mitigate the theoretical elevated infection risk 
(summarized in Section 4.6).
4.2.
Treatment Arms and Duration
Participants will receive a single IV injection of GSK1070806 administered prior to 
kidney allograft reperfusion, and will be followed for 12 months post dose. 


2015N240632_04
CONFIDENTIAL
204824
15
4.3.
Type and Number of Subjects

Adult subjects (18 years of age and older).

Dialysis-dependent, recipient of first and second time, single kidney-only, Donation 
after Circulatory Death (DCD) transplants, receiving a planned immunosuppressive 
standard of care comprised of basiliximab, mycophenolate mofetil (MMF) or 
azathioprine, tacrolimus and corticosteroids. DCD donor kidneys must be 
‘controlled’ meeting either Maastricht Category 3 or 4 criteria.

For details of the number of subjects refer to go/no go decision criteria defined in 
Section 9. The number of subjects to be enrolled will be up to approximately 40.

Since subjects will only receive a single dose of study medication, and patients 
normally undergo frequent clinic visits during the 12 months post transplantation, 
minimal attrition/withdrawal is anticipated for this study. However, if subjects 
prematurely discontinue the study replacements may be enrolled at the discretion of 
the Sponsor.
4.4.
Design Justification
The single-arm, open-label design with a Bayesian sequential approach has been chosen 
in order to provide an early indication of clinical efficacy using a minimal sample size. 
The historical rate of DGF in the 7 days post DCD transplantation (a clinically 
meaningful parameter) was documented at approximately 50% during the time period 
2005-2010 [Summers, 2013], and has been confirmed with contemporary registry data 
(2010-present) held by United Kingdom National Health Service Blood and Transplant 
(NHSBT). This background DGF rate forms the basis of the Bayesian ‘go/no go’ design.
The 12 month follow up period post transplantation, and administration of the single dose 
of GSK1070806, provides sufficient coverage to assess safety and tolerability once 
GSK1070806 levels decline and IL18 signalling is allowed to return. Furthermore, renal 
outcomes at 12 months post-transplant are deemed clinically relevant measures. 
4.5.
Dose Justification
Preclinical Safety: GSK1070806 is a monoclonal antibody with high affinity for human 
and rhesus/ cynomolgus IL-18 that does not interfere with interactions between IL-18 and 
the IL-18 binding protein.  A 4-week repeat IV bolus GLP toxicology study in male and 
female cynomolgus monkey at 3, 30 and 300 mg/kg/week dose levels was conducted to 
assess doses for clinical use. No safety pharmacology findings of concern for clinical use 
were identified at any of these doses. Based on this, the NOAEL was defined as ≥300 
mg/kg/week. The gender averaged exposure at 300 mg/kg/week dose was AUC0-168hr 
of 1775 mg*h/mL and Cmax of 18.8 mg/mL.
Clinical Experience: A single ascending dose study (A18110040) has been completed in 
healthy volunteers with GSK1070806 doses up to 10 mg/kg IV. Another study 
(A18116378) completed in obese subjects with type 2 diabetes mellitus (T2DM) 
evaluated repeat dosing at 2 dose levels (0.25 and 5 mg/kg IV). In this T2DM study two 
doses of GSK1070806 were administered to each cohort 4 weeks apart. Overall, all doses 


2015N240632_04
CONFIDENTIAL
204824
16
up to 10 mg/kg were well tolerated. The geometric mean half-life (t1/2) ranged from 19 to 
49 days, with a trend of dose-dependent increase in half-life. Based on available data, 
doses ≥ 1 mg/kg provide near complete suppression of systemic IL-18.  No reported 
adverse events were associated with GSK1070806 administration in these studies. 
GSK1070806 Dose Modelling for Renal Transplant: A physiological based 
pharmacokinetic (PBPK) model and prior clinical PK data were used to model the dose 
requirement based on the anticipated need to inhibit IL-18 (>90% target engagement) 
rapidly (1-2 hours post-dose) in both the interstitial space of the kidney and the 
circulating plasma. Using preliminary data on circulating IL-18 levels in renal transplant 
patients (anticipated maximum of 1400 pg/mL) and conservative assumptions that 
enhanced IL-18 levels in DGF were driven by increases in IL-18 production (versus 
slower metabolism) and derived within the kidney, target engagement with various doses 
of GSK1070806 was modelled.  The PBPK model parameters were adjusted to test 
sensitivity with respect to extent of target engagement at various dose levels.  Based on 
these data, in the current study we propose to start the study with initial participants 
receiving a single dose of 3 mg/kg administered prior to reperfusion of the transplanted 
kidney. The use of the single 3 mg/kg dose is well supported by the observed safety data 
generated in prior clinical studies (n=36 subjects have received ≥3 mg/kg) and the PBPK 
model based approach outlined above, which predicts a rapid target engagement in the 
kidney interstitium followed by >90% inhibition for the 7 days leading up to assessment 
of the DGF primary endpoint. 
Dose Adjustment: Data will be reviewed at an interim analysis after recruitment of at 
least 6 subjects, who have a minimum of 30 days post-dose safety experience data
[Section 9.3.2]. Depending on an integrated review of safety/tolerability, efficacy, and 
exposure, a dose adjustment will be considered. This review will include available data 
from renal biopsies. If estimated target engagement appears to be suboptimal in the 
majority of subjects, this will support consideration to increase dose above 3 mg/kg in 
subsequent recruited subjects. Any decision to increase dose will be conducted in 
consultation with the GSK safety review team (SRT). The maximum dose level 
administered to patients will not exceed 10mg/kg as precedented by previous clinical 
studies.
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK1070806 can be found in the Investigators’ Brochure.  The following section 
outlines the risk assessment and mitigation strategy for this protocol:  


2015N240632_04
CONFIDENTIAL
204824
17
4.6.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK1070806] 
Infections

IL-18 plays a role in host defense against microbial 
pathogens. IL-18 primes both innate and acquired immunity 
to viruses and other intracellular pathogens. As a result, 
there is a theoretical risk that blocking of IL-18 signalling by 
GSK1070806 may increase a patient’s susceptibility to 
bacterial and viral infections.

In the FTIH study no additional infections were observed 
after a single IV GSK1070806 infusion in 57 healthy and 
obese subjects when compared to placebo. Similarly, in a 
type 2 diabetes study, there was no apparent increase in 
infection rate in either treatment group (total of 25 treated 
subjects) when compared to placebo.

Of note, patients in the current study are pharmacologically 
immunosuppressed as standard of care. Furthermore, IL-18 
system neutralization is likely to have a duration of 
approximately 6-9 months at the 3mg/kg dose, extending to 
9-10 months at themaximal 10mg/kg dose. Accordingly, 
infection is the key risk in this clinical program.

Dose selection
The starting dose of 3 mg/kg has been selected as it is 
considered to be the minimum dose that will achieve sufficient 
IL18 inhibition in the initial hours after transplantation, during 
which it is presumed that the pathological processes causing 
DGF are initiated. This minimizes the duration of prolonged IL18 
inhibition in order to mitigate any potential infection risk due to 
the addition of GSK1070806 to the immunosuppressive 
standard of care.

Eligibility criteria
Patients will be excluded if they are at particular risk for 
infectious complications. Specifically, patients who are HIV+, 
have evidence of acute or chronic hepatitis B infection, are 
hepatitis C+, have a history of TB exposure or infection, are 
being actively managed for ongoing infection, or have a history 
of recent viral illness will be excluded. EBV-ve recipients of 
EBV+ve transplants will be excluded due to elevated risk of 
post-transplant lymphoproliferative disorder (PTLD). Transplant 
recipients receiving allografts from donors with significant 
bacterial, fungal or viral infections at the time of death will be 
excluded.
Patients for whom ‘intensive’ immunosuppressive regimes are 
planned including Alemtuzumab (Campath) or anti-thymocyte 
globulin, Belatacept, OKT3 or mTOR inhibitors- (known to 
increase risk of CMV, PTLD, and other infections) are excluded.


2015N240632_04
CONFIDENTIAL
204824
18
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

Standard of care
Due to immunosuppressive treatments being standard of care 
patients routinely receive prophylactic intravenous antibiotics 
during transplantation, as well as prophylaxis for pneumocystis 
(PCP; usually co-trimoxazole, variable by centre), fungal 
infections (ie. nystatin), and cytomegalovirus (valganciclovir). 
CMV donor - /recipient - patients will receive leukodepleted 
blood and blood products (if needed), to minimise the risk of 
primary infection (per British Transplantation Society 
Guidelines, 2011). 
Subjects will be monitored for symptoms and signs of infection 
including fever, hypotension, tachycardia and respiratory status. 
If necessary, cultures will be taken, and appropriate 
antibacterial, antifungal or antiviral therapy will be initiated.
After discharge from hospital, subjects will be followed at 
regular intervals, being evaluated by professionals experienced 
in care of immunosuppressed organ transplant recipients.

Additions to standard of care
In addition to routine infectious prophylaxis/ surveillance as 
described above, an elevated level of infectious prophylaxis/ 
surveillance will be mandated as follows:
-
PCP prophylaxis will be continued for 12 months (as 
opposed to 3-6 months).
-
CMV prophylaxis using valganciclovir for 200 days (as 
opposed to 100 days in some centres) will be provided 
as follows:

Donor + /Recipient - (prevention of primary 


2015N240632_04
CONFIDENTIAL
204824
19
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
infection)

Donor + /Recipient + (prevention of re-
infection) 

Donor -  / Recipient + (prevention of re-
activation)

CMV PCR will be performed regularly after 
discontinuation of prophylaxis or ‘for cause’ at 
any time after transplantation in accordance 
with UK guidelines.

Donor -  /Recipient – will receive prophylaxis 
with acyclovir for 200 days, dose determined 
based on unit protocol. 
-
BK virus surveillance by BK PCR of whole blood will be 
performed post transplantation. In the event that a 
patient becomes BK +ve, screening will be repeated in 
accordance with UK guidelines. Immunosuppression 
will be reduced / titrated at the discretion of the 
investigator. 
In the event of deteriorating renal function in the context 
of BK viremia, transplant biopsy to diagnose BK 
nephropathy will be considered at the discretion of the 
investigator.
-
Subjects must refrain from travelling to countries with a 
high prevalence of infectious disease from the time 
when the dose is administered until the end of the study 
(1 year post dose).


2015N240632_04
CONFIDENTIAL
204824
20
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Blood Pressure Effects

In the T2DM study, hypertension was one of the most 
frequent AEs reported. Three patients in the placebo group 
(n=12) had mild hypertensive events (max systolic 182 
mm/Hg, max diastolic 106 mm/Hg); five patients in the 
0.25mg/kg group (n=13) had mild hypertensive events (max 
systolic 174 mm/Hg, max diastolic 112 mm/Hg, and in the 
5mg/kg group (n=12), four patients had mild hypertensive 
events (max systolic 176mm/Hg). Detailed safety review 
indicated that the above values did not constitute an overall 
trend. However, blood pressure was flagged as a safety 
endpoint to monitor in subsequent studies. 

In the peri-operative and immediate post-operative period, renal 
transplant patients are closely monitored within an operating 
theatre / critical care environment. Settings are well equipped to 
respond to cardiovascular emergencies, as standard of care.

Throughout the hospital stay, blood pressure will be closely 
monitored, and anti-hypertensive medications titrated as 
standard of care. Thereafter, close outpatient monitoring, 
performed routinely in this population, will be used to identify 
and treat any blood pressure complications.  
Immunogenicity

A host immune response (immunogenicity) against 
GSK1070806 following IV administration is possible. Risk of 
immunogenicity is deemed to be low.

The emergence of anti-GSK1070806 antibodies was 
investigated in the FTIH and Type 2 diabetes studies. To 
date, three subjects (of a total of 82 administered 
GSK1070806) have had confirmed relatively low titre of anti-
GSK1070806 antibodies post-dosing. In 2 out 3 subjects the
presence of anti-drug antibodies was transient, and is 
therefore not considered to be of clinical significance.

To date there was no apparent evidence that anti-drug 
antibodies affected the pharmacokinetic profile of 
GSK1070806. 

Delayed-type, non-acute hypersensitivity reactions have not 
been observed with GSK1070806.

The immunogenicity risk for GSK1070806 is deemed low. 
Nonetheless it is mitigated by use of a single dose in this study 
along with concomitant steroid treatment as SOC.

Patients will be observed for symptoms such as rash, nausea, 
fatigue, myalgia, headache, and facial oedema.
Infusion reactions

Risk of infusion reaction is judged to be low in view of the 
clinical experience with GSK1070806:

Investigators/site personnel will be made aware of the risk of 
hypersensitivity reactions, which may present as an infusion 


2015N240632_04
CONFIDENTIAL
204824
21
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
-
In the FTIH study, no allergic reactions or infusion 
related reactions were observed after a single IV 
GSK1070806 infusion in 57 healthy and obese 
subjects. 
-
Additionally, no allergic or infusion related reactions 
were observed in T2DM study in which 25 subjects 
were administered GSK1070806. 
reaction, and will monitor patients closely for a minimum of 3 
hours. 

Investigational product will be administered by the 
investigator/site personnel prepared to manage infusion 
reactions and anaphylaxis, following their standard practices to 
manage any untoward infusion reactions noted during or after 
the infusion period.

Subjects will be on corticosteroids and hospitalized during 
dosing.

For subjects who have previously received IV immunoglobulin 
(IVIG) or subjects with a history of allergies (allergic responses 
to food, drugs, insects, or a history of urticaria), 
diphenhydramine (12.5 to 50 mg based on clinical judgment) or 
equivalent and paracetamol (acetaminophen) may be 
administered prophylactically prior to dosing.  Antihistamine H2-
receptor antagonists (e.g., ranitidine) are also permitted. 
Study Procedures
Renal biopsy

Renal biopsy may cause bleeding / injury to the transplanted 
organ.

Intra-operative biopsy will be performed under direct 
visualization thus any bleeding will be controlled immediately by 
the operating surgeon. Biopsies are optional per protocol. 
Therefore if a surgeon judges that risk of biopsy is 
unacceptable, they will have the option not to perform this 
procedure.  


2015N240632_04
CONFIDENTIAL
204824
22
4.6.2.
Benefit Assessment
Delayed graft function is an area of considerable unmet need, affecting up to half of renal 
transplant recipients, and contributing to worse long term transplantation outcomes. To 
date no approved therapies are available for DGF, or broader acute kidney injury 
indications. It is anticipated that GSK1070806 will decrease the incidence of DGF and 
thereby improve long term renal function, resulting in lower rates of graft failure. In 
addition, other mechanisms, particularly antagonism of Th1 mediated rejection, may 
support a beneficial effect of IL-18 inhibition and contribute to an enhancement of 1 year 
graft survival.  
4.6.3.
Overall Benefit/Risk Conclusion
Weighing the existing preclinical and clinical safety record of GSK1070806 with the 
potential for benefit in terms of prevention of DGF and reduction in risk of allograft 
rejection, it is judged that the potential risks are justified. 
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
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 Investigators Brochure.
Deviations from inclusion and 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 essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Recipient age range: 18 years of age and older, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Dialysis-dependent recipient of first or second time, single kidney-only, Donation 
after Circulatory Death (DCD) transplant.

Donor kidney must be ‘controlled’ meeting either Maastricht Category 3 
or 4 criteria:

Category 3: Donor awaiting cardiac arrest

Category 4: Cardiac arrest in a brain stem dead donor
3. Eligible for kidney transplantation:  Considered eligible for transplantation after 
undergoing multidisciplinary evaluation at the institution at which the transplantation 


2015N240632_04
CONFIDENTIAL
204824
23
will be performed. 
4. Immunosuppressants (at the time of transplantation):  planned to receive a 
combination of immunosuppressants including basiliximab, mycophenolate mofetil or 
azathioprine, tacrolimus, and corticosteroids.
SEX
5. Male and Female:
Males:
Male subjects with female partners of child bearing potential must utilize a condom and 
female partners must comply with use of one of the highly effective contraceptive 
methods described in Appendix 4 for 180 days post-dose of study medication.
Females: 
a.
Non-reproductive potential defined as:

Females with one of the following procedures documented and no plans to 
utilize assisted reproductive techniques (e.g., in vitro fertilization or donor 
embryo transfer):
-
Bilateral tubal ligation or salpingectomy
-
Hysteroscopic tubal occlusion procedure with follow-up confirmation 
of bilateral tubal occlusion 
-
Hysterectomy
-
Bilateral Oophorectomy (surgical menopause)

Postmenopausal defined as 12 months of spontaneous amenorrhea. 
- In questionable cases (including cases in which amenorrhea is suspected to 
result from a subject’s poor renal function/dialysis) a blood sample with 
simultaneous follicle stimulating hormone (FSH) and estradiol levels 
consistent with menopause are required. If FSH/estradiol results are not 
available in time subjects are to be initiated on contraceptive methods 
(see below and Appendix 4). 
- Females on hormone replacement therapy (HRT) and whose menopausal 
status is in doubt will be required to use one of the highly effective 
contraception methods if they wish to continue their HRT during the 
study.
b.
Reproductive potential: Must not be pregnant or lactating, and agrees to follow one 
of the options listed in the Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) (see Appendix 4) for 180 
days post dose. If a hormonal method of birth control is selected from the list in 
Appendix 4 then subjects must have been using these methods at least 28 days prior 
to GSK1070806 administration, or be abstinent, or utilize a condom as a method of 
contraception until the selected hormonal method has been in place for the 28 day 
period.


2015N240632_04
CONFIDENTIAL
204824
24
The investigator is responsible for ensuring that subjects understand how to 
properly use the indicated methods of contraception by providing counsel directly 
or by referring subjects to health care professionals with expertise in this area.
INFORMED CONSENT
6. Capable of providing signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1.
Liver function: ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
2.
QT interval: single or average QTc > 480 msec or in subjects with bundle branch 
block QTc > 500 msec (these criteria do not apply to subjects with predominately 
paced rhythms).
3.
Ventricular arrhythmia: History of cardiac arrest or malignant ventricular 
arrhythmia at any time.Any acute cardiovascular syndrome within six months 
before screening. These may include acute coronary syndrome (myocardial 
infarction or unstable angina) or coronary intervention (percutaneous or surgical), or 
acute stroke.
CONCOMITANT MEDICATIONS
4.
Concurrent medication: Subjects who receive treatment that is prohibited for safety 
reasons (e.g. live vaccines, cyclophosphamide or other biologic immunosuppressants 
as described in Section 6.11) should not receive investigational product without the 
explicit approval of the Medical Monitor (Sponsor).
5.
Investigational product: Any within 5 half-lives or twice the duration of the 
biological effect whichever is longer (investigational product refers to any drug not 
approved for sale in the country in which it is being used). 
6.
Immunosuppression: Are being considered for steroid-free, anti-thymocyte 
globulin (ATG) or alemtuzumab induction, which have a much more profound and 
prolonged immunosuppressive effect than basiliximab.
7.
Prior biologic immunosuppressives: The subject has received an agent within the 
following time period prior to the day of dosing in the current study: 30 days, 5 half-
lives or twice the duration of the biological effect, whichever is longer.


2015N240632_04
CONFIDENTIAL
204824
25
8.
Vaccines: A live vaccine within 30 days prior to GSK1070806 administration. 
CONTRAINDICATIONS 
9.
Receiving a DCD kidney allograft from a donor with any of the following 
characteristics
a.
cold ischemic time > 36 hours 
b. age < 5 years old
c.
ABO blood type incompatible against the recipient.
d. T- and/or B-cell positive crossmatch by complement dependent 
cytotoxicity or flow cytometry against the recipient (where positive 
crossmatch is unavailable, virtual crossmatch is allowed). 
e.
serology positive for hepatitis B (except hepatitis B surface antibody and 
prior vaccination), hepatitis C or human immunodeficiency virus (HIV)
f.
EBV positive donor allograft with an EBV negative recipient
g. donor had acute or chronic bacterial, viral or fungal infection that 
according to the investigator causes a risk to recipient, particularly if the 
infection was resistant or systemic 
h. normothermic regional machine perfusion organ retrieval techniques were 
utilized
i.
surgical damage to donor allograft during organ procurement (surgical 
damage is defined as damage requiring surgical repair to make the organ 
usable)
j.
‘Uncontrolled’ Maastricht Category 1 (dead on arrival), Category 2 
(unsuccessful resuscitation), and Category 5 (unexpected cardiac arrest in 
a critically ill patient)
10. Previous organ transplantation: has previously undergone any other organ 
transplantation (with the exception of 1st kidney and/or corneal transplantation).
11. Malignancy:  has a history of malignancy in the past 5 years except for adequately 
treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the 
uterine cervix.
12. Acute or chronic infection:  has required management of acute or chronic 
infections (excludes prophylaxis of infections), as follows:
a.
currently being treated for a chronic infection, which in the opinion of the 
investigator, could put the subject at undue risk
b. hospitalized for treatment of infection, or treated for an infection with 
parenteral antibiotics (includes antibacterials, antivirals, anti-fungals, or 
anti-parasitic agents) within 30 days before Day 0, which in the opinion of 
the investigator, could put the subject at undue risk
c.
current evidence, or history within the last 14 days, of an influenza-like 
illness as defined by fever (>38°C) and two or more of the following 


2015N240632_04
CONFIDENTIAL
204824
26
symptoms: cough, sore throat, runny nose, sneezing, limb / joint pain, 
headache, vomiting / diarrhoea 
d. patients with any history of active tuberculosis, recent tuberculosis 
exposure, or judged by investigators to be at risk of tuberculosis will be 
excluded from the study 
13. Other disease/conditions.  Has any of the following:
a.
clinical evidence of significant unstable or uncontrolled acute or chronic 
diseases, which in the opinion of the investigator, could confound the 
results of the study or put the subject at undue risk
b. a surgical procedure planned in the 12 months after Day 0, other than 
kidney transplantation or related procedure
c.
a known history of any other medical disease (e.g., cardiopulmonary), 
laboratory abnormality, or condition (e.g., poor venous access) that, in the 
opinion of the investigator, makes the subject unsuitable for the study 
14. Hepatitis B: patients will be excluded with any evidence of acute or chronic 
infection, or if interpretation of their results is unclear. This includes:
a.
HBsAg +
b. Anti-HBc +
c.
HB DNA+
It is permissible to enrol patients who are anti-HBs+ only, when this is attributable to 
vaccination and there is no history of previous infection.
15. Hepatitis C: patients will be excluded if there is any evidence of past or current 
hepatitis C infection, including hepatitis C antibody, hepatitis C RIBA immunoblot 
or PCR.
16. HIV:  known to have a historically positive HIV test.
17. Immunodeficiency:  recipient with a history of, or laboratory evidence of 
immunodeficiency.
18. Drug Sensitivity:  has a history of sensitivity to any of the study medications 
including:
a.
GSK1070806
b. background immunosuppressive regimen,
c.
designated prophylactic anti-infective therapies 
or components thereof, or a history of drug or other allergy including a previous 
anaphylactic reaction to parenteral administration or biologic therapy (ie monoclonal 
antibody) that, in the opinion of the Investigator or Medical Monitor, contraindicates 
their participation. 
19. Substance abuse:  has clinical evidence of current drug or alcohol abuse or 
dependence.
20. Co enrolment:  participating in another interventional study (participation in purely 


2015N240632_04
CONFIDENTIAL
204824
27
observational or cohort studies is acceptable provided they do not impair feasibility, 
or involve excessive additional sampling).
21. Compliance:  is unlikely to comply with scheduled study visits based on 
investigator judgment or has a history of a psychiatric disorder or condition that may 
compromise communication with the investigator.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
do not receive study medication. In order to ensure transparent reporting of screen failure 
subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, and respond to queries from Regulatory authorities, a minimal set of screen 
failure information is required including Demography, Screen Failure details, Eligibility 
Criteria, and Serious Adverse Events (see Section 7.4.1.5).
5.4.
Withdrawal/Stopping Criteria
A subject may withdraw from study participation at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, behavioural 
or administrative reasons. Since participants will receive a single dose of study 
medication on day 0, once this dose has been given, withdrawal will constitute declining 
to participate in follow-up activities. If a subject withdraws from the study, he/she may 
request destruction of any samples taken, and the investigator must document this in the 
site study records. 
If a subject withdraws from the study, they should be strongly encouraged to return for
subsequent visits, particularly the Safety Follow-up visit at 12 months, and to continue 
with adjustments to infectious prophylaxis/ standard of care medicines intended to 
mitigate safety risks associated with administration of a long-acting, novel 
immunosuppressive.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule. 

