An Open Label Positron Emission Tomography (PET) Imaging Study Using 89Zirconium Labeled GSK3128349 to Investigate the Biodistribution and Clearance of an Albumin Binding Domain Antibody (AlbudAb) GSK3128349 Following Single Dose Intravenous Administration in Healthy Male Subjects
Phase: PHASE1
Conditions: Drug-Related Side Effects and Adverse Reactions
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
RES117169
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TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
An open label positron emission tomography (PET) imaging 
study using 89Zirconium labelled GSK3128349 to investigate the 
biodistribution and clearance of an albumin binding domain 
antibody (AlbudAb) GSK3128349 following single dose
intravenous administration in healthy male subjects.
Compound Number:
GSK3128349
Development Phase
I
Effective Date:
23-MAY-2016
Author(s):
CPSSO, PCPS
Translational Medicine, PTS
Clinical Statistics, PCPS
PTS
Cell & Gene Therapy, PTS
Safety Assessment, PTS
Clinical Immunology, PTS
Translational Medicine, PTS
Clinical Pharmacology Modeling and Simulation, PCPS
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
PPD

PPD
PPD
PPD

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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
 
Upper 
Merion, 
US
Secondary 
Medical 
Monitor
Upper 
Merion, 
US
SAE contact 
information
Medical 
Monitor as 
above
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): N/A
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

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

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY RES117169.................................................8
2.
INTRODUCTION....................................................................................................13
2.1.
Brief background.........................................................................................13
2.2.
Study rationale............................................................................................14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................14
4.
STUDY DESIGN ....................................................................................................15
4.1.
Overall Design ............................................................................................15
4.1.1.
PET/CT Image Acquisition Workflow ...........................................18
4.1.2.
PET scans ...................................................................................19
4.2.
Type and Number of Subjects.....................................................................19
4.3.
Dose Justification........................................................................................20
4.3.1.
GSK3128349 dose selection and safety experience ....................20
4.3.2.
Radioactivity dose........................................................................21
4.4.
Risk Assessment and Management............................................................22
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............25
5.1.
Inclusion Criteria.........................................................................................25
5.2.
Exclusion Criteria........................................................................................26
5.3.
Screening Failures......................................................................................27
5.4.
Study Withdrawal Criteria ...........................................................................28
5.4.1.
Liver Chemistry Management ......................................................28
5.4.2.
QTc Evaluation Criteria................................................................29
5.4.3.
Renal Monitoring..........................................................................30
5.5.
Subject and Study Completion....................................................................30
6.
STUDY TREATMENT ............................................................................................30
6.1.
Treatment Assignment................................................................................31
6.2.
Blinding.......................................................................................................31
6.3.
Packaging and Labeling..............................................................................31
6.4.
Preparation/Handling/Storage/Accountability..............................................31
6.5.
Treatment of Study Treatment Overdose....................................................31
6.6.
Treatment after the End of the Study ..........................................................32
6.7.
Lifestyle and/or Dietary Restrictions............................................................32
6.7.1.
Contraception Requirements .......................................................32
6.7.2.
Caffeine, Alcohol, and Tobacco ...................................................32
6.7.3.
Activity .........................................................................................32
6.8.
Concomitant Medications and Non-Drug Therapies....................................33
6.8.1.
Permitted Medications and Non-Drug Therapies..........................33
6.8.2.
Prohibited Medications and Non-Drug Therapies.........................33
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................33
7.1.
Time and Events Table...............................................................................34
7.1.1.
Screening ....................................................................................34
7.1.2.
Scanning & Dosing ......................................................................35
7.1.3.
Follow-up.....................................................................................37
7.2.
Screening and Critical Baseline Assessments ............................................38

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7.3.
Safety .........................................................................................................38
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........38
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................38
7.3.1.2.
Method of Detecting AEs and SAEs ...........................39
7.3.1.3.
Follow-up of AEs and SAEs........................................39
7.3.1.4.
Regulatory Reporting Requirements for SAEs............39
7.3.2.
Pregnancy ...................................................................................39
7.3.3.
Physical Exams ...........................................................................40
7.3.4.
Vital Signs....................................................................................40
7.3.5.
Electrocardiogram (ECG).............................................................40
7.3.6.
Clinical Safety Laboratory Assessments ......................................40
7.3.7.
Urine protein/creatinine ratio........................................................42
7.4.
Pharmacokinetics .......................................................................................42
7.4.1.
Pharmacokinetic Blood Sample Collection...................................42
7.4.2.
Pharmacokinetic Urine Sample Collection for Scintillation 
Counting ......................................................................................42
7.4.3.
Pharmacokinetic Sample Analysis ...............................................43
7.5.
Immunogenicity...........................................................................................43
8.
DATA MANAGEMENT ...........................................................................................44
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................44
9.1.
Hypotheses.................................................................................................44
9.2.
Sample Size Considerations.......................................................................44
9.2.1.
Sample Size Assumptions ...........................................................44
9.2.2.
Sample Size Re-estimation or Adjustment...................................45
9.3.
Data Analysis Considerations .....................................................................45
9.3.1.
Analysis Populations....................................................................45
9.3.2.
Interim Analysis ...........................................................................45
9.4.
Key Elements of Analysis Plan ...................................................................45
9.4.1.
Primary Analyses.........................................................................45
9.4.2.
Secondary Analyses ....................................................................47
10. STUDY GOVERNANCE CONSIDERATIONS........................................................48
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............48
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................48
10.3.
Quality Control (Study Monitoring) ..............................................................48
10.4.
Quality Assurance.......................................................................................49
10.5.
Study and Site Closure ...............................................................................49
10.6.
Records Retention......................................................................................49
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................50
11. REFERENCES.......................................................................................................51
12. APPENDICES........................................................................................................52
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................52
12.2.
Appendix 2: Liver Safety – Required Actions and Follow up 
Assessments ..............................................................................................55

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12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................57
12.3.1.
Definition of Adverse Events........................................................57
12.3.2.
Definition of Serious Adverse Events...........................................58
12.3.3.
Recording of AEs and SAEs ........................................................59
12.3.4.
Evaluating AEs and SAEs............................................................60
12.3.5.
Reporting of SAEs to GSK...........................................................61
12.4.
Appendix 4: Collection of Pregnancy Information........................................62

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1.
PROTOCOL SYNOPSIS FOR STUDY RES117169
Rationale
GSK3128349: GSK3128349 is a human domain antibody (dAb) that binds non-
covalently to serum albumin with high affinity (also referred to as an ‘AlbudAb™’). It 
contains a cysteine residue engineered at the C terminus of the molecule that can be used 
for the covalent attachment of a pharmacologically active entity As such, GSK3128349 is 
a scaffold that has of itself no pharmacological action, but has the potential to be 
conjugated with a pharmacologically active entity [O’Connor-Semmes, 2014].
GSK3128349 is a platform to extend half-life and alter biodistribution of therapeutics:
Typically, dAbs are small (~15 kDa) and therefore are excreted renally in a matter of 
hours. Due to the combination of the high affinity of GSK3128349 for albumin and the 
high concentrations of albumin, it is expected that GSK3128349 will be bound to 
albumin the majority of the time. Therefore, AlbudAbs, like GSK3128349, form a 
complex too big to be subject to renal clearance. Furthermore, the binding of 
GSK3128349 to albumin confers some of the pharmacokinetic and biodistribution 
properties of albumin to GSK3128349; and hence any pharmacologically active entity 
conjugated to it. This includes AlbudAbs bound to albumin being subject to Neonatal Fc 
Receptor (FcRn) dependent albumin recycling enhancing the exposure half-life. As a 
result of these effects AlbudAbs can persist in the body for several days or even weeks. 
We expect the half life of GSK3128349 in humans to approach that of albumin (~19 days
[Peters, 1985] [Peters, 1996(a)]). Therefore, GSK3128349 has the potential to 
significantly enhance the medicinal value of therapeutics conjugated to GSK3128349 by 
increasing their half-life and/or modulating their biodistribution [Kratz, 2008].
Study Objective: This study will determine the biodistribution and pharmacokinetics of 
the AlbudAb scaffold GSK3128349. The data will inform and validate a Physiologically 
Based Pharmacokinetics (PBPK) model, which will predict the distribution of future 
therapeutics conjugated to GSK3128349, as well as other AlbudAbs. 
The validated PBPK modeling will improve our future clinical study designs by 
providing more accurate estimates of tissue exposures, which will lead to better: dose 
selection, timing of biomarker measurements, target engagement, and ultimately efficacy. 
This could potentially lead to a reduced number of assessments and/or subjects enrolled 
in future clinical trials. Furthermore, the PBPK modeling will be applied pre-clinically,
yielding better selection of targets for discovery programs, and informing affinity 
requirements for discovery lead optimization efforts. 
The data generated through this study will benefit all ongoing and future AlbudAb 
programs, and will provide generally applicable information to support understanding of 
biodistribution processes for all protein-based therapies.