The site must counsel the subject on the importance of maintaining additional 
anti-infectious prophylaxis and testing regimens.

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 


2015N240632_04
CONFIDENTIAL
204824
28

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
5.4.1.
Liver Chemistry Management
Since participants will receive a single dose of study medication, there are no liver-
specific stopping criteria as such. In the event of liver parameters deviating from the 
thresholds described in Appendix 2, follow instructions in that section.
Liver chemistry increased monitoring criteria have been designed to assure subject 
safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
5.4.2.
QTc Evaluation Criteria
Further monitoring and/or evaluation should be considered in any subject who meets the 
following:

QTc >530 msec OR uncorrected QT >600 msec (machine or manual overread)
For subjects with underlying bundle-branch block, follow the evaluation criteria listed 
below:
Baseline QTc with Bundle-Branch Block
Criteria for Further Evaluation and Monitoring of 
QTc with Bundle-Branch Block
<480 msec
>530 msec
480 to 500 msec
≥550 msec

The enhanced monitoring criteria are 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 meets these criteria.

The same QT correction formula must be used for all QTc data being collected for
each individual subject to determine eligibility for the study and to determine 
whether further evaluation and/or monitoring is/are necessary. This formula may not 
be changed or substituted once the subject has been enrolled. (Safety ECGs and other 
non-protocol-specified ECGs are an exception.)
o For example, if a subject is eligible for the protocol based on QTcB, then QTcB 
must be used for instigation of enhanced monitoring criteria of this individual 
subject as well.

Considerations as actions for further monitoring and evaluation should include the 
following, as appropriate:
o Assessment of any relevant symptoms (e.g., presyncope);


2015N240632_04
CONFIDENTIAL
204824
29
o Follow-up ECGs to assess for resolution of QTc prolongation;
o Review of concomitant or recently taken medications, including over the counter 
preparations and herbal supplements
o Evaluation of electrolytes to include magnesium and potassium
o Referral to an emergency facility/cardiology consultation for further evaluation 
and monitoring, or any other evaluation that may be necessary as determined by 
the investigator.
5.5.
Safety Interim Analysis
A safety interim assessment after 6 subjects will be performed at the same time as the 
dose adjustment interim (Section 4.5). If the rate/severity of infectious SAEs exceeds that 
expected on background immunosuppression based on the SRT medical judgement (SRT 
will include an independent transplant infectious disease specialist) then recruitment may 
be paused. The expected background rate of infection will be determined based on data 
from publications, registries, trial site databases, and ongoing studies in comparable renal 
transplant populations.
5.6.
Subject and Study Completion
A completed subject will be defined as a patient who receives the scheduled study 
infusion and completes the 12 month assessment.
The end of the study is defined as the last subject’s last clinic visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Product name:
GSK1070806
Dosage form:
100 mg/mL injectable solution
Unit dose 
strength(s)/Dosage 
level(s):
Single dose of 3 mg/kg (maximum of 10 mg/kg if dose adjustment 
deemed necessary, based on interim analysis - Section 4.5)
Route of 
Administration
IV infusion prior to allograft reperfusion
Dosing instructions:
Dilute into 100 mL sterile IV infusion bag 0.9% Sodium Chloride 
(details see Study Reference Manual)


2015N240632_04
CONFIDENTIAL
204824
30
The rate of infusion should not be increased above the recommended rate, but may be 
slowed or interrupted if the subject appears to develop signs of adverse reactions or 
infusion-related symptoms. See SRM for IV infusion rate details.
6.2.
Treatment Assignment
This is a non-randomized, single-arm study and all subjects will receive active 
investigational product.
6.3.
Blinding
This will be a single-arm unblinded study.
6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK1070806 is 
detailed in the Study Reference Manual (SRM).
Study treatment must be dispensed or administered according to procedures described 
herein and in the SRM. Only subjects enrolled in the study may receive study treatment. 
Only authorized site staff may supply or administer study treatment. All study treatment 
must be stored in a secure area with access limited to the investigator and authorized site 
staff.  
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study 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 administered to subjects. The required accountability unit for this study will be 
the vial. Discrepancies are to be reconciled or resolved. Procedures for final disposition 
of unused study treatment are listed in the SRM.
Investigational product is not expected to pose significant occupational safety risk to site 
staff under normal conditions of use and administration. However, precautions are to be 
taken to avoid direct skin contact, eye contact, and generating aerosols or mists. In the 
case of unintentional occupational exposure notify the monitor, medical monitor and/or 
study manager. 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.


2015N240632_04
CONFIDENTIAL
204824
31
6.6.
Compliance with Study Treatment Administration
GSK1070806 will be administered intravenously to subjects as an infusion at the site; 
they will receive study treatment directly from the investigator or designee, under 
medical supervision.  The date and time of each dose administered in the clinic will be 
recorded in the source documents.  The dose of study treatment and study subject 
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.  
6.7.
Treatment of Study Treatment Overdose
For this study, any dose of GSK1070806 > 10 mg/kg will be considered an overdose.
There are no known antidotes and GSK does not recommend specific treatment for an 
overdose. In the event of an overdose the investigator will use clinical judgement in 
treating the symptoms and should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities per the investigator’s discretion for at least 12 months or 
twice the length of the anticipated biologic effect of the dose received.
3. Obtain a plasma sample for pharmacokinetic (PK) analysis within 2 days from the 
date of the study treatment overdose if requested by the Medical Monitor (determined 
on a case-by-case basis)
4. Document the quantity of the excess dose in the CRF.
6.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because all enrolled subjects are already receiving standard of care as background 
therapy. The investigator is responsible for ensuring that consideration has been given to 
the post-study care of the subject’s medical condition.
6.9.
Lifestyle and/or Dietary Restrictions
All subjects should follow the recommended lifestyle and dietary restrictions deemed as 
standard of care by investigators for renal transplant patients.
Subjects must refrain from travelling to countries with a high prevalence of infectious 
disease from the time when the dose is administered until the end of the study (1 year 
post dose). 
6.10.
Concomitant Medications and Non-Drug Therapies
GSK1070806 will be administered in addition to the defined immunosuppressant regimen 
(Section 6.10.1).  Concomitant medication adjustments will be made as clinically 
indicated and at the investigator’s discretion. All medication that is necessary for the 


2015N240632_04
CONFIDENTIAL
204824
32
appropriate clinical management of subjects in this study will be allowed with the 
exception of those listed in Section 6.11.
6.10.1.
Standard Immunosuppressive Therapy
Patients should be intended to receive a combination immunosuppression comprised of 
basiliximab; mycophenolate mofetil (MMF) or aziothioprine; tacrolimus; and 
corticosteroids. The immunosuppressant regimen may be revised based on the clinical 
judgment of the investigator including titration of tacrolimus target trough levels. Caution 
is advised if target tacrolimus levels are anticipated to exceed 10g/L. Dose adjustments 
of immunosuppressant agents should be recorded.
6.10.2.
Management of low white cell count
If patients are found to have white cell count ≤4 x 109/l then the investigator should 
consider proactively reducing dose of valgancyclovir or MMF per site specific clinical 
practice. In the event that valgancyclovir prophylaxis is discontinued, CMV PCR should 
be performed at a frequency according to the risk perceived by the investigator. If MMF 
dosage is reduced, investigators should be vigilant for increased risk of rejection.
6.10.3.
Graft Dysfunction/Graft rejection
Investigations for the cause of graft dysfunction/rejection and subsequent treatment will 
follow institutional protocol. If additional immunosuppressive medications are 
administered for a diagnosed/suspected rejection episode it is suggested that the 
investigator consider prolonging prophylaxis/surveillance for infection (Section 6.10.4).
6.10.4.
Prophylaxis and Surveillance for Infection
Investigators may consult with the medical monitor in regards to determining individual 
prophylaxis treatment and surveillance plans in order to mitigate any increased risk of 
infection. Investigators should take into consideration that an additional 
immunosuppressive, GSK1070806, has been added to treatment, and therefore intensive 
prophylaxis and surveillance against perioperative bacterial, pneumocystis, viral and 
fungal infections is appropriate.
6.10.4.1.
Pneumocystis and Fungal Infection Prophylaxis
A minimum of 3 months of pneuomocystis and fungal infection prophylaxis with 
cotrimoxazole and nystatin, respectively (or equivalents), should be implemented unless 
otherwise contraindicated. In cases of cotrimoxazole intolerance, then alternative therapy 
may be considered at the discretion of the investigator and in discussion with the medical 
monitor.
6.10.4.2.
Cytomegalovirus Infection
Subjects at risk of CMV disease include:

Donor +ve  /Recipient -ve (risk of primary infection)


2015N240632_04
CONFIDENTIAL
204824
33

Donor +ve  /Recipient +ve (risk of re-infection) 

Donor -ve  /Recipient +ve (risk of re-activation)
CMV infection prophylaxis with a 200 day course of valganciclovir will be administered 
to all subjects at risk of CMV disease as listed above.  If the recipient is prescribed 
additional immunosuppression for allograft rejection during the course of prophylaxis, 
the course will be extended such that the patient receives treatment for 200 days 
afterwards; if anti-rejection medicines are administered at between six and twelve months 
post-transplantation, a repeat 200 day course of valganciclovir will be prescribed.
After completion of prophylaxis, subjects will undergo routine surveillance for CMV 
viraemia by polymerase chain reaction testing of whole blood in accordance with UK 
guidelines. In addition, ‘for cause’ CMV testing may be performed at any time during the 
first post-transplant year at the discretion of the investigator. In cases of low white cell 
counts, valganciclovir dose can be reduced or discontinued at the investigator’s discretion 
in consultation with the medical monitor.  If valganciclovir is discontinued, CMV PCR 
should be performed at a frequency appropriate to the perceived risk of CMV infection.
Subjects that are CMV:

Donor -ve  /Recipient –ve
Should receive prophylaxis with acyclovir for 200 days, with dose determined based on 
unit protocol. 
6.10.4.3.
BK virus
To address a theoretical increased risk of BK virus infection, subjects will undergo 
surveillance by BK PCR of whole blood per UK guidelines, and as outlined in Section 7.
In the event that a patient becomes BK +ve, screening should be repeated at subsequent 
study visits and according to local practice. Immunosuppression will be reduced / titrated 
at the discretion of the investigator. In the event of deteriorating renal function in the 
context of BK viremia a transplant biopsy, to diagnose BK nephropathy, should also be 
considered at the discretion of the investigator.
6.11.
Prohibited Medications and Non-Drug Therapies
6.11.1.
Vaccines
Live vaccines are not permitted 30 days prior to GSK1070806 administration, or during 
the study period.
6.11.2.
Concomitant Medications
Subjects who start prohibited medications or therapies at any time during the study 
should be discussed with the Medical Monitor (Sponsor). Since a single dose of 
GSK1070806 is administered at day 0 in this study subjects should continue with study 
assessments and be closely followed up for safety. 


2015N240632_04
CONFIDENTIAL
204824
34
The following medications and therapies are prohibited at any time during the study:

Use of other investigational agents (biologic or non-biologic, or non-drug therapy; 
investigational applies to any drug not approved for sale in the country in which it is 
used).

Use of other immunosuppressive agents (e.g., alemtuzumab, belatacept, rituximab, 
eculizumab, ATG, OKT3, mTOR inhibitors) is discouraged, although it is 
recognized that use of these therapies may be unavoidable in certain clinical 
situations such as steroid resistant rejection. In these circumstances, the medical 
monitor should be consulted, and investigators should extend infectious prophylaxis 
and surveillance as described above. 
7.
STUDY ASSESSMENTS AND PROCEDURES
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
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.
The following points must be noted: 

If assessments are scheduled for the same nominal time, then assessments 
should occur in the following order:
1.
12-lead ECG
2.
vital signs
3.
blood draws  
Note: The timing of the assessments should allow the blood draw to occur at the 
defined time point.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker assessments may be altered 
during the course of the study based on newly available data to ensure 
appropriate monitoring. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a ‘Note to File’ which is approved by the 
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form. 

Approximately 250-300 mL of blood will be collected over the first 30 days of 
this study, for study-related procedures.  


2015N240632_04
CONFIDENTIAL
204824
35
7.1.
Time and Events Table
Study Day1
Screening
Pre-operative 
(baseline)
Intra-operative 
(D0) 1
4-8h 2
D1
D2
Daily until 
discharge
Discharge
D30
D90
6 & 12 
months 13
Unscheduled 
Visit
Informed Consent/Demographics
X
Medical/drug/alcohol/tobacco history
X
GSK1070806 IV Infusion
--------------------------------15
Kidney preservation fluid IL-18
X16
Kidney biopsy (post-reperfusion) 3
X (~45 min)
Clinical biopsy reports (if applicable)
---------------------------------------------------------------------------------------------------------------------------------------------------------------------
Concomitant medication
X
X
X17
X
X
X
X
X
X
X
X
X
Evidence of infection
X
X
X
X
X
X
X
X
X
X
SAE / AE monitoring
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
DGF status (up to day 7)
--------------------------------------------------
Urine output
X (native output)
X
X
X
X
X
X
Dialysis events since last assessment
X
X
X
X
X
X
X
X
X
X
Graft survival
-------------------------------------------------------------------------------------------------------------------------------------------
Viral serology (recipient & donor – HIV, 
Hep B/C, EBV) 4
X5
X
X
X
Viral serology (recipient & donor  -
herpes, varicella) 4
X
CMV monitoring
X5
X
X
X
BK virus monitoring 6
X
X
X
X
X
Vital signs 7
X
X
X
X
X
X
X
X
X
X
Complete physical 
X
X
X
12-lead ECG
X
X
X
X
Hematology / Clinical Chemistry / 
Urinalysis
X
X
X
X
X18
X
X
X
X
X
Pregnancy test 8
X
X
X
X
X
Serum cytokines / PD biomarkers
X11
X (~45 min at 
biopsy)
X
X
X
X
X
X
X
X
Free, GSK1070806 bound & total IL18 9
X11
X (~45 min at 
biopsy)
X
X
X
X
X
X
X
X


2015N240632_04
CONFIDENTIAL
204824
36
Study Day1
Screening
Pre-operative 
(baseline)
Intra-operative 
(D0) 1
4-8h 2
D1
D2
Daily until 
discharge
Discharge
D30
D90
6 & 12 
months 13
Unscheduled 
Visit
Pharmacokinetics 9,10
X11
X (~45 min at biopsy)
X
X
X (@168 hrs 
or at earlier 
discharge)
X
X
X
X
Immunogenicity 12
X11
X
X
X
X
Urinary biomarkers
X11
X
X
X
X
X
X
X
X
X
Peripheral blood leucocyte flow 
phenotyping, with optional in vitro 
stimulation assays and transcriptomic 
analysis 14
X
X
X
X
1.
Day 0 defined as the calendar day of transplant. Screening begins after the participant gives study informed-consent and is being prepared for surgery; the estimated time window
for screening assessments completion is 12h. Timings outside of 12 hour, but within the time of admission and surgery, will not be considered protocol deviations.
2.
Time post reperfusion. 
3.
Biopsies during transplantation may be ‘core or wedge’ at the discretion of the operating surgeon. If, in the judgement of the operating surgeon, biopsy poses unwarranted risk to 
the patient, it may be omitted.
4.
Viral serology will include HIV, HBsAg, anti-HBc, anti-HBs antibodies, and hepatitis C antibody (if hepatitis C antibody positive, a hepatitis C RIBA immunoblot or polymerase chain
reaction assay should be reflexively performed on the same sample to confirm the results as per NHS standard procedure), and serology for herpes simplex virus, Epstein Barr 
virus, and varicella zoster virus. 
5.
Screening viral status may be the most recent value recorded in the patient’s medical records.
6.
If BK positive then follow up screening should be implemented.
7.
Vital signs will include systolic and diastolic blood pressure, pulse rate, and temperature. 
8.
Pregnancy testing will be performed in women of childbearing potential.  Screening test may be urine or serum.
9.
Sampling time points may be adjusted as appropriate based on emerging data.
10. PK sampling time points are as follows:  predose, 45 min to 1 hr after reperfusion (coinciding with biopsy), 4-8 hrs,  24 hrs, 168 hrs (or pre-discharge if discharge before day 7), 
day 30 day 90, 6 and 12 months.  Exact PK sampling time is to be recorded.
11. Blood and urine samples for immunogenicity and biomarker analyses must be collected prior to infusion with GSK1070806
12. For any non-completer a serum sample for immunogenicity testing will be taken 12 mths post-operatively.
13. For subjects who withdraw from study, where possible, assessments should continue according to the Time and Events table. The 6 and 12 mth safety follow-up should be 
performed. 
14. Samples for subjects from Cambridge site only.
15. GSK1070806 can be infused any time during the pre-operative and/or intra-operative periods, but infusion must be complete prior to reperfusion of the allograft. 
16. Sample to be obtained at time of back-table allograft preparation.
17. Documentation of anaesthetics excluded.
18. If a study participant remains in hospital at Day 10, daily hematology / clinical chemistry / urinalysis assessments may be reduced to being performed every other day, at the 
Principal Investigator’s discretion. 


2015N240632_04
CONFIDENTIAL
204824
37
7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history, including infections, as well as drug/alcohol/tobacco 
history will be assessed as related to the inclusion/exclusion criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management and obtained 
prior to signing of informed consent may be utilized for Screening or baseline purposes 
provided the procedure meets the protocol-defined criteria. 
7.3.
Efficacy
The incidence of DGF is the primary efficacy measure.  Investigations for the cause of 
graft dysfunction / rejection will follow institutional protocol.  Acknowledging the 
subjective component of a DGF diagnosis, a secondary analysis of serum creatinine data 
and dialysis events will be performed. 
In the event that a subject develops graft dysfunction, the assessments described in 
Section 7 ‘unscheduled visit’ will be obtained by the investigator/site staff and their 
results recorded in the eCRF for inclusion in study analyses.  
In order to realise the greatest clinical benefit, a drug reducing incidence of DGF would 
also prolong graft survival. To this end, in addition to short term renal DGF outcome (up 
to day 7), the following will be captured:
a.
Graft survival up to 1 year.
b. 30 & 90 day, and 6 & 12 month serum creatinine.
c.
Urinary biomarkers indicative of injury, including NGAL, KIM-1, IL-18.
d. Clinical, biopsy proven acute rejection episodes.
e.
Biomarkers indicative of risk of allograft rejection, including IP-10, Mig, 
inflammatory cytokines.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  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.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 12.3.


2015N240632_04
CONFIDENTIAL
204824
38
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., 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. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.4.1.3), at the time points specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Section 12.3.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. 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 must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 3.
7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the 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?” 
If such questioning is not possible, the investigator will use his/her medical judgment in 
determining whether an event is considered to be an AE or SAE.
7.4.1.3.
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 SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 


2015N240632_04
CONFIDENTIAL
204824
39
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 3.
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 12.3 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation 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 the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) 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 a 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/IEC, if appropriate according to local requirements.
7.4.2.
Pregnancy

Pregnancy testing must be negative at screening, and be completed within 1 week 
prior to GSK107806 administration in order for female subjects to enrol in this 
study.

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until 180 days post dose.


2015N240632_04
CONFIDENTIAL
204824
40

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.
7.4.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded. 

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
7.4.4.
Vital Signs

Vital sign measurements will include systolic and diastolic blood pressure, pulse 
rate and temperature.

Vital signs will be measured in semi-supine position after 5 minutes rest. 
7.4.5.
Electrocardiogram (ECG)

Single or triplicate 12-lead ECGs will be obtained at each time point indicated in 
TE table (Section 7.1) using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals.  Refer to Section 5.4.2
for when triplicate QTc readings are required, and for QTc enhanced monitoring 
criteria. 
7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 1 below, must be 
conducted in accordance with the Laboratory Manual, and Protocol Time and Events 
Schedule. Laboratory requisition forms must be completed and samples must be clearly 
labelled with the subject number, protocol number, site/centre number, and visit date.
Details for the preparation and shipment of samples will be provided by the laboratory 
and are detailed in the SRM. Reference ranges for all safety parameters will be provided 
to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 1. 


2015N240632_04
CONFIDENTIAL
204824
41
Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC 
Indices:
WBC count with 
Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1,2
Urea
Potassium
GGT
Bilirubin
Creatinine
Sodium
ALT 
Total protein
Glucose 
Calcium
Alkaline 
phosphatase
Albumin
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Tests

HIV, CMV, BK, Herpes, Varicella, EBV

Hepatitis B (HBsAg, anti-HBc, anti-HBs)

Hepatitis C (Hep C antibody)

As needed in women of non-child bearing potential only:
-
FSH and estradiol 

For women of child bearing potential only:
-
hCG pregnancy test, blood (urine only at screening)
NOTES :
1 Details of Liver Chemistry Increased Monitoring Criteria and Required Actions and 
Follow-Up Assessments after an event is reached are given in Section 5.4.1 and 
Appendix 2
2 Urea and Glucose are optional or ‘as needed’ after Day 7.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
7.4.7.
Immunogenicity
Low titres of ADAs have been observed post dosing with GSK1070806, but only one 
patient (of 82 exposed) had levels which were detectable on more than one occasion. 
Serum samples for testing antibodies against GSK1070806 will be collected as described 
in the Time and Events table (Section 7.1). Final samples will be taken when serum 
levels of GSK1070806 are lowest, and are anticipated to be below that causing ADA 


2015N240632_04
CONFIDENTIAL
204824
42
assay interference. For any non-completer, an attempt will be made to obtain a sample at 
30 days or later post dose.
The presence of anti-GSK1070806 binding antibodies will be assessed using a validated 
electrochemiluminescent (ECL) immunoassay. Immunogenicity sample testing will be 
performed by Clinical Immunology, GlaxoSmithKline. Details of blood sample 
collection (including volume to be collected), processing, storage and shipping 
procedures are provided in the SRM. For each subject, immunogenicity results, including 
the incidence and titers, will be reported.
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection and Analysis
Blood samples for pharmacokinetic (PK) analysis of GSK1070806 will be collected at 
the time points indicated in Section 7.1, Time and Events Table.  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.  
Processing, storage and shipping procedures are provided in the Study Reference Manual 
(SRM).
Serum analysis will be performed under the control of PTS-DMPK/Scinovo, 
GlaxoSmithKline, the details of which will be included in the Study Reference Manual 
(SRM). Concentrations of GSK1070806 will be determined in serum samples using the 
currently approved bioanalytical methodology. Raw data will be archived at the 
bioanalytical site (detailed in the SRM).
Once the serum has been analyzed for GSK1070806 any remaining serum may be 
analyzed for other drug-related catabolites and the results reported under a separate PTS-
DMPK/Scinovo, GlaxoSmithKline protocol.
7.5.2.
Renal Graft Biopsies
Graft biopsies will be obtained approximately 45 minutes post reperfusion of the kidney 
prior to closure of the abdominal wall. Post-reperfusion biopsies will be sent to GSK and 
utilized to assess pharmacokinetics/pharmacodynamics by detection of IL-18 and 
GSK1070806 within the renal parenchyma. Evaluating both IL-18 and GSK1070806 
levels within the interstitium of the kidney during early reperfusion is likely to be helpful 
in understanding the level of target engagement.  
Intra-operative biopsies may be ‘core’ or ‘wedge’ at the discretion of the operating 
surgeon with a preference for a wedge biopsy if this can be obtained safely. If the 
operating surgeon deems obtaining the biopsy as a potential risk to the subject this 
procedure may be omitted at their discretion. Processing, storage and shipping procedures 
are provided in the Study Reference Manual (SRM).


2015N240632_04
CONFIDENTIAL
204824
43
7.6.
Mechanistic Biomarker(s)/Pharmacodynamic Markers
Ischemia reperfusion has a direct negative impact in the kidney causing hypoxic cellular 
injury, ATP depletion, membrane depolarization, and free radical toxicity [Kalogeris, 
2012].  These cellular insults induce cytokine release and cellular infiltration to the site of 
injury.  IL-18 is a primary driver of the innate immune response leading to acute renal 
injury.
7.6.1.
Cytokines
IL-18 was first described as an IFNγ–inducing factor in the circulation of endotoxin-
injected mice [Nakamura, 1989].  In this study we will follow the effects of GSK1070806 
on IL-18 signalling following transplant, by taking measures of primary and secondary 
IL-18 responsive cytokines at time points defined in TE table (Section 7.1). 
7.6.2.
Renal Graft Biopsies
Biopsies will be obtained as outlined in Section 7.5.2 and assessed by histology and 
immunohistochemistry. If sufficient tissue is available, the sample will also be examined 
for immune cell infiltrates. Significant influx of innate immune cells has been observed 
on biopsies taken from renal allografts within the first hour of reperfusion, and the burden 
of infiltrating cells has been correlated with graft outcome [Fuggle, 1993], with more 
prominent infiltrates in kidneys from cadaveric donor derived allografts than living 
donors [Koo, 1998]. IL-18 has pleiotropic effects upon multiple cytokine systems and 
immune cells. It is therefore reasonable to hypothesize that IL-18 antagonism will 
decrease cellular infiltrates following ischemic renal injury. 
Where other clinical biopsy reports are available the data will be captured in the eCRF.
7.6.3.
Biomarkers relating to acute rejection
The IFN--inducible chemokines IP10 (CXCL10) and Mig (CXCL9) have been 
identified as early predictive markers of antibody-mediated kidney graft rejection 
[Hancock, 2001; Hauser, 2005; Matz, 2006].  This likely reflects their function in 
recruiting effector T cells to the site of inflammation.   We therefore will monitor changes 
in serum biomarkers, including IP10 and Mig, as IL-18 dependent predictors of allograft 
rejection.
7.6.4.
Clinical Biomarkers
7.6.4.1.
Urinary biomarkers of injury
NGAL: One of the earliest urinary markers of injury to appear is NGAL (Neutrophil-
gelatinase-associated lipocalin) which is transcriptionally induced rapidly following 
ischemia and secreted from intrarenal cells.  Elevated levels of NGAL protein are 
detectable in the urine within 3 hours after injury and its production is sustained for up to
5 days [Mishra, 2003].  


2015N240632_04
CONFIDENTIAL
204824
44
KIM1: KIM1 is expressed on T cells and is shed from the membrane in a matrix 
metalloprotein-dependent fashion following ischemia or toxic injury [Han, 2002]. It is
also considered to be an early marker of AKI. However its peak occurrence in the urine 
within 48 hours reflects a comparatively delayed response to injury consistent with its 
proposed role in renal recovery [Fontanilla, 2011].  
IL-18 is itself rapidly secreted from intracellular stores following inflammasome 
mediated-activation [Keyel, 2014].   Elevated levels of urinary IL-18 appear within 6 
hours after injury and peak at 12-18 hours.  The appearance of IL-18 marks the initiation 
of the inflammatory response leading to further injury [Wu, 2008]. We will monitor 
urinary NGAL and KIM1, and IL-18 levels starting from time 0 (preoperative) and over 
time post-transplantation as outlined in TE table Section 7.1.
Other disease urinary biomarkers may be assessed, as relevant, to enhance understanding 
of the IL-18 mechanism of action. All samples will be retained for a maximum of 5 years 
after the last subject completes the trial.
7.6.4.2.
Renal preservation fluid sampling
Emerging data indicate that higher IL-18 levels in kidney preservation fluid may predict 
delayed graft function and poorer outcome of transplantation. This fluid will be sampled 
and analysed for IL-18. Results will be compared with clinical outcomes.
7.6.5.
Circulating cellular phenotype (Cambridge only)
IL-18 receptor is expressed on macrophages, lymphocytes, neutrophils, and natural killer 
cells. Evidence from published studies suggests that IL-18 influences diverse immune 
functions and regulates other important mediators of immune responses. To understand 
the cellular immune response to transplantation in the absence of IL-18 signalling, serial 
whole blood samples will be examined by flow cytometry, RNA transcriptome analysis 
and in in vitro stimulation assays. Results will be reported separately.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, 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.  

CRFs (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.


2015N240632_04
CONFIDENTIAL
204824
45
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objective is to determine the effect of GSK1070806 on DGF.  Stopping rules 
have been defined to test whether the DGF rate is less than or equal to the null hypothesis 
rate of 50%.
A Bayesian sequential analysis of efficacy data will be utilized to allow for the possibility 
of stopping early for success or failure. Study success/failure will be declared once 
substantial evidence is observed.  “Success” at full enrolment is defined as 11 or fewer 
DGF events in 30 patients. After each patient has been evaluated during the course of the 
study, early success on the primary endpoint may be declared if the predictive probability 
of success is >0.92 (i.e. the probability the eventual number of DGF events would be 11 
or fewer if the study were to continue to full enrolment) and a failure may be declared on 
the primary endpoint if the predictive probability of success is <0.02. This check is made 
sequentially as each patient becomes evaluable by reaching 7 days post transplant. The 
coloured grid in Figure 3 illustrates which events may trigger an early Go (success) 
decision by green as the predictive probability of success >0.92 and No Go (failure) 
decision by red as the predictive probability of success < 0.02.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The DGF rate has been established at approximately 50% based on literature [Summers, 
2013] and contemporary registry data held by NHS Blood and Transplant.
Success in this study with full enrollment would be no more than 11 DGF occurrences in 
30 evaluable subjects. A Beta(5,8) prior distribution is set on the rate of DGF. This prior 
was selected because the Bayes estimate has smaller mean squared error than the 
maximum likelihood estimate over the true range of DGF rates from 20% to 60% for all 
sample sizes less than or equal to 30. 
As shown in Figure 2, at a maximum of 30 subjects, this design yields the probability of a 
‘go’ decision of 0.139 when the GSK1070806 DGF rate is 50% (ie: null hypothesis) and 
0.69 at what has been considered to be a clinically impactful GSK1070806 DGF rate of 
35%.


2015N240632_04
CONFIDENTIAL
204824
46
Figure 2
Operating Characteristic Curve
Up to approximately 30 subjects may be enrolled.  Efficacy data generated during the 
study will be used to inform the probability that GSK1070806 is performing at the above-
mentioned response rates.  This study may therefore conclude prior to completion of 
enrolling 30 subjects.  Under the null hypothesis (i.e. DGF rate = 50%) the probability 
that a no-go decision is declared by 50% enrolment (15 patients) is 0.3271 and by 75% 
enrolment (22 patients) is 0.6033.
9.2.2.
Sample Size Sensitivity
Sample sizes of 25, 30, 35, 40, and 45 were explored. Table 2 shows the type I error rates 
for a DGF rate of 50% and power for detecting a 35% DGF rate for the various sample 
size assumptions.  The type I error rate is the probability of a go decision if the true DGF 
rate is 50% (i.e., the null) and the power is the probability of a go decision if the true 
DGF rate is 35%. Increasing the sample size above 30 subjects has diminishing returns 
on type I error and power for the study.


2015N240632_04
CONFIDENTIAL
204824
47
Table 2
Probability of Go Decision under the Null for Various Sample Sizes
Probability of Go 
Decision
Type I error (if 
true DGF rate 
is 50%) 
Power (if true 
DGF rate is 
35%)
nmax= 25 
0.143 
0.659 
nmax = 30 
0.139 
0.690 
nmax = 35 
0.135 
0.716 
nmax = 40 
0.138 
0.742 
nmax = 45 
0.114 
0.747 
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.  The analysis of the primary endpoint is 
sequential and will be performed adaptively.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
All Subjects Population
The ‘All Subjects Population’ is defined as all subjects who receive a dose of study 
medication.
Analysis Population
For DGF related endpoints the ‘Analysis Population’ (AP) is defined as subjects in the 
‘All Subjects’ population who have been declared to have DGF or have reached 7 days. 
For other endpoints, the AP is defined as subjects having baseline and at least one post-
baseline assessment.
Per Protocol Population (PP)
The ‘Per Protocol Population’ will consist of any AP subjects who are compliant with 
protocol-specific criteria. Subjects with specified protocol deviations will be excluded. 
The Per Protocol population will be used for analysis of DGF rates.
Pharmacokinetic (PK) Population
The ‘PK Population’ is defined as subjects in the ‘All Subjects’ population for whom a 
serum pharmacokinetic sample was obtained and analyzed for GSK1070806.


2015N240632_04
CONFIDENTIAL
204824
48
9.3.2.
Interim Analysis
Safety, tolerability and efficacy data will be reviewed by the GSK study team on an 
ongoing basis throughout the study. These reviews can include individual subject data, 
summaries by treatment group and graphical displays. Preliminary safety, efficacy and 
PK results may be reported prior to database freeze for the purposes of safety review by 
GSK and where required by regulatory bodies.
The sequential decision rule is shown graphically in Figure 3.  The number in the first 
column indicates the number of subjects who have completed study treatment.  From the 
point in time when approximately 6 subjects have reached day 7 post transplantation the 
sponsor study team will begin to evaluate the DGF rates. This will start with the first 6 
subjects and then with addition of data from each subsequent subject that completes 7 
days of the trial.  A sequential Go/No Go/Continue rule is based on the predictive 
probability of success.  A high predictive probability (PP) of success means that 
GSK1070806 is likely to be efficacious by the end of the study given the observed data, 
whereas a low PP suggests that the treatment may not have sufficient activity.  If the PP 
value is less than 2% (red region) the trial may be stopped and the alternative hypothesis 
will be rejected. If the PP is greater 92% (green), the conclusion may be made that 
GSK1070806 has better efficacy than the standard of care.  If the PP is between 2 - 92% 
(white region), the trial will continue to the next interim analysis (to be conducted after 
the next subject has completed treatment) or until reaching 30 completed subjects.
This decision chart serves as guidance for the decision making at interim data reviews in 
terms of the primary efficacy endpoint. However, all efficacy and safety data will also be 
reviewed at the same time.  Decisions will be made based on the totality of the data. Once 
the last patient completes 7-Days post-transplant, an interim analysis will be performed 
of all available data for the primary endpoint in addition to supportive efficacy and safety 
data. The results of this interim analysis will be reviewed by the GSK study team and 
other relevant GSK staff for internal decision making. This review may 
include statisticians, programmers, clinical scientist and operation leads, physician 
project leader, safety review team, therapy area leads, and other GSK decision makers.
In addition to sequential review of the DGF data as noted above, an interim analysis will 
be performed after recruitment of approximately 6 subjects to review for a consideration 
of dose adjustment based on an integrated review of safety/tolerability, efficacy, and 
exposure [Section 4.5]. Any decision to change dose will be conducted in consultation 
with the GSK safety review team. 
If a dose adjustment is deemed necessary, ongoing sequential review based on efficacy 
will be guided by the grid in Figure 4, which includes a stopping criterion when the PP 
value is less than 10%.  If the PP is greater than 92% the conclusion may be made that 
GSK1070806 has better efficacy than the standard of care. Up to a maximum of 
approximately 40 subjects would be recruited into the current study if the dose is 
adjusted. Ongoing decision making for futility may integrate safety, efficacy, PK/PD, and 
biomarker data at both the original and adjusted dose. 


2015N240632_04
CONFIDENTIAL
204824
49
Figure 3
Sequential Decision Rules
Figure 4
Sequential Decision Rules after Dose Adjustment


2015N240632_04
CONFIDENTIAL
204824
50
9.4.
Key Elements of Analysis Plan
Complete details will be documented in the Reporting and Analysis Plan (RAP). Any 
deviations from, or additions to, the original analysis plan described in this protocol will 
be documented in the RAP and final study report.
Final analyses will be performed after all subjects have completed or withdrawn from the 
study and after database freeze. Version 9.1 or higher of the SAS system will be used to 
analyze the data as well as to generate tables, figures, and listings.
For continuous data, descriptive statistics of percentage change from baseline, change 
from baseline data and raw data where indicated in the RAP, (n, arithmetic, standard 
deviation, minimum, median and maximum) will be calculated and summarized by time. 
Graphical displays will be produced by time if deemed appropriate. For binary data, 
number of events and percentages will be calculated.  Subject listings will be produced.
9.4.1.
Primary Analyses
A summary of the observed DGF rate during the study will be provided.  The various 
posterior probabilities that the proportion of subjects experiencing DGF is less than 35% 
and/or 50% may be calculated under different prior assumptions.
9.4.2.
Secondary Analyses
Summaries of baseline and post-dose values or proportions of subjects at various time 
points will be provided.  Graft survival will be summarized by Kaplan-Meier plots.
9.4.3.
Other Analyses
Exploratory analyses will be summarized as noted above.  
9.4.4.
Safety Analyses
Safety data will be presented in tabular and/or graphical format, and will be summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
9.4.5.
Pharmacokinetic Analyses
Pharmacokinetic sampling will be related to the start of the GSK1070806 infusion 
procedure.  
PK analysis will be the responsibility of the GSK Clinical Pharmacology, Modelling and 
Simulation (CPMS) Department. Key PK parameters such as AUC may be calculated 
subject to data availability. PK parameters, if any generated, will be presented using 
appropriate graphic and tabular summaries.  Systemic GSK1070806 concentrations 
obtained from this study may be analyzed in a population PK analysis, to characterize 
further any potential effects of disease status, demographic or other patient characteristics 
based on data availability. The analysis details will be included in the Reporting and 
Analysis Plan (RAP).


2015N240632_04
CONFIDENTIAL
204824
51
Data permitting serum and urinary total and free IL-18 levels will be determined as 
outlined in the Time and Events table (Section 7.1).
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
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.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
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 current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.


2015N240632_04
CONFIDENTIAL
204824
52
10.3.
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 CRF 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
10.4.
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.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

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 non-compliance or futility. For multicenter studies, this can occur at one or 
more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.


2015N240632_04
CONFIDENTIAL
204824
53

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant 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 the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
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 elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site 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 ensure 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, GSK 
standards/procedures, and/or institutional requirements.  

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 is no longer associated with 
the site.
10.7.
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.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 


2015N240632_04
CONFIDENTIAL
204824
54
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.


2015N240632_04
CONFIDENTIAL
204824
55
11.
REFERENCES
Agostini C et al. (2001). Cxcr3 and its ligand CXCL10 are expressed by inflammatory 
cells infiltrating lung allografts and mediate chemotaxis of T cells at sites of rejection. 
Am.J.Pathol. 158, 1703-1711.
Alge JL & Arthur JM (2015). Biomarkers of AKI: A Review of Mechanistic Relevance 
and Potential Therapeutic Implications. Clin.J.Am.Soc.Nephrol. 10, 147-155.
British Transplantation Society Guidelines, 2011 
https://www.bts.org.uk/Documents/Guidelines/Active/Final%20CMV%20Guideline%20f
or%20web%2012-9-2011.pdf
Coca (2014). Urinary Biomarkers of AKI and Mortality 3 Years after Cardiac Surgery. J 
Am Soc Nephrol 25, 1063–1071.
Cruzado J et al. (2000). “Glomerulonephritis associated with hepatitis C virus infection 
after renal transplantation,” Nephrology Dialysis Transplantation, vol. 15, supplement 8, 
pp. 65–67.
Daemen MA, Denecker G, van't Veer C, Wolfs TG, Vandenabeele P, Buurman WA. 
Activated caspase-1 is not a central mediator of inflammation in the course of ischemia-
reperfusion. Transplantation. 2001 Mar 27;71(6):778-84
Dudler J et al. (2007). Gene transfer of interleukin-18-binding protein attenuates cardiac
allograft rejection. Transpl Int. 2007 May;20(5):460-6
Fabrizi F et al. (2004). “HBV infection in patients with end-stage renal disease,” 
Seminars in Liver Disease, vol. 24, no. 1, pp. 63–70.
Field M et al. (2014). The use of NGAL and IP-10 in the prediction of early acute 
rejection in highly sensitized patients following HLA-incompatible renal transplantation. 
Transpl Int. 27, 362-70.
Fontanilla J & Han WK (2011). Kidney injury molecule-1 as an early detection tool for 
acute kidney injury and other kidney diseases. Expert.Opin.Med.Diagn. 5, 161-173.
Fortin CF et al. (2009). Autocrine role of endogenous interleukin-18 on inflammatory 
cytokine generation by human neutrophils. FASEB J. 1, 194-203.
Fuggle SV et al. (1993). Variation in expression of endothelial adhesion molecules in 
pretransplant and transplanted kidneys--correlation with intragraft events. 
Transplantation. 55, 117-23
Futosi K et al. (2013). Neutrophil cell surface receptors and their intracellular signal 
transduction pathways. Int.Immunopharmacol. 17, 638-650.
GlaxoSmithKline Document Number WM2009/00047/04, GSK1070806 Investigator’s 
Brochure v04, 07-APR-2015.


2015N240632_04
CONFIDENTIAL
204824
56
Gracie JA et al. (2003). Interleukin-18. J.Leukoc.Biol. 73, 213-224.
Gu et al. (1997). Activation of interferon-gamma inducing factor mediated by 
interleukin-1beta converting enzyme. Science. 275, 206-9. 
Hall et al. (2010). IL-18 and Urinary NGAL Predict Dialysis and Graft Recovery after 
Kidney Transplantation. J Am Soc Nephrol 21, 189–197.
Hall et al. (2012). Association between Peritransplant Kidney Injury Biomarkers and 1-
Year Allograft Outcomes. Clin J Am Soc Nephrol 7, 1224–1233.
Han WK et al. (2002). Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human 
renal proximal tubule injury. Kidney Int. 62, 237-244.
Hancock et al. (2001). Donor-derived IP-10 initiates development of acute allograft 
rejection. J.Exp.Med. 193, 975-980.
Hatcher RA et al. editors (2011). Contraceptive Technology. 20th edition.  Atlanta, 
Georgia: Ardent Media, Inc., 50. Table 3-2.
Hauser IA et al. (2005). Prediction of acute renal allograft rejection by urinary monokine 
induced by IFN-gamma (MIG). J.Am.Soc.Nephrol. 16, 1849-1858.
He et al. (2008). Interleukin-18 binding protein transgenic mice are protected against 
ischemic acute kidney injury. Am J Physiol Renal Physiol. 295: F1414–F1421.
Issa F et al. (2010). Role of T cells in graft rejection and transplantation tolerance. Expert 
Rev Clin Immunol. 6, 155-69.
Kalia H et al. (2011). Hepatitis B virus and renal transplantation, Transplantation 
Reviews. 25, 102–109.
Kalogeris T et al (2012). Cell biology of ischemia/reperfusion injury. Int.Rev.Cell 
Mol.Biol. 298, 229-317.
Keyel, P.A. (2014). How is inflammation initiated? Individual influences of IL-1, IL-18 
and HMGB1. Cytokine 69, 136-145.
Kimura K et al. (2002). Interleukin-18 Inhibits Hepatitis B Virus Replication in the 
Livers of Transgenic Mice J. Virology 76, 10702–10707.
Koo DD et al. (1998). Ischemia/reperfusion injury in human kidney transplantation: an 
immunohistochemical analysis of changes after reperfusion. Am J Pathol. 153, 557-66.
Kunikata T et al. (1998). Constitutive and induced IL-18 receptor expression by various 
peripheral blood cell subsets as determined by anti-hIL-18R monoclonal antibody. Cell 
Immunol. 189, 135-143.
Kwon O et al. (2003). Urinary actin, interleukin-6, and interleukin-8 may predict 
sustained ARF after ischemic injury in renal allografts. Am.J.Kidney Dis. 41, 1074-1087.


2015N240632_04
CONFIDENTIAL
204824
57
Lewington AJ, Cerdá J, Mehta RL. Raising awareness of acute kidney injury: a global 
perspective of a silent killer. Kidney Int. 2013 Sep;84(3):457-67
Mathurin P et al. (1999). Impact of hepatitis B and C virus on kidney transplantation 
outcome. Hepatology. 29, 257–263.
Matz M et al. (2006) Early post-transplant urinary IP-10 expression after kidney 
transplantation is predictive of short- and long-term graft function. Kidney Int. 69, 1683-
1690.
Melnikov et al. (2001). Impaired IL-18 processing protects caspase-1–deficient mice 
from ischemic acute renal failure. J Clin Invest. 107, 1145–1152.
Melnikov et al. (2002). Neutrophil-independent mechanisms of caspase-1– and IL-18–
mediated ischemic acute tubular necrosis in mice. J. Clin. Invest. 110, 1083–1091.
Mishra J et al. (2003). Identification of neutrophil gelatinase-associated lipocalin as a 
novel early urinary biomarker for ischemic renal injury. J.Am.Soc.Nephrol. 14, 2534-
2543.
Mistry P et al. (2014). Safety, tolerability, pharmacokinetics, and pharmacodynamics of 
single-dose antiinterleukin- 18 mAb GSK1070806 in healthy and obese subjects. Int J 
Clin Pharmacol Ther. 52, 867-79.
Moers C et al.  (2009). The influence of deceased donor age and old-for-old allocation on 
kidney transplant outcome. Transplantation. 88, 542-52.
Musso T et al. (1992).  IL-2 induces IL-6 production in human monocytes. J.Immunol.
148, 795-800.
Nakamura K et al. (1989). Endotoxin-induced serum factor that stimulates gamma 
interferon production. Infect.Immun. 57, 590-595.
Okamura H et al. (1995). A novel costimulatory factor for gamma interferon induction 
found in the livers of mice causes endotoxic shock. Infect Immun. 63, 3966-72.
Parikh C et al. (2011). Postoperative Biomarkers Predict Acute Kidney Injury and Poor 
Outcomes after Adult Cardiac Surgery. J Am Soc Nephrol  22, 1748–1757.
Puren AJ et al. (1998). Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-
1beta via TNFalpha production from non-CD14+ human blood mononuclear cells. 
J.Clin.Invest 101, 711-721.
Puren AJ et al. (1999). Gene expression, synthesis, and secretion of interleukin 18 and 
interleukin 1b are differentially regulated in human blood mononuclear cells and mouse 
spleen cells. PNAS  96, 2256–2261.
Rabant M et al. (2015).  Urinary C-X-C Motif Chemokine 10 Independently Improves 
the Noninvasive Diagnosis of Antibody-Mediated Kidney Allograft Rejection. J Am Soc 
Nephrol. 26, 2840-51.


2015N240632_04
CONFIDENTIAL
204824
58
Rewa O & Bagshaw S (2014). Acute kidney injury—epidemiology, outcomes and 
economics. Nat. Rev. Nephrol. 10, 193–207
Ryden L et al. (2014). Acute Kidney Injury After Coronary Artery Bypass Grafting and 
Long-Term Risk of End-Stage Renal Disease. Circulation. 130, 2005-2011.
Sharma A et al. (2008). Elevation of interleukin-18 in chronic hepatitis C: implications 
for hepatitis C virus pathogenesis Immunology, 128,  e514–e522.
Shigeoka AA, Mueller JL, Kambo A, Mathison JC, King AJ, Hall WF, Correia Jda S, 
Ulevitch RJ, Hoffman HM, McKay DB. An inflammasome-independent role for 
epithelial-expressed Nlrp3 in renal ischemia-reperfusion injury. J Immunol. 2010 Nov 
15;185(10):6277-85
Striz I et al. (2005). Interleukin 18 (IL-18) upregulation in acute rejection of kidney 
allograft. Immunol Lett. 99, 30-5.
Summers D et al. (2013). Effect of donor age and cold storage time on outcome in 
recipients of kidneys donated after circulatory death in the UK: a cohort study. Lancet 
381, 727–34. 
Tak PP et al. (2006). Pharmacokinetics of IL-18 binding protein in healthy volunteers and 
subjects with rheumatoid arthritis or plaque psoriasis. Eur J Drug Metab 
Pharmacokinetics. 31, 109-16.
Tapiawala SN et al. (2010). Delayed graft function and the risk for death with a 
functioning graft. J Am Soc Nephrol. 21, 153-61.
Terrault N et al. (2007). The Kidney Transplant Recipient with Hepatitis C Infection: 
Pre- and Posttransplantation Treatment.   Clin J Am Soc Nephrol 2, 563-575.
Tone et al. (1997). Regulation of IL-18 (Interferon-ϒ inducing factor) gene expression. J. 
Immunol. 159, 6156-63.
Tsutsui H et al. (1996). IFN-gamma-inducing factor up-regulates Fas ligand-mediated 
cytotoxic activity of murine natural killer cell clones. J.Immunol. 157, 3967-3973.
Wu H et al. (2008). IL-18 contributes to renal damage after ischemia-reperfusion. 
J.Am.Soc.Nephrol. 19, 2331-2341.
Yoshimoto T et al. (1998a). IL-12 up-regulates IL-18 receptor expression on T cells, Th1 
cells, and B cells: synergism with IL-18 for IFN-gamma production. J.Immunol. 161, 
3400-3407.
Yoshimoto, T et al. (1998b). IL-12 up-regulates IL-18 receptor expression on T cells, 
Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. J.Immunol. 
161, 3400-3407.
Zhang et al. (2011). IL-18 mediates proapoptotic signaling in renal tubular cells through a 
Fas ligand-dependent mechanism. Am J Physiol Renal Physiol. 301, F171-8.