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Objective(s)/Endpoint(s)
PRIMARY OBJECTIVE
END POINTS
1.1
Evaluate biodistribution of 
89Zr-GSK3128349 in
regions of interest following 
IV administration to support 
future AlbudAb products 
and the development of a 
PBPK model.
Quantitative parameters (including but not limited 
to 89Zr-GSK3128349 concentration) derived from
Positron Emission Tomography – Computed 
Tomography (PET-CT) data (e.g. Standardised 
Uptake Values (SUVs)a, volume of Regions of 
Interest (ROI) to assess average and total uptake 
into regions of interest (e.g. liver, kidney, muscle,
spleen, heart, lung, bladder, thymus – if feasible -, 
blood and bone).
SECONDARY 
OBJECTIVES
END POINTS
2.1
Measure PK of 89Zr-
GSK3128349 by whole 
blood, plasma and urine 
radiolabel detection to 
support future AlbudAb 
products and the 
development of a PBPK 
model.
Whole blood, plasma and urine radioactivity 
concentrations and derived pharmacokinetic 
parameters, as data allows, based on blood, 
plasma and urine scintillation counting.
2.2
Measure PK of 
GSK8128349 by mass 
spectroscopy to support the 
development of a PBPK 
model.
Plasma concentrations and derived 
pharmacokinetic parameters.
Compare plasma exposure assessments via 
different GSK3128349 mass spectroscopy 
methods.
2.3
Measure dosimetry of 89Zr-
GSK3128349 from PET 
scans and blood 
radioactivity.
Organ doses (mSv)
Effective dose (mSv)
2.4
Assess the safety and 
tolerability of 89Zr-
GSK3128349.
Adverse events (AEs), serious adverse events 
(SAEs).
Safety laboratory values, proteinuria, 
electrocardiograms (ECGs) and vital signs.
2.5
Investigate the presence and 
levels of anti-GSK3128349 
antibodies, including pre-
and post-dose.
Incidence of anti-GSK3128349 antibodies.
Serum titres of anti-GSK3128349 antibodies. 
a SUVmean for larger ROI (≥ 3 cm), SUVpeak for smaller ROI.
Overall Design
This open label single centre study will investigate the biodistribution and 
pharmacokinetics of the AlbudAb platform scaffold protein GSK3128349. Hence, 
GSK3128349 will be administered as a single drug product consisting of a mix of 

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unlabeled GSK3128349 and 89Zr-GSK3128349 (GSK3128349 radiolabelled with 
zirconium). 
Study Schematic
Study Overview

On Day 1, enrolled subjects will receive one intravenous (IV) infusion of 89Zr-
GSK3128349 to deliver a dose of 1 mg and undergo PET/CT scans and blood 
sampling assessments prior to discharge at 24 hrs post-dose, on day 2. 

Subjects will be required to visit the clinic repeatedly over the subsequent 42 days 
and undergo further blood sampling and PET/CT scans up to 10-12 days after 
dosing. This will monitor 89Zr-GSK3128349 concentrations in various regions of 
interest (ROI) over time.

Blood samples will be taken for radioactivity, pharmacokinetic, immunogenicity, 
and safety assessments (

After completion of the first 2 subjects, dosimetry assessments will be performed and 
used to refine the radiation dose administered to subsequent subjects.

Urine will be collected during the first 24 hours and measured with respect to 
radioactivity and drug.

The expected total duration of a subject’s participation is approximately 10 weeks, 
including the screening period of up to 28 days. 
Type and Number of Subjects
A single cohort of six to eight healthy male subjects will be enrolled into the study.

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Analysis
Interim Analysis
There are no formal interim analyses planned. However, the following in-stream data 
review is planned:
Following completion of the first two subjects’ PET scans, the study team will evaluate 
the emerging PET-CT scan data for:
Dosimetry to potentially refine the radiation dose estimates, and to identify other ROI 
for further investigation, if required. 
Determine scan time points post dose of subsequent subjects.
Primary Analyses
The following analysis is planned for primary endpoints:
Analysis
Details 
Endpoints

Quantitative parameters (including but not limited to 89Zr-GSK3128349 
concentration) derived from PET-CT data (e.g. Standardised Uptake 
Values (SUVs)a, volume of ROI) to assess average and total uptake into 
regions of interest (e.g. liver, kidney, muscle, spleen, heart, lung, 
bladder, thymus – if feasible -, blood and bone
Endpoint 
Definitions

SUV: A simple way of determining activity in PET imaging for each 
region of interest, which is mathematically derived ratio of tissue 
radioactivity concentration at a point in time C(T) and the injected dose 
of radioactivity per kilogram of the patient's body weight:
SUV = C(T)/[injection dose (MBq)/patient's weight (kg)]

Volume: The volume of specified organ as measured in PET or CT 
images. 
Analysis
(Raw Data)

Descriptive statistics where appropriate, (i.e. n, arithmetic mean, 
geometric mean, standard deviation, minimum, median and maximum) 
will be calculated for all generated PET-CT imaging endpoints over 
time. 

Graphical displays will be produced over time for applicable PET-CT 
imaging endpoints. 

If analysed, all data will be listed.
Statistical 
Analysis 
(Modelled)

If data permits, further statistical analyses (i.e. mixed effects models) 
will be performed to estimate quantitative parameters in ROI over time 
from PET-CT following IV administration.

Full details will be specified in the RAP.
a SUVmean for larger ROI (≥ 3 cm), SUVpeak for smaller ROI

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Secondary Analyses

Pharmacokinetics (Concentration Data & Derived Parameters)
PK
Details 
Concentration

Whole blood, plasma and urine concentrations of 89Zr-GSK3128349
and plasma concentrations of GSK2138349 data will be graphically 
represented, descriptively summarised and listed appropriately.
Parameters

Whole blood and plasma concentrations time data of 89Zr-
GSK3128349 and plasma concentrations time data of GSK3128349 
will be analyzed by non-compartmental methods.

Calculations will be based on the nominal sampling times recorded 
during the study. 

As data permits, from the plasma concentration-time data, the 
following PK parameters may be determined:
o
Maximum observed plasma concentration (Cmax)
o
Time to Cmax (Tmax) 
o
Apparent terminal phase half-life (t1/2). 
o
Area under the curve:
AUC[0-t] for 89Zr-GSK3128349 and GSK3128349, 
AUC[0-∞] only for GSK3128349
o
Clearance
o
Volume of distribution

Additional PK parameters may be included as required.

Pharmacokinetic data will be presented in graphical and/or tabular 
form, summarized descriptively and listed. 

Dosimetry
Dosimetry results as organ radiation doses and subject effective dose will be listed.

Safety, Tolerability & Immunogenicity
Safety, tolerability and immunogenicity data will be presented in tabular and/or graphical 
format and summarized descriptively according to GSK’s Integrated Data Standards 
Library (IDSL) standards.

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2.
INTRODUCT
2.1.
Brief backgro
Albumin is the most prevalen
humans of approximately 19 
albumin is about twice that o
pools at a rate of 4-5% total a
simplification of a complex p
exchange with intravascular a
large amount of extravascular
[Peters, 1996(b)].
GSK3128349 is a human dom
albumin with high affinity (a
residue engineered at the C te
attachment of a pharmacolog
scaffold that has of itself no p
conjugated with a pharmacol
terminal cysteine of GSK312
maleimide in order to avoid u
covalent dimerization.]
Figure 1
Schematic of
(HSA) and wi
Typically, dAbs are small (~1
hours. Due to the combinatio
high concentrations of album
albumin the majority of the ti
complex too big to be subject
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13
TION
ound
nt protein in human plasma (35-54 g/L) and has 
days [Peters, 1985] [Peters, 1996(a)]. Total extr
f the intravascular pool, and exchange occurs be
albumin/hour [Peters, 1996(b)]. However, this is
process. Certain organs (e.g. lungs, liver, kidney)
albumin, and others (e.g. skin, muscle), that acco
ar albumin due to their size, show a much slower
main antibody (dAb) that binds non-covalently t
lso referred to as an ‘AlbudAb’). It contains a cy
erminus of the molecule that can be used for the
gically active entity (Figure 1). As such, GSK312
pharmacological action, but has the potential to
ogically active entity [O’Connor-Semmes, 2014
28349 used in the current study is blocked with N
undesirable chemical reactivity towards serum pr
f GSK3128349 AlbudAb, depicted binding to 
ith a conjugated therapeutic drug.
15 kDa) and therefore are excreted renally in a m
on of the high affinity of GSK3128349 for album
min, it is expected that GSK3128349 will be boun
ime. Therefore, AlbudAbs, like GSK3128349, f
t to renal clearance. Furthermore, the binding of
RES117169
a half-life in 
ravascular 
etween these 
s a 
) show rapid 
ount for a 
r exchange
to serum 
ysteine 
 covalent 
28349 is a 
be 
4]. [The C-
N-ethyl-
roteins or 
albumin 
matter of 
min and the 
nd to 
form a 
f 