2015N240632_04
CONFIDENTIAL
204824
59
Zhang Q et al., (2014). Serum fractalkine and interferon-gamma inducible protein-10 
concentrations are early detection markers for acute renal allograft rejection. Transplant 
Proc. 46, 1420-5.


2015N240632_04
CONFIDENTIAL
204824
60
12.
APPENDICES
12.1.
Appendix 1:  Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ADA
Anti-Drug Antibodies
AKI
Acute Kidney Injury
ALT
Alanine Aminotransferase
AP
Analysis Population
AST
Aspartate Aminotransferase
ATG
Anti-Thymocyte Globulin
ATP
Adenosine Triphosphate
AUC
Area Under the Curve
CD4
Cluster of Differentiation 4
Cmax
Maximum Concentration
CMV
Cytomegalovirus
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CPMS
Clinical Pharmacology, Modelling and Simulation
CV
Cardiovascular
CXCL9
Chemokine (C-X-C motif) Ligand 9
CXCL10
Chemokine (C-X-C motif) Ligand 10
D0
Day 0
DCD
Donation after Circulatory Death
DGF
Delayed Graft Function
DNA
Deoxyribose Nucleic Acid
EBV
Epstein Barr Virus
ECG
Electrocardiogram
ECL
Electrochemiluminescent
eCRF
Electronic Case Report Form
FDA
Food and Drug Administration
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTIH
First Time In Human
GGT
Gamma-Glutamyl Transferase
GSK
GlaxoSmithKline
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
Hep B/C
Hepatitis B and C
HB
Hepatitis B
HBc
Hepatitis B core
HBsAg
Hepatitis B surface Antigen
HIV
Human Immunodeficiency Virus
hrs
Hours


2015N240632_04 
CONFIDENTIAL 
 
 
 
204824 
 
61 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IDSL 
Integrated Data Standards Library 
IEC 
Independent Ethics Board 
IFN 
Interferon-gamma 
IgG1 
Immunoglobulin G1 
IL-1 
Interleukin 1 
IL-6 
Interleukin 6 
IL-8 
Interleukin 8 
IL-18 
Interleukin 18 
IL-18BP 
Interleukin 18 Binding Protein 
IP-10 
Interferon gamma-induced Protein 10 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVIV 
Intravenous Immunoglobulin 
kg 
kilogram 
KIM-1 
Kidney Injury Molecule-1 
l 
liter 
LDH 
Lactate Dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
Mig 
Monokine Induced Gamma interferon 
mL 
milliliter 
MMF 
Myocphenolate Mofetil 
MSDS 
Material Safety Data Sheet 
mTOR 
Mechanistic Target of Rapamycin 
NGAL 
Neutrophil Gelatinase-Associated Lipocalin 
NHSBT 
United Kingdom National Health Service Blood and 
Transplant  
NOAEL 
No Observed Adverse Effect Level 
OKT3 
Muromonab-CD3 
PBMC 
Peripheral Blood Mononuclear Cell 
PBPK 
Physiological Based Pharmacokinetic Model 
PCP 
Pneuomocystis Carinii Pneumonia 
PCR 
Polymerase Chain Reaction 
PK 
Pharmacokinetic 
PD 
Pharmacodynamic 
pg 
picogram 
PP 
Predictive Probability 
PTLD 
Post Transplant Lymphoproliferative Disorder 
PTS-DMPK 
Platform Technology Sciences – Drug Metabolism and 
Pharmacokinetics 


2015N240632_04
CONFIDENTIAL
204824
62
QT
QT Interval
QTc
Corrected QT Interval
QTcB
Bazett Heart Rate Corrected QT Interval
RAP
Results Analysis Plan
RBC
Red Blood Cell
RIBA
Recombinant ImmunoBlot Assay
SAE
Serious Adverse Event
SOC
Standard Of Care
SRM
Study Reference Manual
SRT
Safety Review Team
T2DM
Type 2 Diabetes Mellitus
TB
Tuberculosis 
Th1
T helper cell 1
TLRs
Toll-like Receptors
TNF-
Tumor Necrosis Factor-alpha
UK
United Kingdom
ULN
Upper Limit of Normal
°C
Degrees Celsius
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ADVAIR
Chiron RIBA
SAS
WinNonlin


2015N240632_04
CONFIDENTIAL
204824
63
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
Phase II liver chemistry increased monitoring criteria and required follow up 
assessments 
Liver Chemistry Increased Monitoring Criteria
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Event
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below).  “Baseline” refers to 
the laboratory assessments performed closest 
and prior to dosing of study treatment.
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 72 hrs after an 
identified liver event if within 6 months 
post dose.5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form


2015N240632_04
CONFIDENTIAL
204824
64
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). 

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are 
included in the SRM.


2015N240632_04
CONFIDENTIAL
204824
65
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


2015N240632_04
CONFIDENTIAL
204824
66
12.3.
Appendix 3: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.3.1.
Definition of Adverse Events
Adverse Event Definition:

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.
Events meeting AE definition 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 judgement 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).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.


2015N240632_04
CONFIDENTIAL
204824
67
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the 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.

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.
12.3.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
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 


2015N240632_04
CONFIDENTIAL
204824
68
from baseline is not considered an AE.
d.
Results in disability/incapacity
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.
Other situations:

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.


2015N240632_04
CONFIDENTIAL
204824
69
12.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.3.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

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 CRF page.

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.


2015N240632_04
CONFIDENTIAL
204824
70
12.3.5.
Evaluating AEs and SAEs
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.
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.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


2015N240632_04
CONFIDENTIAL
204824
71
Follow-up of AEs and SAEs

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 CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.3.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

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 Medical Monitor. 

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 subject 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 the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


2015N240632_04
CONFIDENTIAL
204824
72
12.4.
Appendix 4: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.4.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyles. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.

Contraceptive subdermal implant

Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive[Hatcher, 2011])

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]

Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011].  The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination of the 
subject and/or semen analysis, or medical history interview provided by her or her 
partner.
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g.  male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2) 
2009]. 
The investigator is responsible for ensuring that subjects understand how to 
properly use these methods of contraception by providing counsel directly or by 
referring subjects to health care professionals with expertise in this area.
12.4.2.
Collection of Pregnancy Information
Female Participant:

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.


2015N240632_04
CONFIDENTIAL
204824
73

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Female Partner of Male Participant: 

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, 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

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.
References
Hatcher RA, Trussell J,  Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS,
editors. Contraceptive Technology. 20th edition.  Atlanta, Georgia: Ardent Media, Inc., 
2011: 50.  Table 3 2.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals.  ICH M3 (R2). 2009.


2015N240632_04
CONFIDENTIAL
204824
74
12.5.
Appendix 5: Protocol Amendment 1
Where the Amendment Applies
This amendment applies to all sites participating in this clinical trial. 
Summary of Amendment Changes with Rationale
This amendment clarifies sections of the protocol which were unclear. In the List of 
Specific Changes below, previous protocol version text is shown. Revised text with 
strikethrough revision marks denotes removed text; bold text denotes text that has been 
added.
List of Specific Changes
Section 2.2 Background, Paragraph 2, Lines 11 – 12:
PREVIOUS TEXT
membrane potentials) and from immune amplification of injury (stimulation of TLRs, 
cytokine release, complement activation, neutrophil and monocyte chemotaxis).
REVISED TEXT
membrane potentials) and from immune amplification of injury (stimulation of TLRs 
[toll-like receptors], cytokine release, complement activation, neutrophil and monocyte 
chemotaxis).
Section 4.6.1. Risk Assessment, Table (Potential Risks Line: Infection; 
Mitigation Column: Additions to Standards of Care Bullet List):
PREVIOUS TEXT
-
BK virus surveillance by BK PCR of whole blood will be performed post 
transplantation. In the event that a patient becomes BK +ve, screening will be 
repeated in accordance with UK guidelines. Immunosuppression will be 
reduced / titrated at the discretion of the investigator. 
In the event of deteriorating renal function in the context of BK viremia, 
transplant biopsy to diagnose BK nephropathy will be considered at the 
discretion of the investigator.
REVISED TEXT
-
BK virus surveillance by BK PCR of whole blood will be performed post 
transplantation. In the event that a patient becomes BK +ve, screening will be 
repeated in accordance with UK guidelines. Immunosuppression will be 
reduced / titrated at the discretion of the investigator. 
In the event of deteriorating renal function in the context of BK viremia, 
transplant biopsy to diagnose BK nephropathy will be considered at the 
discretion of the investigator.


2015N240632_04
CONFIDENTIAL
204824
75
-
Subjects must refrain from travelling to countries with a high prevalence 
of infectious disease from the time when the dose is administered until the 
end of the study (1 year post dose).
Section 5.1. Inclusion Criterion 5b: Females:
PREVIOUS TEXT
b. Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive 
Potential (FRP)...
REVISED TEXT
b. Reproductive potential: Must not be pregnant or lactating, and agrees to follow one 
of the options listed in the Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP)...
Section 5.2. Exclusion (Contraindications) Criterion 8:
PREVIOUS TEXT
8.
Receiving a DCD kidney allograft from a donor with any of the following 
characteristics
a.
cold ischemic time > 36 hours 
b. age < 5 years old
c.
age >75 years old.
d. ABO blood type incompatible against the recipient.
e.
T- and/or B-cell positive crossmatch by 
complement dependent cytotoxicity or flow 
cytometry against the recipient (where positive 
crossmatch is unavailable, virtual crossmatch is 
allowed). 
f.
serology positive for hepatitis B (except hepatitis B 
surface antibody and prior vaccination), hepatitis C 
or human immunodeficiency virus (HIV)
g. EBV positive donor allograft with an EBV negative 
recipient
h. donor had acute or chronic bacterial, viral or fungal 
infection that according to the investigator causes a 
risk to recipient, particularly if the infection was 
resistant or systemic 
i.
normothermic regional machine perfusion organ 
retrieval techniques were utilized


2015N240632_04
CONFIDENTIAL
204824
76
REVISED TEXT
8 
Receiving a DCD kidney allograft from a donor with any of the following 
characteristics
a.
cold ischemic time > 36 hours 
b. age < 5 years old
c.
age >75 years old.
d. ABO blood type incompatible against the recipient.
e.
T- and/or B-cell positive crossmatch by 
complement dependent cytotoxicity or flow 
cytometry against the recipient (where positive 
crossmatch is unavailable, virtual crossmatch is 
allowed). 
f.
serology positive for hepatitis B (except hepatitis B 
surface antibody and prior vaccination), hepatitis C 
or human immunodeficiency virus (HIV)
g. EBV positive donor allograft with an EBV negative 
recipient
h. donor had acute or chronic bacterial, viral or fungal 
infection that according to the investigator causes a 
risk to recipient, particularly if the infection was 
resistant or systemic 
i.
normothermic regional machine perfusion organ 
retrieval techniques were utilized
j.
surgical damage to donor allograft during organ 
procurement
Section 6.9. Lifestyle and/or Dietary Restrictions:
PREVIOUS TEXT
All subjects should follow the recommended lifestyle and dietary restrictions deemed as 
standard of care by investigators for renal transplant patients.
REVISED TEXT
All subjects should follow the recommended lifestyle and dietary restrictions deemed as 
standard of care by investigators for renal transplant patients.
Subjects must refrain from travelling to countries with a high prevalence of 
infectious disease from the time when the dose is administered until the end of the 
study (1 year post dose). 


2015N240632_04
CONFIDENTIAL
204824
77
Section 7.4.2. Pregnancy:
PREVIOUS TEXT

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until 180 days post dose.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.
REVISED TEXT

Pregnancy testing must be negative at screening, and be completed within 1 
week prior to GSK107806 administration in order for female subjects to 
enrol in this study.

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until 180 days post dose.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.
Section 12.1. Abbreviations and Trademarks:
PREVIOUS TEXT
AE
Adverse Event
GSK
GlaxoSmithKline
REVISED TEXT
AE
Adverse Event
ADA
Anti-Drug Antibodies
AKI
Acute Kidney Injury
ALT
Alanine Aminotransferase
AP
Analysis Population
AST
Aspartate Aminotransferase
ATG
Anti-Thymocyte Globulin
ATP
Adenosine Triphosphate
AUC
Area Under the Curve
CD4
Cluster of Differentiation 4
Cmax
Maximum Concentration
CMV
Cytomegalovirus
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CPMS
Clinical Pharmacology, Modelling and Simulation
CV
Cardiovascular


2015N240632_04
CONFIDENTIAL
204824
78
CXCL9
Chemokine (C-X-C motif) Ligand 9
CXCL10
Chemokine (C-X-C motif) Ligand 10
D0
Day 0
DCD
Donation after Circulatory Death
DGF
Delayed Graft Function
DNA
Deoxyribose Nucleic Acid
EBV
Epstein Barr Virus
ECG
Electrocardiogram
ECL
Electrochemiluminescent
eCRF
Electronic Case Report Form
FDA
Food and Drug Administration
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTIH
First Time In Human
GGT
Gamma-Glutamyl Transferase
GSK
GlaxoSmithKline
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
Hep B/C
Hepatitis B and C
HB
Hepatitis B
HBc
Hepatitis B core
HBsAg
Hepatitis B surface Antigen
HIV
Human Immunodeficiency Virus
hrs
Hours
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Board
IFN
Interferon-gamma
IgG1
Immunoglobulin G1
IL-1
Interleukin 1
IL-6
Interleukin 6
IL-8
Interleukin 8
IL-18
Interleukin 18
IL-18BP
Interleukin 18 Binding Protein
IP-10
Interferon gamma-induced Protein 10
INR
International Normalized Ratio
IRB
Institutional Review Board
IV
Intravenous
IVIV
Intravenous Immunoglobulin
kg
kilogram
KIM-1
Kidney Injury Molecule-1
l
liter
LDH
Lactate Dehydrogenase
MCH
Mean Corpuscular Hemoglobin


2015N240632_04
CONFIDENTIAL
204824
79
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
Mig
Monokine Induced Gamma interferon
mL
milliliter
MMF
Myocphenolate Mofetil
MSDS
Material Safety Data Sheet
mTOR
Mechanistic Target of Rapamycin
NGAL
Neutrophil Gelatinase-Associated Lipocalin
NHSBT
United Kingdom National Health Service Blood and 
Transplant 
NOAEL
No Observed Adverse Effect Level
OKT3
Muromonab-CD3
PBMC
Peripheral Blood Mononuclear Cell
PBPK
Physiological Based Pharmacokinetic Model
PCP
Pneuomocystis Carinii Pneumonia
PCR
Polymerase Chain Reaction
PK
Pharmacokinetic
PD
Pharmacodynamic
pg
picogram
PP
Predictive Probability
PTLD
Post Transplant Lymphoproliferative Disorder
PTS-DMPK
Platform Technology Sciences – Drug Metabolism and 
Pharmacokinetics
QT
QT Interval
QTc
Corrected QT Interval
QTcB
Bazett Heart Rate Corrected QT Interval
RAP
Results Analysis Plan
RBC
Red Blood Cell
RIBA
Recombinant ImmunoBlot Assay
SAE
Serious Adverse Event
SOC
Standard Of Care
SRM
Study Reference Manual
SRT
Safety Review Team
T2DM
Type 2 Diabetes Mellitus
TB
Tuberculosis 
Th1
T helper cell 1
TLRs
Toll-like Receptors
TNF
Tumor Necrosis Factor-alpha
UK
United Kingdom
ULN
Upper Limit of Normal
°C
Degrees Celsius


2015N240632_04
CONFIDENTIAL
204824
80
12.6.
Appendix 6: Protocol Amendment 2
Where the Amendment Applies
This amendment applies to all sites participating in this clinical trial. 
Summary of Amendment Changes with Rationale
This amendment updates eligibility criteria, makes minor formatting changes, and revises 
the protocol author list for technical approver purposes. In the List of Specific Changes 
below, except for author and minor format changes, the previous protocol version text is 
shown. Revised text with strikethrough revision marks denotes removed text; bold text 
denotes text that has been added.
List of Specific Changes
Section 1 Type and Number of Subjects:
PREVIOUS TEXT
Adult subjects (18-75 years of age). Dialysis-dependent, recipient of first-time, single 
kidney-only, Donation after Circulatory Death (DCD) transplants, receiving a planned 
immunosuppressive standard of care comprised of basiliximab, mycophenolate mofetil 
(MMF) or azathioprine, tacrolimus and corticosteroids.
REVISED TEXT
Adult subjects (18-75 years of age and older). Dialysis-dependent, recipient of first or 
second time, single kidney-only, Donation after Circulatory Death (DCD) transplants, 
receiving a planned immunosuppressive standard of care comprised of basiliximab, 
mycophenolate mofetil (MMF) or azathioprine, tacrolimus and corticosteroids. DCD 
donor kidneys must be ‘controlled’ meeting either Maastricht Category 3 or 4 
criteria.
Section 4.3. Type and Number of Subjects :
PREVIOUS TEXT

Adult subjects (18-75 years of age).

Dialysis-dependent, recipient of first-time, single kidney-only, Donation after 
Circulatory Death (DCD) transplants, receiving a planned immunosuppressive 
standard of care comprised of basiliximab, mycophenolate mofetil (MMF) or 
azathioprine, tacrolimus and corticosteroids.
REVISED TEXT

Adult subjects (18-75 years of age and older).


2015N240632_04
CONFIDENTIAL
204824
81

Dialysis-dependent, recipient of first-time and second time, single kidney-only, 
Donation after Circulatory Death (DCD) transplants, receiving a planned 
immunosuppressive standard of care comprised of basiliximab, mycophenolate 
mofetil (MMF) or azathioprine, tacrolimus and corticosteroids. DCD donor kidneys 
must be ‘controlled’ meeting either Maastricht Category 3 or 4 criteria.
Section 5.1. Inclusion Criteria:
PREVIOUS TEXT
AGE
1. Recipient age range: Between 18 and 75 years of age inclusive, at the time of signing 
the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2. Dialysis-dependent recipient of first time, single kidney-only, Donation after 
Circulatory Death (DCD) transplant.
REVISED TEXT
AGE
1. Recipient age range: Between 18 and 75 years of age and older inclusive, at the time 
of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2. Dialysis-dependent recipient of first or second time, single kidney-only, Donation 
after Circulatory Death (DCD) transplant.

Donor kidney must be ‘controlled’ meeting either Maastricht Category 3 
or 4 criteria:

Category 3: Donor awaiting cardiac arrest

Category 4: Cardiac arrest in a brain stem dead donor


2015N240632_04
CONFIDENTIAL
204824
82
Section 5.2. Exclusion Criteria :
PREVIOUS TEXT
CONTRAINDICATIONS 
8. Receiving a DCD kidney allograft from a donor with any of the following 
characteristics
a.
cold ischemic time > 36 hours 
b. age < 5 years old
c.
age >75 years old.
d. ABO blood type incompatible against the recipient.
e.
T- and/or B-cell positive crossmatch by complement dependent 
cytotoxicity or flow cytometry against the recipient (where positive 
crossmatch is unavailable, virtual crossmatch is allowed). 
f.
serology positive for hepatitis B (except hepatitis B surface antibody 
and prior vaccination), hepatitis C or human immunodeficiency virus 
(HIV)
g. EBV positive donor allograft with an EBV negative recipient
h. donor had acute or chronic bacterial, viral or fungal infection that 
according to the investigator causes a risk to recipient, particularly if 
the infection was resistant or systemic 
i.
normothermic regional machine perfusion organ retrieval techniques 
were utilized
j.
surgical damage to donor allograft during organ procurement
9. Previous organ transplantation: has previously undergone any other organ 
transplantation (with the exception of corneal transplantation).
REVISED TEXT
CONTRAINDICATIONS 
8. Receiving a DCD kidney allograft from a donor with any of the following 
characteristics
a.
cold ischemic time > 36 hours 
b. age < 5 years old
c.
age >75 years old.
c.
ABO blood type incompatible against the recipient.
d. T- and/or B-cell positive crossmatch by complement dependent 
cytotoxicity or flow cytometry against the recipient (where positive 
crossmatch is unavailable, virtual crossmatch is allowed). 


2015N240632_04
CONFIDENTIAL
204824
83
e.
serology positive for hepatitis B (except hepatitis B surface antibody and 
prior vaccination), hepatitis C or human immunodeficiency virus (HIV)
f.
EBV positive donor allograft with an EBV negative recipient
g. donor had acute or chronic bacterial, viral or fungal infection that 
according to the investigator causes a risk to recipient, particularly if the 
infection was resistant or systemic 
h. normothermic regional machine perfusion organ retrieval techniques were 
utilized
i.
surgical damage to donor allograft during organ procurement (surgical 
damage is defined as damage requiring surgical repair to make the 
organ usable)
j.
‘Uncontrolled’ Maastricht Category 1 (dead on arrival), Category 2 
(unsuccessful resuscitation), and Category 5 (unexpected cardiac 
arrest in a critically ill patient)
9. Previous organ transplantation: has previously undergone any other organ 
transplantation (with the exception of 1st kidney and/or corneal transplantation).
Section 7.1. Time and Events Table
PREVIOUS TEXT
Peripheral blood leucocyte flow phenotyping 14
PBMCs frozen for in vitro stimulation assays 14
PBMCs placed in trizol for transcriptomic analysis 14
REVISED TEXT
Peripheral blood leucocyte flow phenotyping, with optional in vitro stimulation 
assays and transcriptomic analysis 14
PBMCs frozen for in vitro stimulation assays 14
PBMCs placed in trizol for transcriptomic analysis 14
Section 9.3.2. Interim Analysis:
PREVIOUS TEXT
This decision chart serves as guidance for the decision making at interim data reviews in 
terms of the primary efficacy endpoint. However, all efficacy and safety data will also be 
reviewed at the same time.  Decisions will be made based on the totality of the data.


2015N240632_04
CONFIDENTIAL
204824
84
REVISED TEXT
This decision chart serves as guidance for the decision making at interim data reviews in 
terms of the primary efficacy endpoint. However, all efficacy and safety data will also be 
reviewed at the same time.  Decisions will be made based on the totality of the data. 
Once the last patient completes 7-Days post-transplant, an interim analysis will be 
performed of all available data for the primary endpoint in addition to supportive 
efficacy and safety data. The results of this interim analysis will be reviewed by the 
GSK study team and other relevant GSK staff for internal decision making. This 
review may include statisticians, programmers, clinical scientist and operation 
leads, physician project leader, safety review team, therapy area leads, and other 
GSK decision makers.


2015N240632_04
CONFIDENTIAL
204824
85
12.7.
Appendix 7: Protocol Amendment 3
Where the Amendment Applies
This amendment applies to all sites participating in this clinical trial. 
Summary of Amendment Changes 
The following changes have been made in this protocol amendment:

Following suspension of enrolment of subjects in the 204824 study on March 23rd
2017, due to an SAE of successfully defibrillated/ resuscitated ventricular 
fibrillation/ cardiac arrest, eligibility criteria have been updated to reduce the chance 
of enrolment of patients with high cardiac risk profiles who are at risk of coincident 
events which may confound the ability to define the benefit/risk of treatment in this 
study. The benefit/risk of GSK1070806 remains unchanged. 

Based on emergent efficacy and PKPD data, the number of subjects required to be 
treated prior to a decision to escalate dose has been reduced, and stopping criteria 
following dose escalation have been amended. 

In addition, modifications to study participant assessments have been made to reduce 
assessment burden to study participants while maintaining safety (e.g., allowing 
flexibility in hematology/chemistry/urinalysis assessments). 

Duration of mandated nystatin therapy has been reduced in response to feedback from 
investigators. 

Minor clarifications of text have also been incorporated. 
In the List of Specific Changes below, except for author and minor format changes, the 
previous protocol version text is shown. Revised text with strikethrough revision marks 
denotes removed text; bold text denotes text that has been added.
List of Specific Changes
Section 4.5. Dose Justification:
RATIONALE FOR CHANGE
The original decision to increase the dose, based on data from approximately 8-10 
subjects, is being reduced to 6 subjects based on an integrated review of 
safety/tolerability, efficacy, and exposure data.
Following this integrated review, a decision has been undertaken to increase the dose 
from 3mg/kg to 10mg/kg. The data review indicated possible suboptimal efficacy at the 
3mg/kg dose level, and PKPD data indicative to enhance exposure during early 
reperfusion.


2015N240632_04
CONFIDENTIAL
204824
86
PREVIOUS TEXT
GSK1070806 Dose Modelling for Renal Transplant: A physiological based 
pharmacokinetic (PBPK) model and prior clinical PK data were used to model the dose 
requirement based on the anticipated need to inhibit IL-18 (>90% target engagement) 
rapidly (1-2 hours post-dose) in both the interstitial space of the kidney and the 
circulating plasma. Using preliminary data on circulating IL-18 levels in renal transplant 
patients (anticipated maximum of 1400 pg/mL) and conservative assumptions that 
enhanced IL-18 levels in DGF were driven by increases in IL-18 production (versus 
slower metabolism) and derived within the kidney, target engagement with various doses 
of GSK1070806 was modelled.  The PBPK model parameters were adjusted to test 
sensitivity with respect to extent of target engagement at various dose levels.  Based on 
these data, in the current study we propose to use a single dose of 3 mg/kg administered 
prior to reperfusion of the transplanted kidney. The use of the single 3 mg/kg dose is well 
supported by the observed safety data generated in prior clinical studies (n=36 subjects 
have received ≥3 mg/kg) and the PBPK model based approach outlined above, which 
predicts a rapid engagement in the kidney interstitium followed by >90% inhibition for 
the 7 days leading up to assessment of the DGF primary endpoint. 
Dose Adjustment: Data will be reviewed at an interim analysis after recruitment 8 to 10 
subjects [Section 9.3.2]. Depending on an integrated review of safety/tolerability, 
efficacy, and exposure, a dose adjustment will be considered. This review will include 
available data from the assessment of renal interstitial target engagement performed on 
renal biopsies, in which an estimated target engagement of less than approximately 90% 
in the majority of subjects will support consideration to increase dose above 3 mg/kg in 
subsequent recruited subjects. A minimum of 30 days post-dose safety experience in at 
least 6 subjects, along with a minimum of 7 days post-dose safety experience in the 
remaining interim subjects will be evaluated. Any decision to increase dose will be 
conducted in consultation with the GSK safety review team (SRT). The maximum dose 
level administered to patients will not exceed 10mg/kg as precedented by previous 
clinical studies.
REVISED TEXT
GSK1070806 Dose Modelling for Renal Transplant: A physiological based 
pharmacokinetic (PBPK) model and prior clinical PK data were used to model the dose 
requirement based on the anticipated need to inhibit IL-18 (>90% target engagement) 
rapidly (1-2 hours post-dose) in both the interstitial space of the kidney and the 
circulating plasma. Using preliminary data on circulating IL-18 levels in renal transplant 
patients (anticipated maximum of 1400 pg/mL) and conservative assumptions that 
enhanced IL-18 levels in DGF were driven by increases in IL-18 production (versus 
slower metabolism) and derived within the kidney, target engagement with various doses 
of GSK1070806 was modelled.  The PBPK model parameters were adjusted to test 
sensitivity with respect to extent of target engagement at various dose levels.  Based on 
these data, in the current study we propose to start the study with initial participants 
receiving use a single dose of 3 mg/kg administered prior to reperfusion of the 
transplanted kidney. The use of the single 3 mg/kg dose is well supported by the observed 
safety data generated in prior clinical studies (n=36 subjects have received ≥3 mg/kg) 


2015N240632_04
CONFIDENTIAL
204824
87
and the PBPK model based approach outlined above, which predicts a rapid target
engagement in the kidney interstitium followed by >90% inhibition for the 7 days leading 
up to assessment of the DGF primary endpoint. 
Dose Adjustment: Data will be reviewed at an interim analysis after recruitment of at 
least 6 8 to 10 subjects, who have a minimum of 30 days post-dose safety experience 
data [Section 9.3.2]. Depending on an integrated review of safety/tolerability, efficacy, 
and exposure, a dose adjustment will be considered. This review will include available 
data from the assessment of renal interstitial target engagement performed on renal 
biopsies., in which an If estimated target engagement appears to be suboptimal of less 
than approximately 90% in the majority of subjects, this will support consideration to 
increase dose above 3 mg/kg in subsequent recruited subjects. A minimum of 30 days 
post-dose safety experience in at least 6 subjects, along with a minimum of 7 days post-
dose safety experience in the remaining interim subjects will be evaluated. Any decision 
to increase dose will be conducted in consultation with the GSK safety review team 
(SRT). The maximum dose level administered to patients will not exceed 10mg/kg as 
precedented by previous clinical studies.
Section 4.6.1. Risk Assessment, Infection Mitigation Strategy:
RATIONALE FOR CHANGE
This is a clarification to state that the starting dose for this study is 3mg/kg. The 
mitigation strategy remains the same.
PREVIOUS TEXT

Of note, patients in the current study are pharmacologically immunosuppressed as standard of care. 
Furthermore, IL-18 system neutralization is likely to have a duration of approximately 6-9 months at the 
3mg/kg dose. Accordingly, infection is the key risk in this clinical program.

Dose selection
The dose of 3 mg/kg has been selected as it is considered to be the minimum dose that will achieve 
sufficient IL18 inhibition in the initial hours after transplantation, during which it is presumed that the 
pathological processes causing DGF are initiated. This minimizes the duration of prolonged IL18 
inhibition in order to mitigate any potential infection risk due to the addition of GSK1070806 to the 
immunosuppressive standard of care.
REVISED TEXT

Of note, patients in the current study are pharmacologically immunosuppressed as standard of care. 
Furthermore, IL-18 system neutralization is likely to have a duration of approximately 6-9 months at the 
3mg/kg dose, extending to 9-10 months at themaximal 10mg/kg dose. Accordingly, infection is the 
key risk in this clinical program.

Dose selection
The starting dose of 3 mg/kg has been selected as it is considered to be the minimum dose that will 
achieve sufficient IL18 inhibition in the initial hours after transplantation, during which it is presumed 
that the pathological processes causing DGF are initiated. This minimizes the duration of prolonged 
IL18 inhibition in order to mitigate any potential infection risk due to the addition of GSK1070806 to the 
immunosuppressive standard of care.


2015N240632_04
CONFIDENTIAL
204824
88
Section 5.2. Exclusion Criteria:
RATIONALE FOR CHANGE
A total of seven (7) subjects, receiving a single Donation after Circulatory Death renal 
transplant have been enrolled in the on-going 204824 study. All subjects received a single 
3mg/kg dose of GSK1070806.
The study was paused on the 24th March 2017 due to an SAE occurring in the 7th study 
subject enrolled on the 22nd March 2017, who developed ventricular fibrillation/ cardiac 
arrest during the transplant operation, from which he was successfully defibrillated and 
resuscitated. The subject had a number of risk factors for ischemic heart disease including 
T2DM, ongoing smoking, obesity, end stage renal disease, sleep apnoea, dislipidaemia, a 
history of past cocaine use and hypertension. It transpired that the patient had been 
experiencing chest pain and hypotension during dialysis in the weeks prior to 
transplantation but these were not reported to investigators at the time of enrolment. A 
pre-operative ECG showed left bundle branch block. Coronary angiography performed 
post-operatively demonstrated severe 2-vessel disease (including LAD and RCA) with 
evidence of acute intra-coronary thrombosis and vessel closure, requiring urgent 
revascularization with two drug eluting stents. The intra-operative cardiac arrest was 
attributed to ischemic ventricular fibrillation. No signs or symptoms were indicative of 
infusion reaction. 
Twenty-seven days following surgery (19th April 2017), while the patient remained an 
inpatient, and during hemodialysis, the patient suffered a further cardiac arrest, initially 
diagnosed as asystole, which became ventricular fibrillation after administration of 
adrenaline. Defibrillation and cardiopulmonary resuscitation were successful, and the 
patient recovered. Subsequently, while monitored on the coronary care unit, the patient 
was noted to have ongoing rhythm abnormalities. A rhythm strip supplied by the site 
shows high grade atrioventricular block with a profoundly bradycardic ventricular 
escape, followed by polymorphic ventricular tachycardia (torsades) which terminated 
spontaneously. The clinical picture and ECG data have been reviewed by GSK safety 
committees who feel that the most likely explanation of this arrhythmia is that the 
previous intra-operative myocardial infarction resulted in worsening of baseline 
conduction system disease, and that the ‘asystole’ in the second cardiac arrest was 
probably complete heart block without an escape rhythm that ultimately degenerated into 
polymorphic ventricular tachycardia/ ventricular fibrillation. 
The clinical events were considered in the context of preclinical safety data (see Section 4 
of the Investigator’s Brochure), and the published literature by GSK safety committees, 
and it was concluded that they were unlikely to be related to study drug. Therefore there 
has been no change in the evaluation of risk/benefit, or any planned dose escalation 
decisions. However, subjects with specific cardiac histories will be excluded from study 
participation in order to reduce the risk of additional coincident events which may 
confound the ability to define the benefit/risk of treatment (see Section 5.2 of the 
Protocol – “ventricular arrhythmia” and “acute cardiovascular syndromes within six 
months before screening” added to the list of exclusion criteria). Furthermore, the site 


2015N240632_04
CONFIDENTIAL
204824
89
responsible for enrolment of the affected patient will receive additional training in 
adherence to the clinical protocol prior to recruitment of further subjects. 
PREVIOUS TEXT
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1.
Liver function: ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
2.
QT interval: single or average QTc > 480 msec or in subjects with bundle branch 
block QTc > 500 msec (these criteria do not apply to subjects with predominately 
paced rhythms).
REVISED TEXT
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1.
Liver function: ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
2.
QT interval: single or average QTc > 480 msec or in subjects with bundle branch 
block QTc > 500 msec (these criteria do not apply to subjects with predominately 
paced rhythms).
3.
Ventricular arrhythmia: History of cardiac arrest or malignant ventricular 
arrhythmia at any time.Any acute cardiovascular syndrome within six months 
before screening. These may include acute coronary syndrome (myocardial 
infarction or unstable angina) or coronary intervention (percutaneous or surgical), or 
acute stroke..
Section 5.5. Safety Interim Analysis
RATIONALE FOR CHANGE
This is to amend the number of subjects required to perform a safety interim assessment 
which will be performed at the same time as the dose adjustment interim – see Section 
4.5. 
PREVIOUS TEXT
A safety interim assessment after 8-10 subjects will be performed at the same time as the 
dose adjustment interim (Section 4.5).
REVISED TEXT
A safety interim assessment after 8-10 6 subjects will be performed at the same time as 
the dose adjustment interim (Section 4.5).


2015N240632_04
CONFIDENTIAL
204824
90
Section 6.10.4.1. Pneumocystis and Fungal Infection Prophylaxis
RATIONALE FOR CHANGE
At the request of Principal Investigators, the Sponsor is reducing infection prophylaxis 
requirements to reduce subject burden while maintaining infection and safety surveillance 
during the trial. This request was reviewed by both the Safety Review Team and an 
external infectious disease specialist. 
PREVIOUS TEXT
A minimum of 12 months of pneuomocystis and fungal infection prophylaxis with 
cotrimoxazole and nystatin, respectively (or equivalents), should be implemented unless 
otherwise contraindicated.
REVISED TEXT
A minimum of 12 3 months of pneuomocystis and fungal infection prophylaxis with 
cotrimoxazole and nystatin, respectively (or equivalents), should be implemented unless 
otherwise contraindicated.
Section 7.1. Time and Events Table, Footnotes
RATIONALE FOR CHANGE
Footnotes 1 and 10 are clarifications; footnote 18 has been added to offer flexibility while 
reducing subject burden and maintaining subject safety. 
PREVIOUS TEXT
1.
Day 0 defined as the calendar day of transplant.
2.
Time post reperfusion. 
3.
Biopsies during transplantation may be ‘core or wedge’ at the discretion of the operating surgeon. If, in the 
judgement of the operating surgeon, biopsy poses unwarranted risk to the patient, it may be omitted.
4.
Viral serology will include HIV, HBsAg, anti-HBc, anti-HBs antibodies, and hepatitis C antibody (if hepatitis C 
antibody positive, a hepatitis C RIBA immunoblot or polymerase chain reaction assay should be reflexively 
performed on the same sample to confirm the results as per NHS standard procedure), and serology for herpes 
simplex virus, Epstein Barr virus, and varicella zoster virus. 
5.
Screening viral status may be the most recent value recorded in the patient’s medical records.
6.
If BK positive then follow up screening should be implemented.
7.
Vital signs will include systolic and diastolic blood pressure, pulse rate, and temperature. 
8.
Pregnancy testing will be performed in women of childbearing potential.  Screening test may be urine or serum.
9.
Sampling time points may be adjusted as appropriate based on emerging data.
10. PK sampling time points are as follows:  predose, 45 min to 1 hr into infusion (coinciding with biopsy), 4-8 hrs,  24 
hrs, 168 hrs (or pre-discharge if discharge before day 7), day 30 day 90, 6 and 12 months.  Exact PK sampling
time is to be recorded.
11. Blood and urine samples for immunogenicity and biomarker analyses must be collected prior to infusion with 
GSK1070806
12. For any non-completer a serum sample for immunogenicity testing will be taken 12 mths post-operatively.
13. For subjects who withdraw from study, where possible, assessments should continue according to the Time and 
Events table. The 6 and 12 mth safety follow-up should be performed. 
14. Samples for subjects from Cambridge site only.


2015N240632_04
CONFIDENTIAL
204824
91
15. GSK1070806 can be infused any time during the pre-operative and/or intra-operative periods, but infusion must
be complete prior to reperfusion of the allograft. 
16. Sample to be obtained at time of back-table allograft preparation.
17. Documentation of anaesthetics excluded.
REVISED TEXT
1.
Day 0 defined as the calendar day of transplant. Screening begins after the participant gives study informed-
consent and is being prepared for surgery; the estimated time window for screening assessments 
completion is 12h. Timings outside of 12 hour, but within the time of admission and surgery, will not be 
considered protocol deviations.
2.
Time post reperfusion. 
3.
Biopsies during transplantation may be ‘core or wedge’ at the discretion of the operating surgeon. If, in the 
judgement of the operating surgeon, biopsy poses unwarranted risk to the patient, it may be omitted.
4.
Viral serology will include HIV, HBsAg, anti-HBc, anti-HBs antibodies, and hepatitis C antibody (if hepatitis C 
antibody positive, a hepatitis C RIBA immunoblot or polymerase chain reaction assay should be reflexively 
performed on the same sample to confirm the results as per NHS standard procedure), and serology for herpes 
simplex virus, Epstein Barr virus, and varicella zoster virus. 
5.
Screening viral status may be the most recent value recorded in the patient’s medical records.
6.
If BK positive then follow up screening should be implemented.
7.
Vital signs will include systolic and diastolic blood pressure, pulse rate, and temperature. 
8.
Pregnancy testing will be performed in women of childbearing potential.  Screening test may be urine or serum.
9.
Sampling time points may be adjusted as appropriate based on emerging data.
10. PK sampling time points are as follows:  predose, 45 min to 1 hr into infusion after reperfusion (coinciding with 
biopsy), 4-8 hrs,  24 hrs, 168 hrs (or pre-discharge if discharge before day 7), day 30 day 90, 6 and 12 months.  
Exact PK sampling time is to be recorded.
11. Blood and urine samples for immunogenicity and biomarker analyses must be collected prior to infusion with 
GSK1070806
12. For any non-completer a serum sample for immunogenicity testing will be taken 12 mths post-operatively.
13. For subjects who withdraw from study, where possible, assessments should continue according to the Time and 
Events table. The 6 and 12 mth safety follow-up should be performed. 
14. Samples for subjects from Cambridge site only.
15. GSK1070806 can be infused any time during the pre-operative and/or intra-operative periods, but infusion must
be complete prior to reperfusion of the allograft. 
16. Sample to be obtained at time of back-table allograft preparation.
17. Documentation of anaesthetics excluded.
18. If a study participant remains in hospital at Day 10, daily hematology / clinical chemistry / urinalysis 
assessments may be reduced to being performed every other day, at the Principal Investigator’s 
discretion. 


2015N240632_04
CONFIDENTIAL
204824
92
Section 7.4.1.1. Time Period and Frequency for Collecting AE and SAE 
Information
RATIONALE FOR CHANGE
The correct appendix number has been substituted.
PREVIOUS TEXT
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
REVISED TEXT
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4 Appendix 3.
Section 7.5.2. Renal Graft Biopsies
RATIONALE FOR CHANGE
This is a clarification that wedge biopsies are preferred over core biopsy material due to 
the increased data obtainable from a wedge biopsy’s wider margins. 
PREVIOUS TEXT
Intra-operative biopsies may be ‘core’ or ‘wedge’ at the discretion of the operating 
surgeon.
REVISED TEXT
Intra-operative biopsies may be ‘core’ or ‘wedge’ at the discretion of the operating 
surgeon with a preference for a wedge biopsy if this can be obtained safely.
Section 7.4.6. Clinical Safety Laboratory Assessments, Table 1
RATIONALE FOR CHANGE
This change allows sites to more closely follow their standards of care for safety allowing 
for flexibility.  
PREVIOUS TEXT
NOTES :
1 Details of Liver Chemistry Increased Monitoring Criteria and Required Actions and 
Follow-Up Assessments after an event is reached are given in Section 5.4.1 and 
Appendix 2


2015N240632_04
CONFIDENTIAL
204824
93
REVISED TEXT
NOTES :
1 Details of Liver Chemistry Increased Monitoring Criteria and Required Actions and 
Follow-Up Assessments after an event is reached are given in Section 5.4.1 and 
Appendix 2
2 Urea and Glucose are optional or ‘as needed’ after Day 7.
Section 7.6.5. Circulating Cellular Phenotype (Cambridge only)
RATIONALE FOR CHANGE
This is a clarification change; the data obtained from these samples will not be part of the 
study report generated from this study.  
PREVIOUS TEXT
IL-18 receptor is expressed on macrophages, lymphocytes, neutrophils, and natural killer 
cells. Evidence from published studies suggests that IL-18 influences diverse immune 
functions and regulates other important mediators of immune responses. To understand 
the cellular immune response to transplantation in the absence of IL-18 signalling, serial 
whole blood samples will be examined by flow cytometry, RNA transcriptome analysis 
and in in vitro stimulation assays. 
REVISED TEXT
IL-18 receptor is expressed on macrophages, lymphocytes, neutrophils, and natural killer 
cells. Evidence from published studies suggests that IL-18 influences diverse immune 
functions and regulates other important mediators of immune responses. To understand 
the cellular immune response to transplantation in the absence of IL-18 signalling, serial 
whole blood samples will be examined by flow cytometry, RNA transcriptome analysis 
and in in vitro stimulation assays. Results will be reported separately.
Section 9.3.2. Interim Analysis
RATIONALE FOR CHANGE
The Sponsor is amending the number of subjects (from 8-10 to 6) from which data are 
required to make a decision to escalate the dose of investigational product. This section 
describes the statistical considerations undertaken for increasing the dose given to 
subsequent study subjects, and tightens the point at which futility is assumed to be 
reached: from less than 2% predicted probability of success to less than 10% predicted 
probability of success. Figure 3 has been replaced with a corrected figure and Figure 4 
has been added. 
PREVIOUS TEXT
In addition to sequential review of the DGF data as noted above, an interim analysis will 
be performed after recruitment of approximately 8 to 10 subjects to review for a 


2015N240632_04
CONFIDENTIAL
204824
94
consideration of dose adjustment based on an integrated review of safety/tolerability, 
efficacy, and exposure [Section 4.5]. Any decision to change dose will be conducted in 
consultation with the GSK safety review team. If a dose adjustment is made, then the 
decision grid in Figure 3 would return to the top and up to a maximum of 30 subjects at 
the adjusted dose would be evaluated sequentially using the same Go/No Go/Continue 
rules as defined above. Hence approximately 40 subjects would be recruited into the 
current study if the dose is adjusted. 


2015N240632_04
CONFIDENTIAL
204824
95
Figure 3 Sequential Decision Rules:
REVISED TEXT
In addition to sequential review of the DGF data as noted above, an interim analysis will 
be performed after recruitment of approximately 6 8-10  subjects to review for a 
consideration of dose adjustment based on an integrated review of safety/tolerability, 
efficacy, and exposure [Section 4.5]. Any decision to change dose will be conducted in 
consultation with the GSK safety review team. 
If a dose adjustment is made deemed necessary, ongoing sequential review based on 
efficacy will be guided by the grid in Figure 4, which includes a stopping criterion when 
the PP value is less than 10%.  If the PP is greater than 92% the conclusion may be made 
that GSK1070806 has better efficacy than the standard of care. Up to a maximum of 
approximately 40 subjects would be recruited into the current study if the dose is 
adjusted. Ongoing decision making for futility may integrate safety, efficacy, PK/PD, and 
biomarker data at both the original and adjusted dose. then the decision grid in Figure 3
would return to the top and up to a maximum of 30 subjects at the adjusted dose would be 
evaluated sequentially using the same Go/No Go/Continue rules as defined above. Hence 
approximately 40 subjects would be recruited into the current study if the dose is 
adjusted.


2015N240632_04
CONFIDENTIAL
204824
96
Figure 3
Sequential Decision Rules
Figure 4
Sequential Decision Rules after Dose Adjustment


2015N240632_04
CONFIDENTIAL
204824
97
Section 9.4.1. Primary Analyses
RATIONALE FOR CHANGE
This clarification is to refine appropriate summary statistics. 
PREVIOUS TEXT
A summary of the observed DGF rate during the study will be provided.  The posterior 
probability that the proportion of subjects experiencing DGF is less than 50% will be 
calculated.  
REVISED TEXT
A summary of the observed DGF rate during the study will be provided.  The various 
posterior probabilities that the proportion of subjects experiencing DGF is less than 
35% and/or 50% may be calculated under different prior assumptions. The posterior 
probability that the proportion of subjects experiencing DGF is less than 50% will be 
calculated.  
Section 10.5. Study and Site Closure
RATIONALE FOR CHANGE
PREVIOUS TEXT

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. For multicenter studies, this can occur at one or more 
or at all sites.  
REVISED TEXT

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 non-compliance or futility. For multicenter studies, this can occur at one or 
more or at all sites.  

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
204824
1
Division
:
Worldwide Development
Information Type     
:
Reporting and Analysis Plan
Title
:
Reporting and Analysis Plan for Study 204824: A Phase 2, 
Pilot, Multicenter, Single Arm Study to Evaluate the Efficacy, 
Safety, Tolerability, and Pharmacokinetics of GSK1070806 
plus Standard of Care for the Prevention of Delayed Graft 
Function in Adult Subjects After Renal Transplantation
Compound Number 
:
GSK1070806
Effective Date 
:
May-24-2017
Description :

The purpose of this Reporting and Analysis Plan (RAP) is to describe the planned
efficacy, safety & tolerability, and pharmacokinetics analyses and output to be 
included in the Clinical Study Report for Protocol 204824.  

This document will be provided to the study team members to convey the content of 
interim and final Statistical Analysis Complete (SAC) deliverable.

Purpose of RAP Amendment 1: 
o
Change the number of patients for dose escalation interim analysis from 8 -10 
to 6 to match the protocol amendment.
o
Remove outputs for the IA1 delivery which are no longer required for a dose 
escalation decision, defined as IA1 in this document.
Author’s Name and Functional Area: 
May-24-2017
Principal Statistician (Clinical Statistics)
May-24-2017
Director (Clinical Pharmacology, Modeling and Simulation)
May-24-2017
Director (Quantitative Clinical Pharmacology), PAREXEL
Approved by: 
May-24-2017
Senior Statistics Director (Clinical Statistics)
PPD
PPD
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
204824
2
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.