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GSK3128349 to albumin confers some of the pharmacokinetic and biodistribution 
properties of albumin to GSK3128349; and hence any pharmacologically active entity 
conjugated to it. This includes AlbudAbs bound to albumin being subject to Neonatal Fc 
Receptor (FcRn) dependent albumin recycling enhancing the exposure half-life. As a 
result of these effects AlbudAbs can persist in the body for several days or even weeks.
We expect the half life of GSK3128349 in humans to approach that of albumin (~19 days 
[Peters, 1985] [Peters, 1996(a)]). The medicinal value of therapeutics conjugated to 
GSK3128349 has the potential to be significantly enhanced by increasing their half-life 
and/or modulating their biodistribution [Kratz, 2008].
2.2.
Study rationale
The study will determine the biodistribution and pharmacokinetics of the AlbudAb 
scaffold (GSK3128349). The data will inform and validate a Physiologically Based 
Pharmacokinetics (PBPK) model, which will predict the distribution of future 
therapeutics conjugated to GSK3128349, as well as other AlbudAbs.
The validated PBPK modeling will improve our future clinical study designs by 
providing more accurate estimates of tissue exposures, which will lead to better: dose 
selection, timing of biomarker measurements, target engagement, and ultimately efficacy. 
This could potentially lead to a reduced number of assessments and/or subjects enrolled 
in future clinical trials. Furthermore, the PBPK modeling will be applied pre-clinically 
yielding better selection of targets for discovery programs, and informing affinity 
requirements for discovery lead optimization efforts. 
The data generated through this study will benefit all ongoing and future AlbudAb 
programs, and will provide generally applicable information to support understanding of 
biodistribution processes for all protein-based therapies.
3.
OBJECTIVE(S) AND ENDPOINT(S)
PRIMARY OBJECTIVE
END POINTS
1.1
Evaluate biodistribution of 
89Zr-GSK3128349 in
regions of interest following 
IV administration to support 
future AlbudAb products 
and the development of a 
PBPK model.
Quantitative parameters (including but not limited 
to 89Zr-GSK3128349 concentration) derived from 
Positron Emission Tomography – Computer 
Tomography (PET-CT) data (e.g. Standardised 
Uptake Values (SUVs)a, volume of Regions Of 
Interest (ROI) to assess average and total uptake 
into regions of interest (e.g. liver, kidney, muscle,
spleen, heart, lung, bladder, thymus – if feasible -, 
blood and bone).

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SECONDARY 
OBJECTIVES
END POINTS
2.1
Measure PK of 89Zr-
GSK3128349 by whole 
blood, plasma and urine 
radiolabel detection to 
support future AlbudAb 
products and the 
development of a PBPK 
model.
Whole blood, plasma and urine radioactivity 
concentrations and derived pharmacokinetic 
parameters, as data allows, based on blood, 
plasma and urine scintillation counting.
2.2
Measure PK of 
GSK8128349 by mass 
spectroscopy (MS) to 
support the development of 
a PBPK model.
Plasma concentrations and derived 
pharmacokinetic parameters.
Compare plasma exposure assessments via 
different GSK3128349 mass spectroscopy 
methods.
2.3
Measure dosimetry of 89Zr-
GSK3128349 from PET
scans and blood 
radioactivity.
Organ doses (mSv)
Effective dose (mSv)
2.4
Assess the safety and 
tolerability of 89Zr-
GSK3128349.
Adverse events (AEs), serious adverse events 
(SAEs).
Safety laboratory values, proteinuria, 
electrocardiograms (ECGs) and vital signs.
2.5
Investigate the presence and 
levels of anti-GSK3128349 
antibodies, including pre-
and post-dose.
Incidence of anti-GSK3128349 antibodies.
Serum titres of anti-GSK3128349 antibodies. 
a SUVmean for larger ROI (≥ 3 cm), SUVpeak for smaller ROI.
4.
STUDY DESIGN
4.1.
Overall Design
Using a single cohort of six to eight healthy male subjects, this open label single centre 
study will investigate the biodistribution and pharmacokinetics of the AlbudAb platform 
scaffold protein GSK3128349. Hence, GSK3128349 will be administered as a single 
drug product consisting of a mix of unlabeled GSK3128349 and 89Zr-GSK3128349 
(GSK3128349 radiolabelled with zirconium, see Section 6). 
PET scanning, using 89Zr labelling, is most optimal among available radioisotopes for 
monitoring longer half life therapies, such as antibodies, and is both quantitative and 
capable of assessing sites throughout the body, including within organs such as the 
kidneys and liver [Vugts, 2013]. This strategy has previously been used to monitor the 
distribution of the anti-HER2 antibody, Trastuzumab, among others [Dijkers, 2010].
Specifically, we have radiolabeled GSK3128349 with 89Zr and have demonstrated that 
the rat radio-PK of 89Zr-GSK3128349 is strikingly similar to the Pharmacokinetics (PK)
of unlabeled GSK3128349, providing supportive data that the 89Zr labelling of 

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16
GSK3128349 does not impact its functionality. Likewise, no difference in the albumin 
binding of 89Zr-GSK3128349 was detected using an in vitro assay. Since the half-life of 
the radionuclide zirconium (89Zr) is 3.3 days, labelling GSK3128349 with 89Zr allows
imaging to take place over a maximal time frame of up to about 10-12 days. This 10-12 
day time frame encompasses the expected biodistribution phase and will allow gathering 
of biodistribution information for GSK3128349 via PET scanning and radio PK. The 
biodistribution is key information required to enhance our PBPK modelling ability. As 
89Zr signal will be limited during the elimination phase (beyond 12 days) and the 
anticipated half-life will approach that of albumin (approximately 19 days), measurement 
of plasma PK will be utilized to help inform upon GSK3128349 elimination.
Figure 2
Study Schematic
NOTE: Please refer to time and events table for PET and PK blood sampling timings
Study Overview

On Day 1, enrolled subjects will receive one intravenous (IV) infusion of 89Zr-
GSK3128349 to deliver a dose of 1 mg (for further detail on dose see Section 4.3), 
and undergo PET/CT scans and blood sampling assessments prior to discharge at 24 
hrs post-dose, on day 2.

Subjects will be required to visit the clinic repeatedly over the subsequent 42 days
and undergo further blood sampling and PET/CT scans up to 10 days after dosing.
This will monitor 89Zr-GSK3128349 concentrations in various regions of interest 
(ROI) over time.

Blood samples will be taken for radioactivity, pharmacokinetic, immunogenicity, 
and safety assessments (see Time and Events table, Section 7.1.2).

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
After completion of the first 2 subjects, dosimetry assessments will be performed and 
used to refine the radiation dose administered to subsequent subjects. This will 
ensure the total radiation exposure in subsequent subjects is kept below
approximately 10 mSv. The data obtained with the first 2 subjects may also be used 
to adjust the time post dose for PET scans performed on subsequent subjects.

Urine will be collected during the first 24 hours and measured with respect to 
radioactivity and drug.

The expected total duration of a subject’s participation is approximately 10 weeks, 
including the screening period of up to 28 days. 

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AlbudAb (GSK3128349) radiolabeling and 
89Zr-GSK3128349 study treatment 
preparation, at VUMC Amsterdam
  
STEP 1: Radiolabelling & QC
GMP qualified & QA, Release by QP
Shipment to scanning site
Ready to inject
  
STEP 2: Subject preparation
Routine subject preparation
PET camera familiarisation
IV familiarisation
Site practicalities for IV administration
STEP 3: IV preparation & administration
Single 1 mg IV dose of 89Zr-GSK3128349 study treatment
  
STEP 4: Subject transported to imaging room
Subject lies in PET/CT camera
STEP 5a: Image acquisition 
  
STEP 6a: Blood sampling & processing 
PET/CT scans performed to include head to mid thigh 
to capture ROI.
Scan times bespoke and subject to change based on 
emergent data.
Samples for pharmacokinetic, radioactivity and 
safety endpoints collected at time points in T&E 
table (Section 7).
STEP 5b: Image analysis
Image captures (2D & 3D) via DICOM software.
Image analysis to define ROIs
Quantitative parameters derived from PET-CT 
images for each ROI.
STEP 7: Overall study analyses
STEP 6b: Pharmacokinetic analysis
Plasma concentrations of GSK3128349 analysed 
by non-compartmental methods.
PK parameters derived, as data permits.
4.1.1.
PET/CT Image Acquisition Workflow

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4.1.2.
PET scans

Details of the procedures for the acquisition of PET scans and co-localisation low 
dose CT scans will be included in the Image Acquisition Guidelines. Each PET scan 
will have a typical duration of up to 60 minutes.

PET scan data from the first two subjects will be analysed and used for a potential 
refinement of the radiation dose estimates and post dose scan time points for 
subsequent subjects.

Radioactivity measurements from blood will also be used for dosimetry calculations 
in first 2 subjects (see Section 7.1 Time & Events Table).
Table 1
PET scanning times
Subject
Scan Times
1st Subject
Following completion of the IV infusion the subject will be 
scanned at the following times:
1 hr ± 30 min
6 hrs ± 1 hr
24 hrs ± 1 hr (Day 2)
5 days (Day 6)
2nd Subject
Following completion of the IV infusion the subject will be 
scanned at the following times:
3 hrs ± 30 min
8 hrs ± 1 hr
3 days (Day 4)
5 days (Day 6)
Remaining 
Subjects
Four to six additional subjects will undergo scanning, utilising 
modified scan timings such that the biodistribution is fully 
profiled over the time period of up to 10-12 days post dosing. A 
maximum of 4 PET/CT scans will be undergone by each 
subject.
4.2.
Type and Number of Subjects
A total of six to eight healthy male volunteers will be enrolled. If subjects prematurely 
discontinue the study, additional subjects may be enrolled as replacement subjects at the 
discretion of the sponsor and in consultation with the investigator. Replacement subject 
numbers will be assigned to any additional subjects.
Volunteer ages will be limited from 50 to 65 years of age inclusive. The total radiation 
exposure in the current study is limited to below approximately 10 mSv, which is 
equivalent to about 3 years of average radiation exposure from normal living in Europe. 

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Even though the radiation exposure from this study is quite low, the purpose of the 
selected age range is to further limit the lifetime cancer risk resultant from radiation 
exposure (see GlaxoSmithKline Document Number POL-WWD-0019).
4.3.
Dose Justification
The single dose of GSK3128349 administered in this study is a single drug product 
consisting of a mix of labelled and unlabeled GSK3128349 and is utilized in this study in 
order to facilitate the delivery of requisite data to support PBPK model development. The 
radiolabelled component is critical, as it will allow assessment of the biodistribution time 
course for GSK3128349 into various tissues. However, due to the relatively short half-
life of the 89Zr label the elimination phase for GSK3128349 will not be measurable via 
PET, and therefore the unlabeled GSK3128349 component is essential to assess 
elimination via plasma PK analysis. This measurement of unlabelled GSK3128349 
plasma PK is complementary to the principal PET measurements performed in this study,
and thereby delivers the greatest value from this study in informing and validating the 
PBPK model under development.
4.3.1.
GSK3128349 dose selection and safety experience
Dose selection based on MS detection of GSK3128349 plasma exposures
The total dose of 1 mg has been determined as the minimum dose required in order to 
appropriately measure GSK3128349 PK concentrations by mass spectrometry (MS) 
assays. This was selected based on the lower limit of quantification of the MS assays and 
a need to measure exposure over a minimum of two half-lives. Anticipated plasma levels 
of the 1 mg dose were predicted by both albumin PBPK modelling and scaling of the 
available GSK3128349 rat PK data. The level of radiolabelled GSK3128349 included in 
this 1 mg of product is outlined in Section 4.3.2.
Preclinical safety
The safety profile of GSK3128349 has been evaluated in rodents, a relevant species
based on albumin binding. GSK3128349 was well tolerated in a single IV (bolus) dose 
study in rats (males only) at a dose of 0.36 mg/kg (only dose tested) with no 
GSK3128349- related toxicological findings noted. This provides a 25 fold safety margin
(based on dose) over the 1 mg clinical dose utilized in the current study. Predicted safety 
margins based on exposures are indicated in Table 2.
Table 2
Predicted safety margins based on modelling for proposed 1 mg 
dose in humans
Dose & frequency
Route
Cmax
AUC0-inf.
Pre-clinical 
Safety Margina
g/mL (at t=0)
g.h/mL
For Cmax
For AUC
1 mg single dose
Intravenous
0.322 (plasma)
83 (plasma)
26X
3.7X
a.
Safety margin based on GSK3128349 rodent intravenous single dose (0.36 mg/kg) GLP toxicology study 
exposures at the No Observed Adverse Effect Level (NOAEL). (Cmax and AUC of 8.37 µg/mL and 310
µg.h/mL).

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Further preclinical and clinical safety data generated with other AlbudAb variants 
provides additional support for the safety of the 1 mg single IV dose regime proposed in 
this study.
Other AlbudAbs have been generally well tolerated in preclinical toxicology. The only 
finding of note observed following repeat administration for greater that 4 weeks in 
duration was degeneration of the renal proximal tubule in mice, consistent with the 
exacerbation of a rodent specific chronic progressive nephropathy (CPN). This was 
observed following administration of various AlbudAb molecules (both conjugated and 
non-conjugated) when administered for 13 weeks, but NOT at 3 or 4 weeks in mice. 
There is not a strict counterpart for this lesion in nonhuman primates or human, and this 
is supported by the monkey toxicology studies in which there were no treatment-related 
findings in the kidneys of monkeys. Monkeys were administered conjugated or non-
conjugated AlbudAbs, yielding plasma Area Under the Curve (AUC) values of up to 
500–fold the projected AUC for the 1 mg GSK3128349 IV dose utilised in this clinical 
study. 
Clinical safety
In healthy obese volunteers, single and repeat dose administration of exendin-4 AlbudAb
GSK2374697 were generally well-tolerated [O’Connor-Semmes, 2014]. With the 
exception of the 4 mg single IV dose that resulted in exendin-4 related AEs including 
nausea, loss of appetite and constipation. Single and repeat doses of exendin-4 AlbudAb
over the range of 0.1 mg to 6 mg (2+2+2) total dose administered by subcutaneous 
injection demonstrated sufficient safety and tolerability to be administered in future 
clinical trials. No impact on renal function was apparent based on an assessment of renal 
biomarkers (e.g. creatinine, KIM1).
Therefore, given the overall experience dosing AlbudAbs in preclinical safety studies and 
the exendin-4 AlbudAb First Time In Human (FTIH) clinical experience, the risk for the 
current clinical PET study with a 1 mg single administered dose of GSK3128349 is 
considered quite low.
4.3.2.
Radioactivity dose
The study will be performed with strict consideration of the radiation limits as expressed 
by the Dutch authorities and Groningen local guidelines, as well as GSK guidance on 
exposure by radiation to healthy volunteers, which indicates that the effective radiation 
dose should be limited to approximately 10 mSv (average exposure for daily living in 
Europe is 3 mSv/year, and exposure for a diagnostic PET/CT performed with contrast 
agent is 10-30 mSv), and that subjects should be limited to those 50 years of age and 
above (see GlaxoSmithKline Document Number POL-WWD-0019).
The ionising radiation from a PET/CT study comes from two sources: the radionuclide 
injected for PET detection and the exposure to x-rays resultant from the CT scan. The 4 
CT scans included in the protocol will contribute 2 mSv of exposure (0.5 mSv/scan x 4) 
to each subject, therefore providing a maximum exposure limit of approximately 8 mSv 
due to administration of 89Zr-GSK3128349. The use of 4 PET scans was considered 
optimal, balancing the need to assess the time course of biodistribution in individual 
subjects and subject burden, while not significantly limiting the 89Zr-GSK3128349 dose 