CONFIDENTIAL
GSK1070806
3
TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS....................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ...........................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan .........................................6
2.2.
Study Objective(s) and Endpoint(s) ............................................................................6
2.3.
Study Design ...............................................................................................................8
2.4.
Statistical Hypotheses..................................................................................................7
2.5.
Definition of Renal Graft Function .............................................................................7
3.
PLANNED ANALYSES..........................................................................................................9
3.1.
Interim Analyses..........................................................................................................9
3.2.
Final Analyses ...........................................................................................................10
4.
ANALYSIS POPULATIONS ................................................................................................12
4.1.
Protocol Deviations ...................................................................................................12
5.
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS..............................................................................................13
6.
STUDY POPULATION ANALYSES...................................................................................13
6.1.
Planned Analyses Overview......................................................................................13
7.
PRIMARY STATISTICAL ANALYSES..............................................................................14
7.1.
Final Analyses ...........................................................................................................13
8.
SECONDARY STATISTICAL ANALYSES........................................................................14
8.1.
Efficacy Analyses......................................................................................................14
8.1.1.
Overview of Planned Efficacy Analyses..................................................14
8.1.2          AUC and 1/2 Life Time...........................................................................15
8.2.
Safety Analyses .........................................................................................................17
8.2.1.
Overview of Planned Analyses.................................................................17
8.3.
Pharmacokinetic Analyses.........................................................................................18
8.3.1.
Overview of Planned Pharmacokinetic Analyses.....................................18
8.3.2.
Drug Concentration Measures..................................................................18
8.3.3.
Pharmacokinetic Parameters.....................................................................18
8.3.3.1.
Deriving Pharmacokinetic Parameters..................................18
9.
OTHER STATISTICAL ANALYSES.................................................................................209
9.1.
Overview of Planned Pharmacokinetic / Pharmacodynamic Analyses.....................19
10. REFERENCES.......................................................................................................................21
11. APPENDICES........................................................................................................................23
11.1.
Appendix 1: Protocol Deviation Definitions for Per Protocol Population ................24
11.2.
Appendix 2: Time and Events ...................................................................................24
11.3.
Appendix 3: Treatment States and Phases...............................................................287
11.3.1.
Treatment Phases......................................................................................27
11.3.2.
Treatment States .....................................................................................287


CONFIDENTIAL
GSK1070806
4
11.3.3.
Treatment States for AE Data.................................................................287
11.4.
Appendix 4: Data Display Standards & Handling Conventions ...............................28
11.4.1.
Baseline Definition & Derivations ...........................................................29
11.4.1.1.
Baseline Definitions..............................................................29
11.4.1.2.
Derivations and Handling of Missing Baseline Data............29
11.4.2.
Reporting Process & Standards................................................................29
11.5.
Appendix 5: Derived and Transformed Data...........................................................321
11.5.1.
General ...................................................................................................321
11.5.2.
Study Population.....................................................................................321
11.5.3.
Safety......................................................................................................332
11.6.
Appendix 6: Premature Withdrawals & Handling of Missing Data..........................34
11.6.1.
Premature Withdrawals ..........................................................................343
11.6.2.
Handling of Missing Data.......................................................................344
11.6.2.1.
Handling of Missing Dates .................................................344
11.6.2.2.
Handling of Partial Dates....................................................355
11.7.
Appendix 7: Values of Potential Clinical Importance.............................................376
11.7.1.
Laboratory Values ..................................................................................376
11.7.2.
ECG........................................................................................................387
11.7.3.
Vital Signs ..............................................................................................387
11.8.
Appendix 8 – Abbreviations & Trade Marks ............................................................38
11.8.1.
Abbreviations............................................................................................38
11.8.2.
Trademarks...............................................................................................39
11.9.
Appendix 9: List of Data Displays ............................................................................40
11.9.1.
Data Display Numbering..........................................................................40
11.9.2
Deliverable ...............................................................................................40
11.9.3.
Study Population Tables...........................................................................41
11.9.4.
Efficacy Tables.........................................................................................43
11.9.5.
Efficacy Figures........................................................................................49
11.9.6.
Safety Tables ............................................................................................50
11.9.7.
Pharmacokinetic Tables............................................................................54
11.9.8.
Pharmacokinetic Figures ..........................................................................55
11.9.9.
Pharmacokinetic / Pharmacodynamic Figures..........................................56
11.9.10.
ICH Listings .............................................................................................56
11.9.11.
Non-ICH  Listings ....................................................................................59
11.10. Appendix 10: Example Mock Shells for Data Displays............................................64


CONFIDENTIAL
GSK1070806
5
1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP 
Purpose

This RAP details all planned analyses and outputs required for the final Clinical
Study Report (CSR) of study 204824. 
Protocol

This RAP is based on the protocol (Dated: 03-FEB-2016 for study 204824
[GlaxoSmithKline Document Number: 2015N240632_01].
Primary 
Objective

Evaluate the efficacy of single intravenous dose administrations of 
GSK1070806 in prevention of delayed graft function (DGF) after 
transplantation.
Primary 
Endpoint

Proportion of subjects requiring dialysis during the first 7 days post transplant 
(excluding requirement for dialysis due to hyperkalemia within first 24 post-
operative hours). 
Study 
Design

Pilot, multicenter, single arm Bayesian sequential design study to evaluate the 
efficacy, safety, tolerability and pharmacokinetics (PK) of GSK1070806 in 
patients undergoing renal transplantation. 

Sample size (maximum of 30) had been selected to yield the probability of a 
“go” decision of 0.139 when the GSK1070806 DGF rate is 50% and 0.69 at 
what has been considered to be a clinically impactful GSK1070806 DGF rate of 
35%.
Planned 
Analyses

Interim analyses are detailed within Section 3.1 where applicable.

All decisions regarding final analysis, as defined in this RAP document, will be 
made prior to Database Freeze of the study data. 
Primary 
Analysis 
Population

The ‘Analysis Population’ will be used to evaluate DGF related endpoints 

The ‘All Subjects Population’ will be used to evaluate study population; safety; 
PD/Biomarkers and other efficacy endpoints.

The ‘PK’ population will be used to evaluate pharmacokinetics.

The ‘Per-Protocol’ population will be used to evaluate the DGF rate in addition 
to the ‘Analysis Population’.
Hypothesis

The study is to determine the effect of GSK1070806 on DGF. Stopping rules 
have been defined to test whether the DGF rate is less than or equal to the null 
hypothesis rate of 50%.
Primary 
Analyses

A summary of the observed DGF rate during the study will be provided.

The posterior probability that the proportion of subjects experiencing DGF is 
less than 50% will be calculated. 
Secondary 
Analyses

Summaries of baseline and post-dose values or proportions of subjects at 
various time points will be provided.

Graft survival will be summarized by Kaplan-Meier plots.


CONFIDENTIAL
GSK1070806
6
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Not applicable.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary 
Primary

To assess the frequency of 
delayed graft function (DGF) in 
donation after circulatory death 
(DCD) renal transplant recipients 
treated with GSK1070806.

Proportion of subjects requiring dialysis 
during the first 7 days post transplant, 
(excluding requirement for dialysis due to 
hyperkalemia within first 24 post-operative 
hours).
Secondary 
Secondary 

To assess graft function in DCD 
renal transplant recipients treated 
with GSK1070806.

Serum creatinine at baseline and over time 
post transplant.

Urine output at baseline and over time post 
transplant.

Proportion of subjects in the first 7 days 
with: 
-
Primary Non Function
-
Functional DGF
-
Intermediate Graft Function
-
Immediate Graft Function

To assess the effect of 
GSK1070806 on acute rejection 
risk, and rejection/PD 
biomarkers.

Proportion of subjects with episodes of 
biopsy-proven acute rejection.

Rejection biomarkers/ PD markers 
(including serum IP-10 and Mig) at baseline 
and over time post transplant.

To assess the effect of 
GSK1070806 on dialysis 
dependency and graft survival.

Number of dialysis events per patient in the 
first 30 days post transplant.

Proportion of subjects who are dialysis-
independent at visits up to 12 months post 
transplant.

To assess the safety and 
tolerability of GSK1070806 in 
renal transplant recipients.

AEs and SAEs
-
Clinical laboratory values
-
Vital signs
-
Frequency, type and severity of infections

To assess the pharmacokinetics of 
GSK1070806 in renal transplant 
recipients.

Serum concentrations of GSK1070806 over 
time, and derived pharmacokinetic 
parameters if feasible (AUC, Cmax). 


CONFIDENTIAL
GSK1070806
7
Objectives
Endpoints

To assess the effect of 
GSK1070806 administration on 
serum IL-18 levels.

Free, total, and GSK1070806 bound IL-18 
at baseline and over time post transplant.

To determine immunogenicity of 
GSK1070806 in renal transplant 
recipients.

Frequency of anti-drug antibodies (ADAs) 
before and after GSK1070806 
administration.

ADA titers.
Objectives
Endpoints
Exploratory
Exploratory

To assess the impact of
GSK1070806 on urine biomarkers 
of renal injury.

Serial measurements of urinary biomarkers, 
including KIM-1, NGAL and IL-18, at 
baseline and over time post transplant.

To assess IL-18 target engagement 
in the kidney.

GSK1070806 and IL-18 levels within renal 
graft biopsies, as assessed by 
immunohistochemistry.

To assess the relation between IL-
18 levels in renal preservation 
fluid and graft function.

Level of IL-18 in renal preservation fluid.

To assess the impact of 
GSK1070806 administration on 
IL-18 binding protein levels.

Serum IL-18 binding protein at baseline and 
over time post transplant.

To assess the humoral and cellular 
response to the transplanted organ 
in the presence of GSK1070806.

Serum cytokine levels at baseline and over 
time post transplant.

Histological analysis of biopsies with 
respect to cellular infiltrate.

To assess health outcomes in 
renal transplant recipients 
following GSK1070806 
administration.

Length of hospital stay

Re-hospitalization


CONFIDENTIAL
GSK1070806
8
2.3.
Study Design
Overview of Study Design and Key Features
Overview of Key Study Design Features
Design 
Features :

Multi-centre, single arm Bayesian sequential design.
Dosing :

A single infusion prior to kidney allograft reperfusion.
Treatment 
Assignment :

Single arm study. All patients will be received GSK1070806. No 
randomization is needed.
Interim 
Analysis

DGF data will be reviewed sequentially.

Safety, tolerability and efficacy data will be reviewed by the GSK 
study team on an ongoing basis throughout the study.

An interim analysis will be performed after recruitment of 8 to 10 
patients to review for a consideration of dose adjustment based on an 
integrated review of safety/tolerability, efficacy, and exposure.

Once the last patient completes 7-Days post-transplant, an interim 
analysis will be performed of all available data for the primary 
endpoint in addition to supportive efficacy and safety data. The 
results of this interim analysis will be reviewed by the GSK study 
team and other relevant GSK staff for internal decision making.
2.4.
Statistical Hypotheses
The study is to determine the effect of GSK1070806 on DGF.  Stopping rules have been 
defined to test whether the DGF rate is less than or equal to the null hypothesis rate of 
50%.
2.5.
Definition of Renal Graft Function
Primary Non Function:

Permanent lack of function of the allograft defined as an inability to discontinue 
dialysis from the time of transplantation. Note: The study site will decide whether 
patients have primary non function DGF or not and record it in data set. 
3 day Functional Delayed Graft Function:


CONFIDENTIAL
GSK1070806
9

<10% fall in SCr versus baseline per day averaged over first 3 days with OR without 
dialysis
7 day Functional Delayed Graft Function:

<30% reduction in baseline SCr in first 7 days with OR without dialysis
3 day Intermediate Graft Function:

10- 20% fall in SCr versus baseline per day averaged over first 3 days without 
dialysis
7 day Intermediate Graft Function:

30-70% reduction in baseline Cr in first 7 days without dialysis
3 day Immediate Graft Function:

>20% fall in SCr versus baseline per day averaged over first 3 days without dialysis
7 day Immediate Graft Function:

>70% reduction in baseline Cr during the first 7 days without dialysis
3.
PLANNED ANALYSES
3.1.
Interim Analyses
3.1.1
        Bayesian Sequential Analysis
The DGF data will be reviewed sequentially. The sequential decision rule is shown 
graphically in Figure 1.  The number in the first column indicates the number of subjects 
who have completed study treatment.  From the point in time when approximately 6 
subjects have reached day 7 post transplantation the sponsor study team will begin to 
evaluate the DGF rates. This will start with the first 6 subjects and then with addition of 
data from each subsequent subject that completes 7 days of the trial.  A sequential Go/No 
Go/Continue rule is based on the predictive probability of success.  A high predictive 
probability (PP) of success means that GSK1070806 is likely to be efficacious by the end 
of the study given the observed data, whereas a low PP suggests that the treatment may 
not have sufficient activity.  If the PP value is less than 2% (red region) the trial may be 
stopped and the alternative hypothesis will be rejected. If the PP is greater 92% (green), 
the conclusion may be made that GSK1070806 has better efficacy than the standard of 
care.  If the PP is between 2 - 92% (white region), the trial will continue to the next 
interim analysis (to be conducted after the next subject has completed treatment) or until 
reaching 30 completed subjects.
3.1.2
        Planned Interim Analysis
The following interim analyses are planned (protocol defined):


CONFIDENTIAL
GSK1070806
10
Interim 
Analysis
Details
During  
Study

The DGF data will be reviewed sequentially.

An interim analysis will be performed after recruitment of approximately 8 
to 10 patients to review for a consideration of dose adjustment based on an 
integrated review of safety/tolerability, efficacy, and exposure.

The preliminary PK data which involves but not limited to GSK1070806 
concentrations, total, free, drug bound IL-18 levels as data permit and 
applicable.

Once the last patient completes 7-Days post-transplant, an interim analysis 
will be performed of all available data for the primary endpoint in addition 
to supportive efficacy and safety data. The results of this interim analysis 
will be reviewed by the GSK study team and other relevant GSK staff for 
internal decision making.
3.2.
Final Analyses
A summary of the observed DGF rate during the study will be provided. The posterior 
probability that the proportion of subjects experiencing DGF is less than 50% will be 
calculated. 


CONFIDENTIAL
GSK1070806
11
Figure 1
Sequential Decision Rules


CONFIDENTIAL
GSK1070806
12
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Comprise of subjects who receive the dose of 
study medication.

Safety/tolerability
Analysis 

For DGF related endpoints the ‘Analysis 
Population’ (AP) is defined as subjects in the 
‘All Subjects’ population who have been 
declared to have DGF or have reached 7 days. 
For other endpoints, the AP is defined as 
subjects having baseline and at least one post-
baseline assessment.

Efficacy

PD/Biomarker
Per 
Protocol 

Comprised of Analysis Population subjects who 
are compliant with protocol-specific criteria. 
Subjects with specified protocol deviations will 
be excluded per Appendix 1.

Primary efficacy 
endpoint 
PK

Subjects in the ‘All Subjects’ population for 
whom a serum pharmacokinetic sample is 
obtained and analyzed for GSK1070806.

PK
NOTE : 

Please refer to Appendix 10: List of Data Displays which details the population to be used for each 
display being generated.
4.1.
Protocol Deviations

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Important deviations which result in exclusion from the analysis population will also 
be summarised and listed. (Please refer to Appendix 1: Protocol Deviation
Definitions for Per Protocol Population).

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.  
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.


CONFIDENTIAL
GSK1070806
13
5.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
AND DATA HANDLING CONVENTIONS

There are no planned adjustments made for multiple centres in this study.
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
11.1
Appendix 1: Protocol Deviation Definitions for Per Protocol Population
11.2
Appendix 2: Time and Events
11.3
Appendix 3: Treatment States and Phases
11.4
Appendix 4: Data Display Standards & Handling Conventions
11.5
Appendix 5: Derived and Transformed Data
11.6
Appendix 6: Premature Withdrawals & Handling of Missing Data
11.7
Appendix 7: Values of Potential Clinical Importance
Error! 
Referenc
e source
not 
found.
Error! Reference source not found.: Laboratory A&R (QUEST: LAB) Dataset 
Details
Error! 
Referenc
e source 
not 
found.
Appendix 1: Abbreviations
11.10
Appendix 10: List of Data Displays
11.11
Appendix 11: Mock Data Displays
6.
STUDY POPULATION ANALYSES
6.1.
Planned Analyses Overview
The study population analyses will be based on the “All Subjects” population, unless 
otherwise specified.
Table 2 provides an overview of the planned study population analyses with full details 
of data displays being presented in Appendix 11.10: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Display’s Generated


CONFIDENTIAL
GSK1070806
14
Figure
Table
Listing
Subject Disposition
Subject Disposition
Y
Reasons for Screening Failures
Y
Y
Reasons for Withdrawals
Y
Y
Important Protocol Deviations
Y
Deviations Leading to Exclusions from PP 
Population
Y
Inclusion and Exclusion Criteria Deviations
Y
Demography (recipient)
Demographics Characteristics
Y
Y
Race & Racial Combinations
Y
Y
Study Populations
Y
Y [1]
Medical Condition & Concomitant  Medications
Medical Conditions (Current/Past)
Y
Y
Concomitant Medication
Y
Y
Virology (recipient)
Y
Donor Kidney Data
Virology (donor)
Y
Demography (donor)
Y
Y
Characteristics (donor)
Y
NOTES:
1.
Listing of subjects excluded from any population will be generated only.
7.
PRIMARY STATISTICAL ANALYSES
A summary of the observed DGF rate during the study will be provided. The observed 
DGF rate will be calculated based on “Analysis” population as the primary analysis and 
based on “Per Protocol” population as sensitivity analysis.
8.
SECONDARY STATISTICAL ANALYSES
8.1.
Efficacy Analyses
8.1.1.
Overview of Planned Efficacy Analyses
The secondary efficacy analyses will be based on the “Analysis“ population, unless 
otherwise specified.


CONFIDENTIAL
GSK1070806
15
Table 3 provides an overview of the planned efficacy analyses with further details of data 
displays being presented in Appendix 11.10: List of Data Displays.
Table 3
Overview of Planned Efficacy Analyses
Endpoints
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T 
F
F
L
Graft function
Serum creatinine
Y
Y
Y
Y
Y
Y
Y
Y
Creatinine - AUC
Y
Y
Creatinine – ½ life
Y
Y
Urine output
Y
Y
Y
Primary Non 
Functions
Y
Y
Functional DGF
Y
Y
Intermediate graft 
function
Y
Y
Immediate graft 
function
Y
Y
Acute rejection risk and rejection/PD biomarker
Episode of biopsy-
proven acute 
rejection
Y
Y
Serum IP-10
Y
Y
Y
Y
Y
Y
Serum Mig
Y
Y
Y
Y
Y
Y
Serum IL-18 levels
Free IL-18
Y
Y
Y
Y
Y
Y
Bound IL-18
Y
Y
Y
Y
Y
Y
Total IL-18
Y
Y
Y
Y
Y
Y
Urine biomarkers
IL-18
Y
Y
Y
NGAL
Y
Y
Y
KIM1
Y
Y
Y
Dialysis dependency and graft survival
Number of dialysis 
events per patient in 
the first 30 days post 
transplant
Y
Y
Proportion of 
subjects who are 
dialysis-independent 
at visits up to 12 
months post 
transplant
Y


CONFIDENTIAL
GSK1070806
16
Exploratory
% free GSK1070806 
within renal graft 
biopsies
Y
Y
% bound 
GSK1070806 within 
renal graft biopsies
Y
Y
Level of IL-18 in 
renal preservation 
fluid
Y
Y
Serum IL-18 binding 
protein
Y
Serum cytokine 
levels
Y
Y
Y
Y
Histological analysis 
of biopsies with 
respect to cellular 
infiltrate
Y
Length of hospital 
stay
Y
Y
Re-hospitalization
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.1.2.
AUC and ½ Life Time
For serum creatinine, the 7-Day Area under the Curve (AUC), 30-Day AUC and 30 Day 
½ life time will be calculated.  The formula to calculate the AUC is:
 = ∑
1/2( + )( −)


  where  is the serum creatinine value at Day 
and M is the total number of measures the patient has. The 7 Day AUC will be calculated 
based on patients who have serum creatinine value at Day 7. The patients who will be 
discharged before Day 7 will be excluded from calculation.  All patients are expected to 
have serum creatinine 30 Day post transplant. If the value is missing, the patient will be 
excluded from calculation.
The algorithm to determine the ½ life time is:
1. Determine the ½ value by / =

 ∗ where  is the baseline value for non-
DGF patient and the value after dialysis finished for DGF patient. Denote the 
corresponding day 


CONFIDENTIAL
GSK1070806
17
2. Find the time interval between  and 30 where / <  and  / > . If no 
such interval, then report “NA” for that patient. 
3. The approximate ½ life time is / =
/  
 !  ( −) + 
8.2.
Safety Analyses
8.2.1.
Overview of Planned Analyses
The safety analyses will be based on the “All Subjects” population, unless otherwise 
specified.
Table 4 provides an overview of the planned analyses with further details of data displays 
being presented in Appendix 11.10: List of Data Displays.
Table 4
Overview of Planned Safety Analyses
Endpoint / 
Parameter/ Display 
Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Adverse Events1
All
Y
Y
Drug-Related
Y
Y
Serious
Y
Y
Leading to 
Withdrawal
Y
Y
Laboratory Assessments
Haematology
Y
Y
Clinical Chemistry2:
Y
Y
Routine Urinalysis:
Y
ECG
ECG Findings
Y
Y
ECG Measures
Y
Y
Y
Y
Y
Vital Signs
Vital Signs
Y
Y
Y
Y
Immunogenicity
Frequency of Anti-
drug antibodies
Y
ADA titers
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated..

Summary represents any summaries (i.e. descriptive statistics) of the observed raw data.

Individual represents any displays of individual subject observed raw data.
1.
Listings will include subject’s numbers for individual AE’s & AE system organ classes, preferred terms 
and verbatim text.


CONFIDENTIAL
GSK1070806
18
Endpoint / 
Parameter/ Display 
Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
2.
Chemistry (includes LFTs and lipids) & haematology/coag summaries will include both changes from 
baseline & emergent results by PCI criteria. Listings for subjects with abnormalities of PCI will be 
prepared.
8.3.
Pharmacokinetic Analyses
8.3.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” population, 
unless otherwise specified.
Table 5 provides an overview of the planned analyses with full details being presented in
Appendix 11.10: List of Data Displays. 
Table 5
Overview of Planned Pharmacokinetic Analyses
Endpoints
Untransformed
Log-Transformed
Summary
Individual
Summary
Individual
F
T
F
L
F
T
F
L
Plasma Drug Concentrations
Y23
Y3
Y1
Y
Derived PK Parameters
Y3
Y
Y3
NOTES :

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.    
1.
Linear and Semi-Log plots will be created on the same display.
2.
Mean (Linear and Semi-Log on same display) and Median (Linear and Semi-Log on same display) 
plots will be created.
3.
Displays generated using the “PK” populations.
8.3.2.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 11.4.2
Reporting Process & Standards).
8.3.3.
Pharmacokinetic Parameters
8.3.3.1.
Deriving Pharmacokinetic Parameters

Refer to Appendix 4: Data Display Standards & Handling Conventions
(Section 11.4.2 Reporting Process & Standards).


CONFIDENTIAL
GSK1070806
19

The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using Phoenix Win Nonlin.

All calculations of non-compartmental parameters will be based on actual sampling 
times.

Pharmacokinetic parameters described in Table 6 will be determined from the 
plasma GSK1070806 concentration-time data, as data permits. 

Any deviation from the planned analyses will be described in detail in the study 
report.


CONFIDENTIAL
GSK1070806
20
Table 6
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve until the last time point of PK sample. 
Partial AUCs such as over 7, 30 or 90 days may be generated if deemed necessary.
Cmax
Maximum observed concentration, determined directly from the concentration-
time data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
Lamda_z
Terminal phase rate constant
The number of points to determine Lambda_z 
The first point used to determine Lambda_z
The last point used to determine Lambda_λz
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / Lambda_z
AUC(0-∞)
Area under the concentration time curve from predose to infinity.
NOTES:

Additional parameters may be included as required.
9.
OTHER STATISTICAL ANALYSES
9.1.
Overview of Planned Pharmacokinetic / Pharmacodynamic 
Analyses
The pharmacokinetic / pharmacodynamic (PK/PD) analyses will be based on the “All 
Subjects” population, unless otherwise specified.
For the other biomarker variables/PD endpoints, summary tables will be reviewed to 
identify those biomarker variables/PD endpoints where there is a potential trend. If there 
is a trend then exploratory plots (scatter plots) will be presented for individual and/or 
pooled plasma GSK1070806 concentrations versus corresponding biomarker 
variables/PD endpoints (e.g. IL-18, IP-10).

Table 7 provides an overview of the planned PK/PD analyses with further details of 
data displays being presented in Appendix 11.10: List of Data Displays. Any 
deviation from the planned analyses or additional analyses performed based on 
emerging data will be described in detail in the study report.
Table 7
Overview of Planned PK/PD Analyses
Endpoints
Absolute
Summary
Individual
F
T
F
L
Serum IL-18 (drug bound, total or free) vs. PK Plasma 
Concentrations
Y


CONFIDENTIAL
GSK1070806
21
Endpoints
Absolute
Summary
Individual
F
T
F
L
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data

Individual = Represents FL related to any displays of individual subject observed raw data.