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that can be administered and hence the intensity of the PET signal detected. PBPK 
modelling and allometric scaling of available rat PK data for GSK3128349 supports that 
a reasonable PET signal will be measurable in the organs of interest and will inform and 
validate the PBPK model.  
We have estimated that administering 15 MBq of 89Zr-GSK3128349 as part of the 1 mg 
product should provide approximately 7.9 mSv of exposure and limit the total exposure
when combined with the 4 CT scans in each subject to about 10 mSv. Although, we do 
not specifically have 89Zr-GSK3128349 PET data from preclinical species to use for 
clinical dosimetry estimation, the radiation exposure attributed to the anticipated 
distribution and low clearance (based on other preclinical AlbudAb PET studies, historic 
AlbudAb PK (see GlaxoSmithKline Document Number 2014N199359_00. Investigator 
Brochure), and current albumin based PBPK modelling predictions) is expected to mimic 
that previously reported for a 89Zr-radiolabelled monoclonal antibody (mAb) [Börjesson, 
2009]. In the previous 89Zr-mAb PET study the mean effective dose was reported to be 
0.53 mSv/MBq. Hence 15 MBq of 89Zr-GSK3128349 in this study would provide 
approximately 7.9 mSv (15 MBq X 0.53 mSv/MBq) of exposure.
After completion of the first 2 subjects in this study, dosimetry estimates will be 
performed. This data will be used to refine, if needed, the 89Zr-GSK3128349 radiation 
dose included in the administered 1 mg of GSK3128349 product for subsequent subjects.
Overall, the estimates of radioactivity to be administered in the first 2 subjects (described 
above) and the refined dosimetry analyses based on data from these first 2 subjects, aim 
to ensure that the total radiation exposure (that from the radioactivity administration plus 
the associated low dose CT scans) is limited to approximately 10 mSv.
4.4.
Risk Assessment and Management
Summaries of findings from non-clinical studies conducted with GSK3128349 can be 
found in the GlaxoSmithKline Document Number 2014N199359_00 Investigator 
Brochure. Although GSK3128349 was well tolerated in a rat toxicology study, it has not 
been tested in humans before therefore potential adverse affects may be encountered. The 
table below summarises the potential key risks and mitigation strategy for this protocol.

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Table 3
Summary of protocol-specific risks and mitigation strategies
Potential risk
Summary of data
Impact- eligibility criteria
Strategy-monitoring/stopping 
criteria
Renal injury
The AlbudAb platform has been 
associated with degenerative 
changes in the proximal renal 
tubule in the mouse with repeat and 
long duration (greater than 4 weeks) 
dose regimen only. These 
observations appear reversible on 
washout and have not been 
observed in monkey safety studies
(see summary Section 4.3 and IB
for detailed information).
Subjects with history of renal 
disease and/or abnormalities 
are excluded, including 
proteinuria and reduced 
estimated Glomerular 
Filtration Rate (eGFR) (see 
exclusion criteria Section 5.2
points 3, 11 and 12 for more 
information).
Renal function and proteinuria 
will be closely monitored using 
standard serum and urine 
chemistry biomarkers.
Acute infusion reaction
Infusion / acute allergic reactions
upon administration are a potential 
risk with all protein therapeutics.
Subjects are excluded with a 
history of sensitivity to any of 
the study treatment, or 
components thereof or a 
history of drug or other 
allergies.
Subjects will be monitored for 
symptoms of hypersensitivity or 
other potentially immune-
mediated reactions post-infusion, 
and will be treated promptly as 
appropriate.
Immunogenicity
As is the case for all protein 
therapeutics, antibodies may 
develop against the agent
administered.
None
Immunogenicity samples will be 
drawn at baseline and following 
dosing of GSK3128349 to 
monitor the immunogenicity 
potential of this molecule.
Radioactivity exposure
The total radioactivity exposure due 
to combined PET ligand 
Subjects with previous 
involvement in a research 
After completion of the first 2 
subjects, dosimetry analysis will 

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Potential risk
Summary of data
Impact- eligibility criteria
Strategy-monitoring/stopping 
criteria
administration and CT scanning 
will be limited to approximately 10 
mSv.
and/or medical protocol 
involving nuclear medicine, 
PET or radiological 
investigations in which the
total radiation burden in the 
last 3 years, including that 
which will be provided by the 
current study, is 10 mSv or 
greater will be excluded.
Clinical exposure from which 
the subject receives a direct 
benefit (ex. diagnostic test) is 
not included in these 
calculations.
Only male subjects between 
50 and 65 year old will be 
included to limit the lifetime 
cancer risk resultant from 
radiation exposure.
be performed, and the 
radioactive dose may be adjusted 
for subsequent subjects (if 
required) in order to limit total 
exposure to approximately 10 
mSv.
Overall the risk to the healthy volunteers following administration of GSK3128349 is considered low. This is based on the low dose of 
GSK3128349, preclinical safety assessment of GSK3128349 and other AlbudAb platform based molecules in pre-clinical and clinical 
studies. The benefit provided through the data generated in this small exploratory FTIH study of 6-8 healthy volunteers will be in the 
validation of our PBPK based modelling capabilities. Solidifying the PBPK model will enhance future clinical study designs for our 
AlbudAb based medicines: leading to more efficient dose selection and biomarker assessment.  The risk benefit balance is considered 
positive and therefore supportive of progression of this proposed study to the clinic

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5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK product or other study treatment that may 
impact subject eligibility is provided in the GlaxoSmithKline Document Number 
2014N199359_00 Investigator 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. Between 50 and 65 years of age inclusive at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS 
2. Healthy as determined by a responsible and experienced physician, based on a 
medical evaluation including medical history, physical examination, laboratory tests 
and cardiac monitoring.  A subject with a clinical abnormality or laboratory 
parameters outside the reference range for the population being studied may be 
included only if the Investigator and the GSK Medical Monitor agree that the finding 
is unlikely to introduce additional risk factors and will not interfere with the study 
procedures.
3. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase and bilirubin ≤1.5x Upper Limit Normal (ULN) (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
WEIGHT
4. Body Mass Index (BMI) within the range 19.0 – 31.0 kg/m2 (inclusive).
SEX
5. Male.
CONTRACEPTION
6. Subjects must agree to use one of the contraception methods listed in Section 6.8.1.
This criterion must be followed from the time of the first dose of study treatment until 
100 days post dose.

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INFORMED CONSENT
7. Capable of giving written informed consent as described in Section 10.2, which 
includes compliance with the requirements and restrictions listed in the consent form.
CARDIOVASCULAR
8. Average Corrected QT interval (QTc) ≤450 msec
NOTES:

The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or 
manually over-read.

The specific formula that will be used to determine eligibility and discontinuation 
for an individual subject should be determined prior to initiation of the study. In 
other words, several different formulae cannot be used to calculate the QTc for an 
individual subject and then the lowest QTc value used to include or discontinue 
the subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).
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 
1. Current evidence or history of an influenza-like illness as defined by fever (>38C) 
and two or more of the following symptoms within 7 days before dosing: cough, sore 
throat, rhinorrhea, sneezing, limb/joint pain, headache, vomiting/diarrhea.
2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
3. History of, or current, acute renal failure, known renal disease, or a renal disorder or 
abnormality that may compromise renal function. This includes having one kidney.
4. Previous inclusion in a research and/or medical protocol involving nuclear medicine, 
PET or radiological investigations or occupational exposure that, together with the 
proposed study, will result in a total radiation exposure greater than 10 mSv over a 3 
year period. Clinical exposure from which the subject receives a direct benefit (eg
diagnostic test) is not included in these calculations.

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RELEVANT HABITS
5. History of regular alcohol consumption within 6 months of the study defined as: 
a.
An average weekly intake of >21 units.  One unit is equivalent to 8 g of 
alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) 
measure of spirits.
6. Unable to refrain from the use of prescription drugs within 7 days or 5 half-lives 
(whichever is longer) prior to the first dose of study treatment, unless in the opinion 
of the Investigator and GSK Medical Monitor the medication will not interfere with 
the study procedures or compromise subject safety.
7. Subject is a smoker ≥5 cigarettes/day or with a smoking history of >5 pack yearsa.
a.
(Pack years = [cigarettes per day smoked/20] x [number of years smoked]).
CONTRAINDICATIONS 
8. History of sensitivity to any of the study treatment or components thereof or a history 
of drug or other allergy that, in the opinion of the investigator or GSK Medical 
Monitor, contraindicates their participation.
9.
Subject suffers from claustrophobia that limits the ability to remain still in the 
PET/CT scanner for the required amount of time to complete the scanning protocol. 
10. Subject has metal present in their body that will interfere with the PET/CT scanning.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
11. eGFR <60 mL/min/1.73 m2 (utilising the Chronic Kidney Disease Epidemiology 
Collaboration (CKI-EPI) equation).
12. Urine mg protein/mg creatinine Urine Protein Creatinine Ratio (UPCR) >0.3.
13. Evidence of haematuria by urinalysis (1+ or greater dipstick test).
14. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C (Hep C)
antibody result within 3 months of screening.
15. A positive test for Human Immunodeficiency Virus (HIV) antibody.
16. A positive pre-study drug/alcohol screen.
17. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
18. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
19. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within a 56 day period.
5.3.
Screening Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 

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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 any Serious Adverse Events.
5.4.
Study Withdrawal Criteria
A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. The reason(s) for subjects not completing the study will be 
recorded in the Case Report Form (CRF).The investigator must document, if applicable, 
the reason (if specified by the subject) for withdrawal of consent. 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 any trends or unexpected increases in safety signals are observed, which in the 
Investigator’s opinion, are of greater intensity, frequency, or duration than expected for 
the subject group under investigation, the GSK Medical Monitor should be notified as 
soon as possible. If the Investigator and GSK Medical Monitor consider that there is a 
reasonable possibility that the event was related to treatment with the product, the study 
may be put on-hold until all available safety data from the study has been reviewed.
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 and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

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. 

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 this study is a single dose study, 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 Food and Drug 
Administration (FDA) premarketing clinical liver safety guidance). 

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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 
either of the bulleted criteria below:

QTc >500 msec OR Uncorrected QT >600 msec

Change from baseline of QTc >60 msec
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
<450 msec
>500 msec
450 to 480 msec
≥530 msec

The enhanced monitoring criteria are based on an average QTc value of triplicate 
ECGs. If an ECG demonstrates a prolonged QT interval, two additional ECGs must 
be obtained over a brief period, and then the averaged QTc values of the 3 ECGs will 
be used to determine whether the subject meets these criteria.

The same QT correction formula must be used for each individual subject to 
determine eligibility for the study, and whether further evaluation and/or monitoring 
is/are necessary. This formula may not be changed or substituted once the subject 
has been enrolled.
-
For example, if a subject is eligible for the protocol based on QT interval 
corrected for heart rate according to Fridericia’s formula (QTcF) then QTcF
must be used for discontinuation of this individual subject as well.
-
Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis. Safety electrocardiograms (ECGs) and other 
non-protocol-specified ECGs are an exception.  

Considerations for further monitoring and evaluation should include the following, 
as appropriate:
-
Assessment of any relevant symptoms (e.g., presyncope);
-
Follow-up ECGs to assess for resolution of QTc prolongation;
-
Review of concomitant or recently taken medications, including over the counter 
preparations and herbal supplements
-
Evaluation of electrolytes to include magnesium and potassium

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-
Referral to urgent care or to an emergency facility for further evaluation and 
monitoring
-
Any other evaluation that may be necessary as determined by the investigator.
5.4.3.
Renal Monitoring
If a subject develops any of the following signs: 
i)
haematuria (in the absence of urinary tract infection)
ii)
demonstrates a UPCR>0.5
iii)
demonstrates a >15% decline in eGFR
and findings are confirmed on a second assessment within 48 hours, then the subject 
should be referred for a nephrology consult. 
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
The term ‘study treatment’ or ‘89Zr-GSK3128349’ is used throughout the protocol to 
describe the drug product, which is a mix of 89Zr labeled and unlabelled GSK3128349
received by the subjects as per the protocol design. Details of 89Zr labelled GSK3128349
can be found in the relevant non Investigational Medicinal Product (IMP) document.
Product name:
89Zr-GSK3128349
Formulation 
Description:
50 mM sodium acetate buffer and 200 mM sucrose at pH 
5.20-5.80, associated with about 15 MBq of radioactivity.
Dosage Form:
Solution for IV administration
Unit Dose 
Strength 
Approximately 10 mL of 0.1mg/mL  89Zr-GSK312834
Dose level
1 mg
Route/
Administration/ 
Duration:
IV as a continuous infusion over 20 mins
Dosing 
Instructions:
Single dose
Physical 
Description:
Liquid in 50mL vial
Manufacturer/
Source of 
procurement:
VUMC, Amsterdam

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6.1.
Treatment Assignment
Subjects will be identified by a unique subject number at screening that will remain 
consistent for the duration of the study. Upon completion of screening subjects will be 
enrolled and will receive 1 mg of 89Zr-GSK3128349. There will be no placebo in this 
study. 
There are no randomisation requirements for the study. However, for internal study 
reporting, subjects will be assigned to randomisation numbers in accordance with the 
randomisation schedule generated by Clinical Statistics, prior to the start of the study, 
using validated internal software.
6.2.
Blinding
This will be an open-label study.
6.3.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.4.
Preparation/Handling/Storage/Accountability
A full description of the method and materials required for administration of 89Zr-
GSK3128349 will be provided in the Study Reference Manual (SRM).
Study treatment must be dispensed or administered according to procedures described 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. 
Storage instructions for all study treatments supplied by GSK (including study product as 
well as prepared solutions) are provided in the SRM. Maintenance of a temperature log 
(manual or automated) is required.
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye 
or skin contact and the generation of aerosols or mists. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study contact.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK.
6.5.
Treatment of Study Treatment Overdose
For this study, any dose of 89Zr-GSK3128349 over and above the dose specified in the 
protocol will be considered an overdose.

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GSK does not recommend specific treatment for an overdose. The investigator or 
physician in charge of the subject at the time will use clinical judgment to treat any 
overdose.
6.6.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation.
6.7.
Lifestyle and/or Dietary Restrictions
6.7.1.
Contraception Requirements
Male subjects with female partners of child-bearing potential must use one of the 
following contraceptive methods for 100 days post dose of study treatment. Investigators 
are responsible for consulting with subjects on selection of contraceptive methods.

Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception

Condom plus partner use of a highly effective contraceptive (see list below). 
Highly Effective Contraceptive Methods with a Failure Rate of < 1%

Oral contraceptive, either combined or progestogen alone

Injectable progestogen 

Implants of etonogestrel or levonorgestrel

Percutaneous contraceptive patches
6.7.2.
Caffeine, Alcohol, and Tobacco
Subjects will abstain from alcohol for 48hr before each visit to the clinic and during the 
in-house stay.
Subjects who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the Clinical 
Unit.
6.7.3.
Activity
Subjects must refrain from strenuous exercise for approximately 72 hours before all study 
visits.

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6.8.
Concomitant Medications and Non-Drug Therapies
6.8.1.
Permitted Medications and Non-Drug Therapies
Paracetamol or Acetaminophen, at doses of ≤ 2 grams/day is permitted for use.  Other 
concomitant medication may be considered on a case by case basis by the GSK Medical 
Monitor.
6.8.2.
Prohibited Medications and Non-Drug Therapies
Subjects must abstain from taking prescription or non-prescription drugs, within 7 days 
or 5 half-lives (whichever is longer) prior to the first dose of study treatment until 
completion of the follow-up visit, unless in the opinion of the Investigator and sponsor 
the medication will not interfere with the study.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1. 
Detailed procedures for obtaining each assessment may be provided in the Study 
Reference Manual (SRM), where necessary. Whenever vital signs, 12-lead ECGs and 
blood draws are scheduled for the same nominal time, the assessments should occur in 
the following order: 12-lead ECG, vital signs, blood draws.  The timing of the 
assessments should allow the blood draw to occur at the exact nominal time.
The timing and number of planned study assessments, including: safety, pharmacokinetic 
or pharmacodynamic/biomarker assessments may be altered during the course of the 
study based on newly available data (e.g. to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. The timing of PET-CT scans may be 
changed but not the maximum number of four PET-CT sessions. The change in timing or 
addition of time points for any planned study assessments must be approved and 
documented by GSK, but this will not constitute a protocol amendment. The Institutional 
Review Board (IRB)/ Independent Ethics Committee (IEC) will be informed of any 
safety issues that require alteration of the safety monitoring scheme. No more than 500 
mL of blood will be collected within a 56 day period as per exclusion criteria 19 (Section 
5.2), including any extra assessments that may be required.