CONFIDENTIAL
GSK1070806
22
10.
REFERENCES
GlaxoSmithKline Document Number 2015N240632_01 : A Phase 2 Pilot, Single Arm 
Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of GSK 
1070806 plus Standard of Care for the Prevention of Delayed Graft Function in Adult 
Subjects After Renal Transplantation Effective date: 03-FEB-2016


CONFIDENTIAL
GSK1070806
23
11.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 11.1
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling 
Conventions
Section 11.2
Appendix 2: Time and Events
Section 11.3
Appendix 3: Treatment States & Phases
Section 11.4
Appendix 4: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 11.5
Appendix 5: Derived and Transformed Data

General, Study Population & Safety

Efficacy

Pharmacokinetic

Pharmacodynamic / Biomarkers
Section 11.6
Appendix 6: Premature Withdrawals & Handling of Missing Data

Handling of Missing Dates

Handling of Partial Dates
Section 11.7
Appendix 7: Values of Potential Clinical Importance

Laboratory Values

ECG’s 

Vital Signs
Other RAP Appendices
Section 11.88
Appendix 8: Abbreviations & Trade Marks
Section 11.9
Appendix 9: List of Data Displays
Section 11.10
Appendix 10: Example Mock Shells for Data Displays


CONFIDENTIAL
GSK1070806
24
11.1.
Appendix 1: Protocol Deviation Definitions for Per Protocol 
Population
11.1.1.
Exclusions from Per Protocol Population 
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01
Subject takes prohibited Concomitant Medications
02
Others as defined in the PDMP
NOTES: For the details for prohibited concomitant medications, please refer to protocol Section 6.11.2 


CONFIDENTIAL
GSK1070806
25
11.2.
Appendix 2: Time and Events
Study Day1
Screening
Pre-operative 
(baseline)
Intra-
operative (D0) 
1
4-8h 2
D1
D2
Daily 
until 
discharge
Discharge
D30
D90
6 & 12 
months 13
Unschedule
d Visit
Informed Consent/Demographics
X
Medical/drug/alcohol/tobacco history
X
GSK1070806 IV Infusion
--------------------------------15
Kidney preservation fluid IL-18
X16
Kidney biopsy (post-reperfusion) 3
X (~45 min)
Clinical biopsy reports (if applicable)
--------------------------------------------------------------------------------------------------------------------------------------------
-------------------------
Concomitant medication
X
X
X17
X
X
X
X
X
X
X
X
X
Evidence of infection
X
X
X
X
X
X
X
X
X
X
SAE / AE monitoring
------------------------------------------------------------------------------------------------------------------------------------------------------------
------------------------
DGF status (up to day 7)
--------------------------------------------------

Urine output
X (native output)
X
X
X
X
X
X
Dialysis events since last assessment
X
X
X
X
X
X
X
X
X
X
Graft survival
----------------------------------------------------------------------------------------------------------------------
---------------------
Viral serology (recipient & donor – HIV, 
Hep B/C, EBV) 4
X5
X
X
X
Viral serology (recipient & donor  -herpes, 
varicella) 4
X
CMV monitoring
X5
X
X
X
BK virus monitoring 6
X
X
X
X
X
Vital signs 7
X
X
X
X
X
X
X
X
X
X
Complete physical 
X
X
X
12-lead ECG
X
X
X
X
Hematology / Clinical Chemistry / 
Urinalysis
X
X
X
X
X
X
X
X
X
X
Pregnancy test 8
X
X
X
X
X
Serum cytokines / PD biomarkers
X11
X (~45 min at 
biopsy)
X
X
X
X
X
X
X
X


CONFIDENTIAL
GSK1070806
26
Study Day1
Screening
Pre-operative 
(baseline)
Intra-
operative (D0) 
1
4-8h 2
D1
D2
Daily 
until 
discharge
Discharge
D30
D90
6 & 12 
months 13
Unschedule
d Visit
Free, GSK1070806 bound & total IL18 9
X11
X (~45 min at 
biopsy)
X
X
X
X
X
X
X
X
Pharmacokinetics 9,10
X11
X (~45 min at 
biopsy)
X
X
X (@168 
hrs or at 
earlier 
discharge)
X
X
X
X
Immunogenicity 12
X11
X
X
X
X
Urinary biomarkers
X11
X
X
X
X
X
X
X
X
X
Peripheral blood leucocyte flow 
phenotyping 14
X
X
X
X
PBMCs frozen for in vitro stimulation 
assays 14
X
X
X
X
PBMCs placed in trizol for transcriptomic 
analysis 14
X
X
X
X
1.
Day 0 defined as the calendar day of transplant. 
2.
Time post reperfusion. 
3.
Biopsies during transplantation may be ‘core or wedge’ at the discretion of the operating surgeon. If, in the judgement of the operating surgeon, biopsy poses 
unwarranted risk to the patient, it may be omitted.
4.
Viral serology will include HIV, HBsAg, anti-HBc, anti-HBs antibodies, and hepatitis C antibody (if hepatitis C antibody positive, a hepatitis C RIBA 
immunoblot or polymerase chain reaction assay should be reflexively performed on the same sample to confirm the results as per NHS standard procedure), and 
serology for herpes simplex virus, Epstein Barr virus, and varicella zoster virus. 
5.
Screening viral status may be the most recent value recorded in the patient’s medical records.
6.
If BK positive then follow up screening should be implemented.
7.
Vital signs will include systolic and diastolic blood pressure, pulse rate, and temperature. 
8.
Pregnancy testing will be performed in women of childbearing potential.  Screening test may be urine or serum.
9.
Sampling time points may be adjusted as appropriate based on emerging data.
10. PK sampling time points are as follows:  predose, 45 min to 1 hr into infusion (coinciding with biopsy), 4-8 hrs,  24 hrs, 168 hrs (or pre-discharge if discharge 
before day 7), day 30 day 90, 6 and 12 months.  Exact PK sampling time is to be recorded.
11. Blood and urine samples for immunogenicity and biomarker analyses must be collected prior to infusion with GSK1070806
12. For any non-completer a serum sample for immunogenicity testing will be taken 12 mths post-operatively.
13. For subjects who withdraw from study, where possible, assessments should continue according to the Time and Events table. The 6 and 12 mth safety follow-up 
should be performed. 
14. Samples for subjects from Cambridge site only.
15. GSK1070806 can be infused any time during the pre-operative and/or intra-operative periods, but infusion must be complete prior to reperfusion of the allograft. 


CONFIDENTIAL
GSK1070806
27
16. Sample to be obtained at time of back-table allograft preparation.
17. Documentation of anaesthetics excluded.


CONFIDENTIAL
GSK1070806
28
11.3.
Appendix 3: Treatment States and Phases
11.3.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to 
study treatment, unless otherwise specified.
Treatment Phase
Definition
Pre-Treatment 
Date/Time ≤ Study Treatment Start Date/Time
Post-Treatment
Date /Time> Study Treatment Stop Date/Time
Treatment Description 
Code 
Treatment Description
Final Data Display (i.e. HARP/other)
A
3 mg/kg GSK1070806
3 mg/kg GSK1070806
11.3.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date/time of the study treatment.
11.3.3.
Treatment States for AE Data
Treatment State
Definition
AE = Pre-
Treatment
AE Start Date/Time < Study Treatment Start Date/Time
AE Onset Time
Since 1st Dose
(Days)
If Treatment Start Date/Time ˃ AE Onset Date/Time : 
= AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date : 
= AE Onset Date – Treatment Start Date + 1
Missing otherwise 
AE Duration 
(Days) 
AE Resolution Date/Time – AE Onset Date/Time (follow SOP)
AE = Drug-related
If relationship is marked ‘YES’ on [Inform/CRF OR value is missing.
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment


CONFIDENTIAL
GSK1070806
29
11.4.
Appendix 4: Data Display Standards & Handling Conventions
11.4.1.
Baseline Definition & Derivations
11.4.1.1.
Baseline Definitions
For all endpoints baseline value will be the latest pre-dose assessment. 
11.4.1.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Baseline Visit Value – Baseline
[% Change from Baseline]
= [ (Post-Baseline Visit Value – Baseline) / Baseline ] x 100]
NOTE :

Unless otherwise specified, the baseline definitions specified in 11.4.1.1Baseline Definitions will be 
used for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to 
missing.

The baseline definition will be footnoted on all change from baseline displays.
11.4.2.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS and R software will be used to perform all 
data analyses, generate tables, figures, and listings. 
Reporting Area
HARP Server
: Us1salx00259-HARP PROD-US
HARP Area
: \ARPROD\GSK1070806\204882
QC Spreadsheet
: \ARWORK\GSK1070806\204882\ReportingEffort\Documents
Analysis Datasets 

Analysis datasets will be created according to Integrated Data Standards Library 
standards.
Generation of RTF Files

RTF files will be generated for SAC tables.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for 
reporting, unless otherwise stated:

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings


CONFIDENTIAL
GSK1070806
30

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

In the top left header on each page of output the study part will be indicated after the 
protocol number (ie, “204824”)

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be 
adopted for reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical 
principles but may be adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Planned time relative to dosing will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or 
scheduled visit days on the analyses and interpretation of the results will be 
assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings 
(Refer to IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s 
listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol 
deviations) will be included in listings but omitted from figures, summaries and 
statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables or figures, unless 
otherwise stated.

All unscheduled visits will be listed.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration


CONFIDENTIAL
GSK1070806
31
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Handling NQ values per GUI_51487
Reporting of Pharmacokinetic Parameters
Descriptive 
Summary Statistics 
(Log Transformed 
Data)   
N, n, geometric mean, 95% CI of geometric mean, standard 
deviation (SD) of logged data and between geometric coefficient of 
variation (CVb/w (%)): 
CVb (%) = √ (exp(SD2) - 1) * 100
(NOTE: SD is the SD of log transformed data)
Parameters Not 
Being Log 
Transformed  
tmax, first point, last point and number of points used in the 
determination of Lambda_λz.
Parameters Not 
Being Summarised
tmax, first point, last point and number of points used in the 
determination of Lambda_λz.
Listings
Include the first point, last point and number of points used in the 
determination of Lambda_λz.
Graphical Displays

Refer to IDSL Statistical Principles 7.01 to 7.13.

The same symbol and line type will be used across figures to represent a given 
treatment group. 

X-axis variables of time and dose will be plotted as continuous numeric variables.


CONFIDENTIAL
GSK1070806
32
11.5.
Appendix 5: Derived and Transformed Data
11.5.1.
General
Multiple Measurements at One Time Point

Mean of the measurements will be calculated and used in any derivation of summary 
statistics but if listed, all data will be presented.

If there are two values within a time window the value closest to the target day for 
that window will be used. If values are the same distance from the target then the 
mean will be taken.

Subjects having both High and Low values for Normal Ranges at any post-baseline 
visits for safety parameters will be counted in both the High and Low categories of 
“Any visit post-baseline” row of related summary tables. This will also be applicable 
to relevant Potential Clinical Importance summary tables.
Study Day

Calculated as the number of days from dosing date :
[1] Assessment Date = Missing                       → Study Day = Missing 
[2] Assessment Date < Transplant Date   → Study Day = Assessment Date –
Transplant Date
[3] Assessment Data ≥ Transplant Date   → Study Day = Assessment Date –
Transplant Date
11.5.2.
Study Population
Demographics 
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will 
be imputed as follows:
[1] Any subject with a missing day will have this imputed as day ‘15’. 
[2] Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)]2


CONFIDENTIAL
GSK1070806
33
11.5.3.
Safety
+++ ECG Parameters +++
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
o
If QTcB is machine read & QTcF is not provided, then :
"" = #$ %&
%&'()

* ∗1000
o
If QTcF is machine read and QTcB is not provided, then: 
"" = #$ %&
%&',)
-
* ∗1000

If ECGs are manually read, the RR value preceding the measurement QT interval 
should be a collected value THEN do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the 
availability of other measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTCF will be derived as 
: 
%&'( =
%&
. ""
1000
%&', =
%&
3. ""
1000
+++ Laboratory Parameters +++

If a laboratory value which is expected to have a numeric value for summary purposes, 
has a non-detectable level reported in the database, where the numeric value is 
missing, but typically a character value starting with '<x' or '>x' (or indicated as less 
than x or greater than x in the comment field) is present, the number of significant 
digits in the observed values will be used to determine how much to add or subtract in 
order to impute the corresponding numeric value. 

Example 1: 2 Significant Digits = '< x ' becomes x - 0.01

Example 2: 1 Significant Digit   =  '> x' becomes x + 0.1

Example 3: 0 Significant Digits = '< x' becomes x - 1.    

If there is more than one value of a particular parameter for a subject for a visit, the 
scheduled value will be used in summary; all values will be listed.  
11.5.4.
Pharmacokinetic
GSK1070806 Derived PK Parameters

Refer to PK Guidance document GUI00000051487: Non-compartmental Analysis of 
Pharmacokinetic Data for more information.


CONFIDENTIAL
GSK1070806
34
11.6.
Appendix 6: Premature Withdrawals & Handling of Missing Data
11.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion was defined as Safety who either prematurely 
withdrawn or completed FU visits and assessments. 

Withdrawn subjects were not replaced in the study.

All available data from subjects who were withdrawn from the study 
will be listed and all available planned data will be included in summary 
tables and figures, unless otherwise specified.
11.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to 
blank fields on the collection instrument :
[1] These data will be indicated by the use of a “blank” in subject listing 
displays. 
[2] Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses 
will be documented along with the reason for exclusion in the clinical 
study report.
Biomarkers
Free IL-18
Drug 
Bound IL-
18 and 
total IL-18

LLQ will be set as LLQ/2

ULQ will be set as ULQ

Values used for the computation of the change from baseline and for 
summaries, plots and analysis, if deemed applicable. 

Number of data imputed will be highlighted in the summaries where as listings 
will report the values as below LLQ or above ULQ. 

If more than a third of obs are below LLQ or above LLQ then no imputation 
will be performed for that subject.

To enable the data to be plotted (i.e. some groups may remain below BLQ) this 
rule may not be applied to Free & Drug Bound IL18 parameters.
11.6.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and 
year) to be recorded for AE start and end dates; that is, the day of the 
month may be missing. In such a case, the following conventions will be 


CONFIDENTIAL
GSK1070806
35
Element
Reporting Detail
applied for calculating the time to onset and the duration of the event:

For a missing start day, the 1st of the month will be used unless this 
is before the start date of investigational product; in this case the 
study treatment start date will be used (and hence the event is 
considered On-treatment as per Section 11.3: Treatment States and 
Phases.

For a missing stop day, the last day of the month will be used, unless 
this is after the stop date of study treatment; in this case the study 
treatment stop date will be used.

Completely missing start or end dates will remain missing, with no 
imputation applied. Consequently, time to onset and duration of such 
events will be missing.

Start or end dates which are completely missing (i.e. no year specified) 
will remain missing, with no imputation applied.
11.6.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will 
be imputed using the following convention:

If the partial date is a start date, a '01' will be used for the day and 
'Jan' will be used for the month

If the partial date is a stop date, a '28/29/30/31' will be used for the 
day (dependent on the month and year) and 'Dec' will be used for
the month.

The recorded partial date will be displayed in listings.
Adverse 
Events

Any partial dates for adverse events will be raised to data management. 
If the full date cannot be ascertained, the following assumptions will be 
made:

If the partial date is a start date, a '01' will be used for the day and 
'Jan' will be used for the month. 

However, if these results in a date prior to Week 1 Day 1 and the 
event could possibly have occurred during treatment from the 
partial information, then the Week 1 Day 1 date will be assumed to 
be the start date. 

The AE will then be considered to start on-treatment (worst case).

If the partial date is a stop date, a '28/29/30/31' will be used for the 
day (dependent on the month and year) and 'Dec' will be used for 
the month.

The recorded partial date will be displayed in listings.


CONFIDENTIAL
GSK1070806
36
11.6.2.3.
Handling of Missing Data for Statistical Analysis/Efficacy Endpoints
Element
Reporting Detail
All 
Endpoints

Missing values will not be imputed.


CONFIDENTIAL
GSK1070806
37
11.7.
Appendix 7: Values of Potential Clinical Importance
11.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆from 
BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆from 
BL
↓25
Lymphocytes 
GI/L
0.8
Neutrophil Count 
GI/L
1.5
Platelet Count 
GI/L
100
550
While Blood Cell Count 
(WBC)
GI/L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
G/L
30
Calcium
mmol/L
2
2.75
Creatinine
umol/L
∆from 
BL
↑ 44.2
Glucose
mmol/L
3
9
Magnesium
mmol/L
0.5
1.23
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18
32


CONFIDENTIAL
GSK1070806
38
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
IU/L
High
2x ULN
AST/SGOT 
IU/L
High
2x ULN
AlkPhos 
IU/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT
11.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450
Absolute PR Interval
msec
< 110
> 220
Absolute QRS Interval
msec
< 75
> 110
Change from Baseline
Increase from Baseline 
QTc
msec
> 60 
11.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
Temperature 
°C
35.5
37.5


CONFIDENTIAL
GSK1070806
39
11.8.
Appendix 8 – Abbreviations & Trade Marks
11.8.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
GSK
GlaxoSmithKline
ADA
Anti-Drug Antibodies
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
BMI
Body mass index
BPM
Beat Per Minute
CL
Systemic clearance of parent drug
Cmax
Maximum observed concentration 
CI
Confidence Interval
CV
Coefficient of variance
HR
Heart rate
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IDSL
Integrated Data Standards Library
Kg
Kilogram
z
Terminal phase rate constant
LLQ
Lower limit of quantification
NQ
Non-quantifiable concentration measured as below LLQ
PK
Pharmacokinetic
QC
Quality control
RAP
Reporting and Analysis Plan
SAS
Statistical Analysis Software
SI
System Independent 
SD
Standard deviation
SOP
Standard Operating Procedure
t OR tlast 
Time of last observed quantifiable concentration
t½
Terminal phase half-life
tlag
Lag time before observation of drug concentrations in sampled matrix
tmax
Time of occurrence of Cmax
ULQ
Upper limit of quantification 
ULN
Upper limit of normal
UK
United Kingdom


CONFIDENTIAL
GSK1070806
40
11.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of 
Companies
NONE
NONMEM
SAS
WinNonlin


CONFIDENTIAL
GSK1070806
41
11.9.
Appendix 9: List of Data Displays
11.9.1.
Deliverable
Delivery
Description
IA1
Interim analysis after recruitment of approximately 8 to 10 
patients to review for a consideration of dose adjustment
IA2
Interim analysis once the last patient completes 7-Days post-
transplant.
SAC
Final Statistical Analysis Complete
11.9.2.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.01 to 1.10
N/A
Efficacy
2.01 to 2.29
2.01 to 2.17
Safety
3.01 to 3.24
N/A
Pharmacokinetic
4.01 to 4.03
4.01 to 4.03
PK/PD
NA
5.01
Section
Listings
ICH Listings
1 to 19
Other Listings
20 to 41


CONFIDENTIAL
204824
42
11.9.3.
Study Population Tables
Study Population Tables
No.
Populatio
n
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable
Subject Disposition 
1.01
All 
Subjects
ES1
Summary of Subject Disposition 
IA2, SAC
1.02
All 
Subjects
ES6
Summary of Reasons for Screening Failure
IA2, SAC
1.03
All 
Subjects
DV1a
Summary of Important Protocol Deviations
IA2, SAC
1.04
All 
Subjects
SA2
Summary of Deviations Leading to Exclusion 
from Per Protocol Population
IA2, SAC
1.05
All 
Subjects
ES5
Summary of Reasons for Withdrawals
IA2, SAC
Demographics
1.06
All 
Subjects
DM1
Summary of Demographic Characteristics 
IA2, SAC
1.07
All 
Subjects
DM5
Summary of Race and Racial Combinations 
IA2, SAC
1.08
All 
Subjects
SA1
Summary of Study Populations
IA2, SAC


CONFIDENTIAL
204824
43
Study Population Tables
No.
Populatio
n
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable
Medical Condition & Con Meds
1.09
All 
Subjects
MH1
Summary of [Current/Past] Medical 
Conditions
IA2, SAC
1.10
All 
Subjects
CM1
Summary of Most Frequently used 
Concomitant Medications by Generic Term
Footnote: Most Frequently means the 
overall concomitant medication used is 
>= 10%
IA1, IA2, 
SAC


CONFIDENTIAL
204824
44
11.9.4.
Efficacy Tables
Efficacy Tables
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
DGF
2.01
Analysis 
Population
Non-Standard
EFF_T3
Proportion of Subjects with DGF
IA1, IA2,
SAC
2.02
Per 
Protocol
Non-Standard
EFF_T3
Proportion of Subjects with DGF
IA2, SAC
Graft function
2.03
Analysis 
Population
Non-Standard
EFF_T1
Summary Statistics of Serum Creatinine 
IA1, IA2,
SAC
2.04
Analysis 
Population
Non-Standard
EFF_T2
Summary of Serum Creatinine Change from 
Baseline
IA1, IA2,
SAC
2.05
Analysis 
Population
Non-Standard
EFF_T1
Summary Statistics of AUC of 7 Day Serum 
Creatinine
Only consider patients who have Day 7 serum 
creatinine value
IA1, IA2,
SAC
2.06
Analysis 
Population
Non-Standard
EFF_T1
Summary Statistics of AUC of 30 Day Serum 
Creatinine
IA1, IA2, 
SAC
2.07
Analysis 
Population
Non-Standard
EFF_T1
Summary Statistics of ½ -Life of 30 Day Serum 
Creatinine
IA1, IA2, 
SAC


CONFIDENTIAL
204824
45
Efficacy Tables
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
2.08
All 
Subjects
Non-Standard
EFF_T4
Proportion of Subjects with Renal Functional 
Graft within 7 Days after Transplant
Including primary non function;3 day
functional DGF; 7 day functional DGF; 3 
day intermediate graft function; 7 day 
intermediate graft function; 3 day 
immediate graft function; 7 day 
immediate graft function
IA1, IA2,
SAC
Acute rejection risk
2.09
All 
Subjects
Non-Standard
EFF_T3
Proportion of Subjects with Episodes of Biopsy-
Proven Acute Rejection
IA2, SAC
2.10
All 
Subjects
Non-Standard
EFF_T2
Summary Statistics of Episodes of Biopsy-
Proven Acute Rejection
IA2, SAC
PD biomarker
2.11
All 
Subjects
Non-Standard
EFF_T1
Summary Statistics of Serum IP-10 
IA2, SAC
2.12
All 
Subjects
Non-Standard
EFF_T2
Summary Statistics of Serum IP-10 Change 
from Baseline 
IA2, SAC
2.13
All 
Subjects
Non-Standard
EFF_T1
Summary Statistics of Mig 
IA2, SAC
2.14
All 
Subjects
Non-Standard
EFF_T2
Summary Statistics of Mig Change from 
Baseline 
IA2, SAC


CONFIDENTIAL
204824
46
Efficacy Tables
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
2.15
All 
Subjects
Non-Standard
EFF_T1
Summary Statistics of Free IL-18
IA2, SAC
2.16
All 
Subjects
Non-Standard
EFF_T2
Summary Statistics of Free IL-18 Change from 
Baseline 
IA2, SAC
2.17
All 
Subjects
Non-Standard
EFF_T1
Summary Statistics of Bound IL-18 
IA2, SAC
2.18
All 
Subjects
Non-Standard
EFF_T2
Summary Statistics of Bound IL-18 Change 
from Baseline 
IA2, SAC
2.19
All 
Subjects
Non-Standard
EFF_T1
Summary Statistics of Total IL-18 
IA2, SAC
2.20
All 
Subjects
Non-Standard
EFF_T2
Summary Statistics of total IL-18 Change from 
Baseline 
IA2, SAC
Urine biomarker
2.21
All 
Subjects
Non-Standard
EFF_T1
Summary Statistics of IL-18 
IA2, SAC
2.22
All 
Subjects
Non-Standard
EFF_T1
Summary Statistics of NGAL 
IA2, SAC
2.23
All 
Subjects
Non-Standard
EFF_T1
Summary Statistics of KIM1 
IA2. SAC