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7.1.
Time and Events Table
7.1.1.
Screening
Procedures
Screening 
up to 28 days prior 
to day 1
Informed Consent
X
Demographics
X
Eligibility
X
Full Physical Exam
X
Medical/Medication/Drug/Alcohol Hx
X
12-lead ECG (triplicate)
X
Vital Signs
X
Urine Drug/Alcohol
X
HIV, Hep B and Hep C Screen1
X
Haem/Chem/Urinalysis Tests/UPCR
X
Concomitant Medication Review
X
1 If test performed within 3 months prior to first dose of study 
treatment, testing at screening is not required

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7.1.2.
Scanning & Dosing
Day of study
Day -
1
Day 1
Day 2
Day 4
Day 6
Day 13 1 day
Day 
20 
2
days
Day 31
2
days
Time post dosing
Pre-dose
0
1 hour
3 hours
6 hours
8 hours
24 hours
Admission to Unit
X
Brief Physical Exam
X
Xg
Medical/Medication/Drug/Alcohol Hx
X
12-lead ECG
Xf
X
X
Vital Signs
X
X
X
Urine Drug/Alcohol
X
Urinalysis
X
Xi
X
X
X
Spot Urine Protein/Creatinine ratio
X
Xe
X
Haematology
X
X
Clinical chemistry
X
X
X
X
X
X
Randomisation
X
Immunogenicity Blood Sample
X
IV Infusion Dosing
X
PET imaging and co-localising CT
(first subject)a
X
X
X
X
PET imaging and co-localising CT
(second subject)a
X
X
X
X
PET imaging and co-localising CT 
(subsequent subjects)a, b
-------------------------------------------------------------------------------
PK Blood Sampling for MS
X
X
X
X
X
X
X
X
X
X
X
PK Blood Sampling for scintillation 
countingh
X
X
X
X
X
X
X
X
X
Bladder Voidc
X
Urine Collectiond
--------------------------------------------------------

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Day of study
Day -
1
Day 1
Day 2
Day 4
Day 6
Day 13 1 day
Day 
20 
2
days
Day 31
2
days
Time post dosing
Pre-dose
0
1 hour
3 hours
6 hours
8 hours
24 hours
Adverse Event Review
-------------------------------------------------------------------------------------------------------------------------------
Concomitant Medication Review
----------------------------------------------------------------------------------------------------------------------------------------------------------
Discharge
X
Outpatient Visit
X
X
X
X
X
a.
Each PET/CT scan must be preceded by heart rate and blood pressure assessments. 
b.
For subsequent subjects (3rd and beyond) timings of PET scans will be based on data analysis from subjects 1 and 2 and may be carried out anytime between 1 and 10-12 days 
post injection. A maximum of 4 PET scans will be conducted in each subject.
c.
Pre-dose urine will not be retained.
d.
24 hour urine collection. Total volume will be measured. Part of urine sample will be used for scintillation counting. An aliquot will be utilized for UPCR assessment and another 
stored for later MS PK analysis if required. Based on data from first 2 subjects, urine may be collected for longer than 24 hrs post dose for subsequent subjects.
e.
Aliquot from 24 hr collection sample, taken after 24 hr collection is complete.
f.
Triplicate measurement
g.
Prior to discharge
h.
Aliquot from MS PK blood sample
i.
Urine sample to be collected prior to discharge
Note: all time points are relative to start of infusion administration.

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7.1.3.
Follow-up
Procedure
Day 43
2 days
Brief Physical Exam
X
12-lead ECG
X
Vital Signs
X
Haem/Chem/Urinalysis Tests/UPCR
X
Immunogenicity Sample 
X
PK Sample for MS
X
Concomitant medication review
X
Adverse Event Review
X
Outpatient Visit
X

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7.2.
Screening and Critical Baseline Assessments
The following demographic parameters will be captured: year of birth, race and ethnicity.
Medical/medication/alcohol history will be assessed as related to the eligibility criteria 
listed in Section 5.1 and Section 5.2.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Tables. 
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.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up visit at the time points specified in the Time and Events Table (Section 7.1).

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. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in
Appendix 3.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the electronic Case Report Form (eCRF) page 
within 72 hours of submission of the SAE.

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.

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7.3.1.2.
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?” 
7.3.1.3.
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 will be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or until the subject is lost to 
follow-up (as defined in Section 5.4). Further information on follow-up procedures is 
given in Appendix 3.
7.3.1.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs 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.
7.3.2.
Pregnancy
Details of all pregnancies in female partners of male subjects will be collected after the 
start of dosing and until the follow-up visit.
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.

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7.3.3.
Physical Exams

A complete physical examination will include assessments of the head, eyes, ears, 
nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and 
spleen), lymph nodes and extremities. Height and weight will also be measured and 
recorded.

A brief physical examination will include assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).

A full physical examination will be conducted at screening and a brief physical exam 
will be conducted on Day -1, at 24 hr post dose prior to discharge and at Follow-up.
7.3.4.
Vital Signs

Vital sign measurements will include systolic and diastolic blood pressure, pulse 
rate, and temperature.

All vital sign measurements will be made with the subject in a supine position 
having rested in this position for at least 5 minutes before each reading.
7.3.5.
Electrocardiogram (ECG)

ECG measurements will be made with the subject in a supine position having rested 
in this position for at least 5 minutes before each reading.

Triplicate 12-lead ECGS will be obtained at screening and pre dose at Day 1 and 
single 12-lead ECGs will be obtained at other time points during the study.

12-lead ECGs will be obtained using an ECG machine that automatically calculates 
the heart rate and measures PR, RR, QRS, QT, and QTcF intervals (if the machine 
does not automatically calculate QTcF, manual calculation is acceptable).

Extreme changes in room temperature should be avoided as far as possible (the 
volunteers should be comfortable at all times in appropriate clothing). Hot and cold 
drinks and food should be avoided where possible 30 minutes before an ECG 
measurement. 

Care should be taken to ensure that the electrodes are placed in the positions dictated 
by standard ECG methodology. 
If a subject’s QTcF interval extends beyond 500msec on two or more ECG tracings 
separated by at least 5 minutes then the ECG tracing should be examined and manual 
measurement by a trained physician should be performed to confirm the accuracy of the 
equipment being used. If the reading is accurate the subject should be monitored closely 
and followed until the QT and QTcF interval returns to within 30msec of their baseline.
7.3.6.
Clinical Safety Laboratory Assessments
Values for the laboratory parameters should be within the normal range for the relevant 
subject population as specified by the clinical laboratory, which will be an accredited 
facility. Subjects with screening laboratory values outside of the normal range will be 
accepted into the study only after the Investigator, or a qualified designee, and the GSK 

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Medical Monitor have determined that the out of range value(s) are not clinically 
significant and would not pose an increased risk to the subject. 
At the Principal Investigator and GSK Medical Monitor’s discretion, additional 
laboratory tests other than those outlined below may be included to further assess safety 
and tolerability.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed below:
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes
Reticulocyte Count
MCHC
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
RBC- Red blood cell; WBC- White Blood Cell; MCV- Mean Corpuscular Volume; MCH- Mean 
Corpuscular Hemoglobin; MCHC- Mean Corpuscular Hemoglobin Concentration.
Clinical Chemistry
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
(eGFR)
Chloride
ALT (SGPT)
Uric Acid
Glucose
Calcium
GGT
Albumin
Sodium
Alkaline phosphatase
Total Protein
BUN- Blood Urea Nitrogen; AST (SGOT)- Aspartate Aminotransferase (Serum Glutamic Oxaloacetate 
Transaminase); eGFR-ALT- Alanine Aminotransferase (SGPT)- (Serum Glutamic Pyruvic Transaminase); 
GGT- Gamma Glutamyl Transpeptidase.
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal) includes RBC, WBC, casts 
and bacteria

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Other tests
HIV
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody -- if second generation Hepatitis C antibody positive, a 
hepatitis C antibody Chiron RIBA immunoblot assay (or other third generation 
immunoassay) should be reflexively performed on the same sample to confirm the 
result) 
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids and benzodiazepines).
Proteinuria (UPCR)
NOTE :
Details of Liver Safety Required Actions and Follow-Up Assessments after a
liver event are given in Appendix 2.
Additional drug screens may be performed at the discretion of site staff, if 
needed/required by local standard operating procedures.
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.
7.3.7.
Urine protein/creatinine ratio
Urine samples will be collected as outlined in the Time and Events Table (Section 7.1) to 
assess the urine protein/creatinine ratio (mg/mg). 
7.4.
Pharmacokinetics
Samples for pharmacokinetic analysis of GSK3128349 will be collected at the time 
points indicated in the Time and Events Tables (Section 7.1).
7.4.1.
Pharmacokinetic Blood Sample Collection
Sampling time points are defined in the Time and Events tables (Section 7.1).
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.
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the Study Reference Manual (SRM).
7.4.2.
Pharmacokinetic Urine Sample Collection for Scintillation 
Counting
Sampling time points are defined in the Time and Events tables (Section 7.1).