CONFIDENTIAL
204824
47
Efficacy Tables
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
Dialysis dependency and graft survival
2.24
All 
Subjects
Non-Standard
EFF_T3
Proportion of Subjects Who are Dialysis-
Independent at Visits up to 12 Months post 
Transplant
IA2, SAC
Exploratory
2.25
All 
Subjects
Non-Standard
EFF_T2
Summary Statistics of % Free GSK1070806 
within Renal Graft Biopsies
IA2, SAC
2.26
All 
Subjects
Non-Standard
EFF_T2
Summary Statistics of % Bound GSK1070806 
within Renal Graft Biopsies
IA2, SAC
2.27
All 
Subjects
Non-Standard
EFF_T2
Summary Statistics of Level of IL-18 in Renal 
Preservation Fluid
IA2, SAC
2.28
All 
Subjects
Non-Standard 
EFF_T2
Summary Statistics of Serum Cytokine Levels
IA2, SAC
2.29
All 
Subjects
Non-Standard 
EFF_T1
Summary Statistics of Length of Hospital Stay
IA2, SAC


CONFIDENTIAL
204824
48
11.9.5.
Efficacy Figures
Efficacy Figures
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
Serum Creatinine
2.01
All 
Subjects
Non-Standard
EFF_F1
Individual Line Plot of Serum Creatinine over 
Time 
Including the mean line plot; starting from 
baseline
IA1, IA2,
SAC
2.02
All 
Subjects
Non-Standard
EFF_F1
Individual Line Plot of Serum Creatinine 
Change from Baseline over Time
Including the mean line plot
IA1, IA2,
SAC
Graft function
2.03
All 
Subjects
Non-Standard
EFF_F2
Individual Line Plot of Urine Output over Time
IA2, SAC
2.04
All 
Subjects
Non-Standard
EFF_F3
Kaplan-Meier Curve of Graft Survival up to 12 
Months post Transplant
IA2, SAC
PD biomarkers
2.05
All 
Subjects
Non-Standard
EFF_F1
Individual Line Plot of Serum IP-10 over Time
Including the mean line plot; starting from 
baseline
IA2, SAC
2.06
All 
Subjects
Non-Standard
EFF_F1
Individual Line Plot of Serum IP-10 Change 
from Baseline over Time
Including the mean line plot
IA2, SAC
2.07
All 
Subjects
Non-Standard
EFF_F1
Individual Line Plot of Serum Mig over Time
Including the mean line plot; starting from 
baseline
IA2, SAC


CONFIDENTIAL
204824
49
Efficacy Figures
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
2.08
All 
Subjects
Non-Standard
EFF_F1
Individual Line Plot of Serum Mig Change from 
Baseline over Time
Including the mean line plot
IA2, SAC
2.09
All 
Subjects
Non-Standard
EFF_F1
Individual Line Plot of Serum IL-18 Levels over 
Time
Including free IL-18; bound IL-18 and total IL-
18
Including the mean line plot
IA1, IA2,
SAC
2.10
All 
Subjects
Non-Standard
EFF_F1
Individual Line Plot of Serum IL-18 Levels
Change from Baseline over Time
Including free IL-18; bound IL-18 and total IL-
18
Including the mean line plot
IA2, SAC
Urine Biomarkers
2.11
All 
Subjects
Non-Standard
EFF_F3
Mean (95% CI) Plot of Urine IL-18
Two sided confidence interval
IA2, SAC
2.12
All 
Subjects
Non-Standard
EFF_F3
Mean (95% CI) Plot of Urine NGAL
Two sided confidence interval
IA2, SAC
2.13
All 
Subjects
Non-Standard
EFF_F3
Mean (95% CI) Plot of Urine KIM1
Two sided confidence interval
IA2, SAC
Exploratory
2.14
All 
Subjects
Non-Standard
EFF_F2
Individual Line Plot of Serum IL-18 Binding 
Protein over Time
starting from baseline
IA2, SAC
2.15
All 
Subjects
Non-Standard
EFF_F2
Individual Line Plot of Serum Cytokine Levels 
over Time
starting from baseline
IA2, SAC


CONFIDENTIAL
204824
50
Efficacy Figures
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
2.16
All 
Subjects
Non-Standard
EFF_F1
Individual Line Plot of Serum Cytokine Levels 
Change from Baseline over Time 
Including the mean line plot
IA2, SAC
Patient Profile
2.17
All 
Subjects
Non-Standard
EFF_F5
Patient Profile Plot of Biomarker/PD Endpoints
Incuding serum IP-10; serum mig; free IL-18; 
bound IL-18; total IL-18
IA2, SAC


CONFIDENTIAL
204824
51
11.9.6.
Safety Tables
Safety Tables
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
Adverse Events – Overall
3.01
All 
Subjects
AE1
Summary of All Adverse Events
IA1, IA2,
SAC
3.02
All 
Subjects
AE3
Summary of Common Adverse Events by 
Preferred Term
Common AE = Frequency > 1%
IA1, IA2,
SAC
3.03
All 
Subjects
AE1
Summary of Drug-Related Adverse Events by 
System Organ Class
IA1, IA2,
SAC
3.04
All 
Subjects
AE1
Summary of Serious Adverse Events by System 
Organ Class
IA1, IA2,
SAC
3.05
All 
Subjects
AE1
Summary of Adverse Events Leading to 
Withdrawals from Study or Study Treatment
IA1, IA2,
SAC
Adverse Events – in patients (before discharge)
3.06
All 
Subjects
AE1
Summary of All Adverse Events before 
Discharge
IA2, SAC
3.07
All 
Subjects
AE3
Summary of Common Adverse Events by 
Overall Frequency before Discharge
IA2, SAC
3.08
All 
Subjects
AE5
Summary of Drug-Related Adverse Events by 
System Organ Class before Discharge
IA2, SAC


CONFIDENTIAL
204824
52
Safety Tables
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
3.09
All 
Subjects
AE1
Summary of Serious Adverse Events by System 
Organ Class before Discharge
IA2, SAC
3.10
All 
Subjects
AE1
Summary of Adverse Events Leading to 
Withdrawals from Study / Permanent 
Discontinuation of Study Treatment before 
Discharge
IA2, SAC
Adverse Events – out patients (after discharge)
3.11
All 
Subjects
AE1
Summary of All Adverse Events after Discharge
IA2, SAC
3.12
All 
Subjects
AE3
Summary of Common Adverse Events by 
Overall Frequency after Discharge
IA2, SAC
3.13
All 
Subjects
AE5
Summary of Drug-Related Adverse Events by 
System Organ Class after Discharge
IA2, SAC
3.14
All 
Subjects
AE1
Summary of Serious Adverse Events by System 
Organ Class after Discharge
IA2, SAC
3.15
All 
Subjects
AE1
Summary of Adverse Events Leading to 
Withdrawals from Study / Permanent 
Discontinuation of Study Treatment after 
Discharge
IA2, SAC
Labs
3.16
All 
Subjects
LB1
Summary of Chemistry Changes from Baseline
IA2, SAC


CONFIDENTIAL
204824
53
Safety Tables
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
3.17
All 
Subjects
LB1
Summary of Emergent Chemistry Results of
Potential Clinical Importance
IA1, IA2, 
SAC
3.18
All 
Subjects
LB1
Summary of Haematology Changes from 
Baseline 
IA2, SAC
3.19
All 
Subjects
LB1
Summary of Emergent Haematology of Potential 
Clinical Importance
IA1, IA2, 
SAC
Vital Signs 
3.20
All 
Subjects
VS1
Summary of Change from Baseline in Vital 
Signs 
Include the Respiration Rate and Temperature 
IA2, SAC
3.21
All 
Subjects
VS2
Summary of Emergent Vital Signs Results of 
Potential Clinical Importance
IA1, IA2, 
SAC
ECGs
3.22
All 
Subjects
EG1
Summary of ECG Findings
IA2, SAC
3.23
All 
Subjects
Non-Standard
EFF_T5
Frequency of Maximum Emergent QTc Values 
by Category
IA1, IA2, 
SAC
3.24
All 
Subjects
EG2
Summary of Change from Baseline in ECG 
Values 
IA2, SAC


CONFIDENTIAL
204824
54
11.9.7.
Pharmacokinetic Tables
Pharmacokinetic Tables
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
PK Concentration Data 
4.01
PK
PK01
Summary of Plasma GSK1070806
Pharmacokinetic Concentration-Time Data 
(mg/mL) 
IA1, IA2, 
SAC
PK Derived Parameters
4.02
PK
PKPT1
Summary Statistics of Derived Plasma 
GSK1070806 Pharmacokinetic Parameters 
Parameters with units 
IA1, IA2, 
SAC
4.03
PK
PKPT3
Summary Statistics of Log-Transformed 
Derived Plasma GSK1070806 Pharmacokinetic 
Parameters 
Parameters with units; exclude non-continuous 
PK parameters;
IA2, SAC


CONFIDENTIAL
204824
55
11.9.8.
Pharmacokinetic Figures
Pharmacokinetic Figures
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
Individual Plots
4.01
PK
PKCF1P
Individual GSK1070806 Plasma Concentration-
Time Plot by Subject (Linear and Semi-Log)
Paginate by Subject
IA2, SAC
Mean / Median Plots
4.02
PK
PKCF2
Mean and Median Plasma GSK1070806 
Concentration-Time Plots by Treatment (Linear 
and Semi-log)
IA2, SAC
4.03
PK
PKCF3
Median and Median Plasma GSK1070806 
Concentration-Time Plots by Treatment (Linear 
and Semi-log)
IA2, SAC


CONFIDENTIAL
204824
56
11.9.9.
Pharmacokinetic / Pharmacodynamic Figures
Pharmacodynamic / Biomarker Figures
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
5.01
PK
Non-Standard
PKPD_F1
Scatter Plot of Free and Drug Bound IL-18 
Serum Levels Versus GSK1070806 Plasma 
Concentration
Panel : by free and drug bound IL-18
X-Axis : Plasma Concentration
Y-Axis : free and drug bound IL-18
Add Footnote
X-Axis: Untransformed data presented using 
Log10 scale
IA2, SAC


CONFIDENTIAL
204824
57
11.9.10.
ICH Listings
ICH Listings
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
Subject Disposition
1
All 
Subjects
ES2
Listing of Reasons for Study Withdrawal
IA1, IA2, 
SAC
2
All 
Subjects
ES7
Listing of Reasons for Screening Failure
IA1, IA2, 
SAC
3
All 
Subjects
SA3a
Listing of Subjects Excluded from Any 
Populations
IA2, SAC
4
All 
Subjects
DV2
Listing of Important Protocol Deviations
IA1, IA2, 
SAC
5
All 
Subjects
IE3
Listing of Subjects with Inclusion/Exclusion 
Criteria Deviations
IA1, IA2, 
SAC
Demographics
6
All 
Subjects
DM2
Listing of Demographic Characteristics
IA1, IA2, 
SAC
7
All 
Subjects
DM9
Listing of Race
IA1, IA2, 
SAC
Exposure


CONFIDENTIAL
204824
58
ICH Listings
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
8
All 
Subjects
EX3
Listing of Exposure
SAC
Adverse Events
9
All 
Subjects
AE7
Listings of Subject Numbers for Individual 
Adverse Events
IA1, IA2, 
SAC
10
All 
Subjects
AE8
Listing of All Adverse Events
IA1, IA2, 
SAC
11
All 
Subjects
AE8
Listing of Serious Adverse Events
IA1, IA2, 
SAC
12
All 
Subjects
AE8
Listing of Adverse Events Leading to 
Withdrawal from Study
IA1, IA2, 
SAC
LABS
13
All 
Subjects
LB5
Listing of Haematology Laboratory Data for 
Subjects with Abnormalities of Potential 
Clinical Importance
IA1, IA2, 
SAC
14
All 
Subjects
LB5
Listing of Clinical Chemistry Laboratory Data 
for Subjects Abnormalities of Potential Clinical 
Importance.
IA1, IA2, 
SAC
15
All 
Subjects
UR2b
Listing of Urinalysis Data
IA2, SAC


CONFIDENTIAL
204824
59
ICH Listings
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
16
All 
Subjects
Non-Standard
SAFE_L1
Listing of Clinical Chemistry Laboratory Values 
(Total cholesterol, HDL, LDL, Triglycerides, 
Creatinine Clearance (MDRD) and Associated 
Ratios).
IA2, SAC
ECGs
17
All 
Subjects
EG3
Listing of ECG Values for Subjects with 
Abnormalities of Potential Clinical Importance.
IA1, IA2, 
SAC
Vital Signs
18
All 
Subjects
CP_VS4
Listing of Vital Signs for Subjects with 
Abnormalities of Potential Clinical Importance
IA1, IA2, 
SAC
Immunogenicity
19
All 
Subjects
IMM2
Listing of Immunogenicity Results
ADA tiers
IA2, SAC


CONFIDENTIAL
204824
60
11.9.11.
Non-ICH Listings
Non-ICH Listings
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
PK
20
PK
PKCL1P
Listing of Plasma GSK1070806
Pharmacokinetic Concentration-Time Data
IA2, SAC
21
PK
PKPL1P
Listing of Derived Plasma GSK1070806
Pharmacokinetic Parameters 
Include dose and dose number
IA2, SAC
Graft Function
22
Analysis 
Population
Non-Standard
SAFE_L1
Listing of Individual Serum Creatinine 
IA1, IA2,
SAC
23
Analysis 
Population
Non-Standard
SAFE_L1
Listing of Individual AUC of 7 Day Serum 
Creatinine 
No change from baseline column
IA1, IA2,
SAC
24
Analysis 
Population
Non-Standard
SAFE_L1
Listing of Individual AUC of 30 Day Serum 
Creatinine
No change from baseline column
IA1, IA2,
SAC
25
All 
Subjects
Non-Standard
SAFE_L2
Listing of Individual Graft Function in the First 7 
Days
Including primary non function;3 day 
functional DGF; 7 day functional DGF; 3 
day intermediate graft function; 7 day 
intermediate graft function; 3 day 
immediate graft function; 7 day 
immediate graft function
IA1, IA2,
SAC


CONFIDENTIAL
204824
61
Non-ICH Listings
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
26
All 
Subjects
Non-Standard
SAFE_L2
Listing of Individual Urine Output 
Including change from baseline
IA2, SAC
27
All 
Subjects
Non-Standard
SAFE_L1
Listing of Individual with Episodes of Biopsy-
Proven Acute Rejection
IA2, SAC
Pharmacodynamic & Biomarkers
28
All 
Subjects
Non-Standard
EFF_L1
Listing of Individual of IL-18 
IA1, IA2,
SAC
29
All 
Subjects
Non-Standard
EFF_L1
Listing of Individual of NGAL 
IA2, SAC
30
All 
Subjects
Non-Standard
EFF_L1
Listing of Individual of KIM1 
IA2, SAC
31
All 
Subjects
Non-Standard
PD_L1
Listing of Biomarkers
IA2, SAC
32
All 
Subjects
Non-Standard
PD_L1
Listing of Free and Drug-bound IL-18 Levels In 
Serum
IA2, SAC
Dialysis dependency and graft survival
33
All 
Subjects
Non-Standard
SAFE_L1
Listing of Number of Dialysis Events per Patient 
in the First 30 Days Post Transplant
IA1, IA2, 
SAC


CONFIDENTIAL
204824
62
Non-ICH Listings
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
Recipient Kidney Data
34
All 
Subjects
Non-Standard
SAFE_L3
Listing of Recipient Virology
IA2, SAC
Exploratory
35
All 
Subjects
Non-Standard
SAFE_L1
Listing of Individual % bound GSK1070806 
within Renal Graft Biopsies
IA2, SAC
36
All 
Subjects
Non-Standard
SAFE_L1
Listing of Individual Level of IL-18 in Renal 
Preservation Fluid
IA2, SAC
37
All 
Subjects
Non-Standard
SAFE_L1
Listing of Individual Change from Baseline 
Histological Analysis of Biopsies with Respect 
to Cellular Infiltrate
IA2, SAC
38
All 
Subjects
Non-Standard
SAFE_L2
Listing of Individual of Length of Hospital and 
Re-hospitalization Stay
IA1, IA2,
SAC
Donor Kidney Data
39
All 
Subjects
Non-Standard
SAFE_L3
Listing of Donor Virology
IA2, SAC
40
All 
Subjects
Non-Standard
SAFE_L4
Listing of Donor Characteristics 
Cold ischiemic time; warm ischemic time; 
age; sex; last creatinine before transplant; 
medical conditions; biopsy performed 
yes/no, transport system (ice or perfusion)
IA1, IA2, 
SAC


CONFIDENTIAL
204824
63
Non-ICH Listings
No.
Populatio
n
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
PK/PD
41
PK
Non-Standard
SAFE_L5
Listing of Serum IL-18 (drug bound, total or 
free) vs. PK Plasma Concentrations
IA2, SAC


CONFIDENTIAL
204824
64
11.10.
Appendix 10: Example Mock Shells for Data Displays


CONFIDENTIAL
204824
65
Example 
: EFF_F1
                                  Page 1 of X
Protocol
: 204824
Population
: All Subjects
Figure X
Individual Subject Spaghetti Plot with Mean Line 
NOTE: This is example only. Plot adjusted accordingly to study data.
The linked image cannot be displayed.  The file may have been moved, renamed, or deleted. Verify that the link points to the correct file and location.


CONFIDENTIAL
204824
66
Example 
: EFF_F2
                                   Page 1 of X
Protocol
: 204824
Population
: All Subjects
Figure X
Individual Subject Spaghetti Plot
NOTE: This is example only. Plot adjusted accordingly to study data.
The linked image cannot be displayed.  The file may have been moved, renamed, or deleted. Verify that the link points to the correct file and location.


CONFIDENTIAL
204824
67
Example 
: EFF_F3
                                   Page 1 of X
Protocol
: 204824
Population
: All Subjects
Figure X
Mean Plot of xxx
NOTE: Plot adjusted accordingly to study data
The linked image cannot be displayed.  The file may have been moved, renamed, or deleted. Verify that the link points to the correct file and location.


CONFIDENTIAL
204824
68
Example 
: EFF_F4
                                   Page 1 of X
Protocol
: 204824
Population
: All Subjects
Figure X
Kaplan-Meier Curve of Graft Survival up to 12 Months post Transplant
NOTE: Plot adjusted accordingly to study data, with plot also including the other treatments groups on subsequent pages.


P
P
D
PPD


CONFIDENTIAL
204824
70
Example 
: PKPD_F1
                                   Page 1 of X
Protocol
: 204824
Population
: All Subjects
Figure X
Scatter Plot of Free and Drug Bound IL-18 Serum Levels Versus GSK1070806 Plasma Concentration


CONFIDENTIAL
204824
71
Example
: EFF_T1 
Page 1 of X
Protocol
: 204824
Population
: All Subjects
Table X
Summary Statistics of XXX (unit)
Summary: Absolute
Treatment
N
Visit
Planned 
Relevant 
Time
n
Mean
S.D
Median
Min
Max
GSK1070806 3 mg/kg
xx
xx
x
xxx.x
xx.xx
xxx.x
xxx
xxx
xx
x
xxx.x
xx.xx
xxx.x
xxx
xxx
xx
xx
x
xxx.x
xx.xx
xxx.x
xxx
xxx
xx
x
xxx.x
xx.xx
xxx.x
xxx
xxx


CONFIDENTIAL
204824
72
Example
: EFF_T2
Page 1 of X
Protocol
: 204824
Population
: All Subjects
Table X
Summary Statistics of XXX (unit)
Summary: Change from Baseline
Treatment
N
Visit
Planned 
Relevant 
Time
n
Mean
S.D
Median
Min
Max
GSK1070806 3 mg/kg
xx
xx
x
xxx.x
xx.xx
xxx.x
xxx
xxx
xx
x
xxx.x
xx.xx
xxx.x
xxx
xxx
xx
xx
x
xxx.x
xx.xx
xxx.x
xxx
xxx
xx
x
xxx.x
xx.xx
xxx.x
xxx
xxx


CONFIDENTIAL
204824
73
Example 
: EFF_T3
Page 1 of n
Protocol  
: 204824
Population 
: All Subjects.
Table X
Proportion of Subjects with DGF
                               
                                         
Number of Subjects (%)
(N)
Subjects with DGF
XXX (%)
                               
                                         


CONFIDENTIAL
204824
74
Example 
: EFF_T4
Page 1 of n
Protocol  
: 204824
Population 
: All Subjects.
Table X
Proportion of Subjects with Renal Functional Graft within 7 Days after Transplant
                               
                                         
Number of Subjects (%)
(N)
Primary Non DGF
XXX (%)
3 day Functional DGF
XXX (%)
7 day Functional DGF
XXX (%)
3 day Intermediate Graft Function
XXX (%)
7 day Intermediate Graft Function
XXX (%)
3 day Immediate Graft Function
XXX (%)
7 day Immediate Graft Function
XXX (%)


CONFIDENTIAL
204824
75
Example
: EFF_T5
Page 1 of X
Protocol
: 204824
Population
: All Subjects
Table X
Summary of Maximum Emergent QTc Values by Category
Baseline (N = xx)
Enhanced Monitoring (N = xx)
Criteria
N
Mean QTc
SD
Criteria
N
Mean max 
QTc
SD
QT <= 480 msec 
xx
xx.x
xx.xx
QTc > 530 msec
xx
xx.x
xx.xx
QT (uncorr) > 600 msec
xx
xx.x
xx.xx
Bundle Branch Block with 
QT < =500 msec
xx
xx.x
xx.xx
QTc >= 550 msec
xx
xx.x
xx.xx
QT (uncorr) > 600 msec
xx
xx.x
xx.xx
Note: QTc value could be QTcB or QTcF depends on collected data.


CONFIDENTIAL
204824
76
Example 
: SAFE_L1
                                               Page 1 of X
Protocol
: 204824
Population
: All Subjects
Listing X
Listing of XXX
Treatment
Subj.
Analyte
(units)
Visit
Actual Date
Planned
Relative
Time
Time
Sample
Taken
Result
Change
from
Baseline
GSK1070806 
3mg/kg
XXX
DAY 1
PRE DOSE
9:48
0.9
DAY 1
4 Hr
9:48
1.10
0.20
DAY 29
4 Hr
9:48
2.60
1.70
DAY 85
4 Hr
9:48
1.10
0.20
NOTE: Table adjusted accordingly to the study data.
PPD
PPD


CONFIDENTIAL
204824
77
Example
: SAFE_L2 
Page 1 of X
Protocol
: 204824
Population
: All Subjects
Listing X
Listing of Patients Hospitalization and Re-hospitalization Stay 
Subject 
Age/Gender
Race
DGF (Y/N)
Hosp. Date
Discharge Date
Length of Stay (Day)
XXXXXXX
XX/X
XX
X
XX/XX/XXXX
XX/XX/XXXX
XX
XX/XX/XXXX
XX/XX/XXXX
XX
XXXXXXX
XX/X
XX
X
XX/XX/XXXX
XX/XX/XXXX
XX


CONFIDENTIAL
204824
78
Example
: SAFE_L3 
Page 1 of X
Protocol
: 204824
Population
: All Subjects
Table X
Listing of Donor Virology 
Subject 
Age/Gender 
Race
Virology Type
Positive (yes/no)
XXXXXXX
XX/X
XX
Hepatitis B
Hepatitis C
HIV
EBV


CONFIDENTIAL
204824
79
Example
: SAFE_L4 
Page 1 of X
Protocol
: 204824
Population
: All Subjects
Table X
Listing of Donor Characteristics 
Subject 
Age/Gender
Race
Characteristics
Value
XXXXXXX
XX/X
XX
Cold Ischiemic Time
Warm Ischemic Time
Last Creatinine before Transplant
Donor Medical Conditions
Biopsy Performed
Yes/No
Transport System
Ice/Perfusion


CONFIDENTIAL
204824
80
Example
: SAFE_L5 
Page 1 of X
Protocol
: 204824
Population
: PK
Table X
Listing of Serum IL-18 vs. PK. Plasma Concentrations
Subject 
Age/Gender
Race
Serum IL-18
(drug bound, total or free)
PK Plasma Concentrations
XXXXXXX
XX/X
XX
XX.X
XX.X


CONFIDENTIAL
204824
81
11.11.
Appendix 11: Summary of Change of Amendment 1
Consistent with the recent protocol amendment, change the number of patients for the dose escalation interim analysis from 8 – 10 to 6.
The following outputs have been removed from the IA1 delivery as a result of a team decision that these variables are no longer required 
for a dose escalation decision:
Table 2.11; 2.12; 2.13; 2.14; 2.15; 2.16; 2.17; 2.18; 2.19; 2.20; 2.21; 2.25; 2.26
Figure 2.03; 2.05; 2.06; 2.07; 2.08
Table 4.03
Figure 4.01; 4.02; 4.03; 5.01
ICH listing 3; 9
Non-ICH listing 26; 27; 41