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The actual start and end date and time of each urine sample collection will be recorded. 
The total volume collected will be recorded and an aliquot will be scintillation counted. 
If the 24 hr urine sample contains > 3% of the administered radioactive dose, then a spot 
urine collection will be performed on Day 4 and Day 6 for scintillation counting and PK 
analysis by mass spectroscopy. Based on scintillation count data from Day 4 and Day 6, 
urine may be collected at subsequent visits for MS PK only.
Details of PK urine sample collection, processing and storage procedures are provided in 
the SRM.
7.4.3.
Pharmacokinetic Sample Analysis
Plasma analysis will be performed under the management of Drug Metabolism and 
Pharmacokinetics (DMPK), GSK. Radioactivity counts of blood and plasma plus urine 
PK sample aliquots will be performed at the clinical site. Remaining samples will be 
retained for at least 10.5 half lives (test for radioactivity > 35 days) before shipping to 
GlaxoSmithKline for analysis. Concentrations of GSK3128349 will be determined in 
plasma samples using the currently approved analytical methodologies. Raw data will be 
stored in the Good Clinical Practice (GLP) Archives, GlaxoSmithKline. 
Once the plasma has been analyzed for GSK3128349 any remaining plasma may be 
analyzed qualitatively for other circulating catabolites and the results reported under a 
separate DMPK protocol.
The urine samples may be analyzed for GSK3128349 (pending results of other endpoints) 
and the results will be reported under a separate DMPK protocol.
Details of the analysis procedures are provided in the SRM.
7.5.
Immunogenicity
Blood samples for testing antibodies against GSK3128349 will be collected at the time 
points indicated in the Time and Events Tables (Section 7.1). The actual date and time of 
each blood sample collection will be recorded. The first blood sample will be taken pre-
dose at baseline to determine the presence, if any, of pre-existing Anti Drug Antibodies 
(ADAs).
The presence of such antibodies will be assessed using an electrochemiluminescent 
(ECL) immuno assay. If sera contain anti-GSK3128349 antibodies, they will be further 
analyzed for the antibody specificity and titres. The results of anti-GSK3128349 antibody 
tests will be reported at the end of the study. The report will include the incidence of 
immunogenicity and titres.
Details on sample preparation, storage and analysis will be given in the SRM. 

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8.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system. 
Management of clinical data will be performed in accordance with applicable GSK
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing
errors and inconsistencies in the data. Adverse events and concomitant medications terms 
will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and an 
internal validated medication dictionary, GSKDrug. Subject initials will not be collected 
or transmitted to GSK according to GSK policy.
PET and CT images will be anonymized and transmitted to GSK in Digital Imaging and 
Communications in Medicine (DICOM) format to be stored in a GSK repository.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
There are no formal statistical hypotheses being tested, due to the exploratory nature of 
the study. 
Where applicable, an estimation approach will be adopted to evaluate the primary 
objectives.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
There are no formal calculations of power or sample size for this exploratory study. A 
review of the literature was conducted and identified a number of PET studies using 89Zr 
labelled mAbs [Dijkers, 2010] [Börjesson, 2009]. The majority of these were in oncology 
where the objective was to assess tumour uptake of mAbs. One study was identified 
[Börjesson, 2009] which examined biodistribution of 89Zr labelled mAbs to organs over 
time. This paper provides some guidance in our study design with respect to dosimetry 
but provides very limited insight into variability and sample size requirements.
Sepp et al describes the PBPK model to be used for exploratory modelling in this study 
[Sepp, 2015]. This was developed in 18 animals using n=3 mice sacrificed at each of 6 
time points. Sepp et al were able to demonstrate CV of approx ≤30% on estimated flow 
rate parameters for the majority of organs using n=3 for each post dose time point.
Therefore, based on the limited literature and novelty of this study, sample size has been 
primarily based on feasibility, but is also in the range of prior clinical immunoPET 
studies [Dijkers, 2010] [Börjesson, 2009]. Six to eight healthy male subjects will be 
recruited to complete this single dose level study protocol, and with conducting 4 

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PET/CT scans post dose per subject should provide the ability to assess the PET signal 
across a suitable range of post dose time points.
9.2.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Population
Definition / Criteria
Screen 
Failures

Comprised of all potentially eligible subjects who have signed the ICF 
and subsequently fail screening.
Safety

Comprised of all subjects who receive a dose of 89Zr-GSK3128349.
PK

Subjects in the ‘Safety’ population for whom a PK sample was 
obtained and analysed, and/or for which a PET scan was completed.
Additional analysis populations maybe defined in the Reporting and Analysis Plan 
(RAP).
9.3.2.
Interim Analysis
There are no formal interim analyses planned. However, the following in-stream data 
review is planned:
Following completion of the first two subjects’ PET scans, the study team will evaluate 
the emerging PET-CT scan data for:
Dosimetry to potentially refine the radiation dose estimates, and to identify other ROI 
for further investigation, if required. 
Determine scan time points post dose of subsequent subjects.
9.4.
Key Elements of Analysis Plan
Full details of the planned analyses will be specified in the Reporting and Analysis Plan 
(RAP).
9.4.1.
Primary Analyses
The following analysis is planned for primary endpoints:

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Analysis
Details (Study Objective Section 3 (1.1))
Endpoints

Quantitative parameters (including but not limited to 89Zr-
GSK3128349 concentration) derived from PET-CT data (e.g. 
Standardised Uptake Values (SUVs)a, volume of ROI) to assess 
average and total uptake into regions of interest (e.g. liver, kidney, 
muscle, spleen, heart, lung, bladder, thymus – if feasible -, blood and 
bone
Endpoint 
Definitions

SUV: A simple way of determining activity in PET imaging for each 
region of interest, which is mathematically derived ratio of tissue 
radioactivity concentration at a point in time C(T) and the injected dose 
of radioactivity per kilogram of the patient's body weight:
SUV = C(T)/[injection dose (MBq)/patient's weight (kg)]

Volume of ROI: The volume of specified organ as measured in PET or 
CT images.
Analysis
(Raw Data)

Descriptive statistics where appropriate, (i.e. n, arithmetic mean, 
geometric mean, standard deviation, minimum, median and maximum) 
will be calculated for all generated PET-CT imaging endpoints over 
time.

Graphical displays will be produced over time for applicable PET-CT 
imaging endpoints. 

If analysed, all data will be listed, including unscheduled and/or repeat 
assessments.
Statistical 
Analysis 
(Modelled)

If data permits, further statistical analyses (i.e. mixed effects models) 
will be performed to estimate quantitative parameters in ROI over time 
from PET-CT following IV administration.

Full details will be specified in the RAP.
a SUVmean for larger ROI (≥3 cm), SUVpeak for smaller ROI

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9.4.2.
Secondary Analyses
Pharmacokinetics (Concentration Data & Derived Parameters)
PK
Details (Study Objective Section 3 (2.1 & 2.2))
Concentration

Whole blood, plasma and urine concentrations of 89Zr-GSK3128349
and plasma concentrations of GSK2138349 data will be graphically 
represented, descriptively summarised and listed appropriately.
Parameters

Whole blood and plasma concentrations time data of 89Zr-
GSK3128349 and plasma concentrations time data of GSK3128349 
will be analyzed by non-compartmental methods.

Calculations will be based on the nominal sampling times recorded 
during the study. 

As data permits, from the plasma concentration-time data, the 
following PK parameters may be determined as data permits: 
o
Maximum observed plasma concentration (Cmax)
o
Time to achieve Cmax (Tmax) 
o
Apparent terminal phase half-life (t1/2). 
o
Area under the curve:
Area under the concentration-time curve from time zero (pre-
dose) to last time of quantifiable concentration within a subject 
(AUC[0-t]) for 89Zr-GSK3128349 and GSK3128349, 
Area under the concentration-time curve from time zero (pre-
dose) extrapolated to infinite time (AUC[0-∞]) only for 
GSK3128349
o
Clearance
o
Volume of distribution

Additional PK parameters may be included as required.

Pharmacokinetic data will be presented in graphical and/or tabular 
form, summarized descriptively and listed. 
Dosimetry
Dosimetry (objective Section 3 (2.3)) results as organ radiation doses and subject 
effective dose will be listed.
Safety, Tolerability & Immunogenicity
Safety, tolerability and immunogenicity data (study objectives Section 3 (2.4 and 2.5)
respectively) will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.

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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
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 International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (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. 

Signed informed consent to be obtained for each subject before participation in the 
study (and for amendments as applicable).

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.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures,  
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

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
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 severe 
non-compliance. 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.

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 
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
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 
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.

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11.
REFERENCES
Börjesson P et al. Radiation Dosimetry of 89Zr-Labeled Chimeric Monoclonal Antibody 
U36 as Used for Immuno-PET in Head and Neck Cancer Patients. The Journal of nuclear 
medicine (2009) 50 (11)
Dijkers EC, et al. Biodistribution of 89Zr-trastuzumab and PET Imaging of HER2-
Positive Lesions in Patients With Metastatic Breast Cancer. Clin Pharmacol Ther. (2010) 
87(5), 586-92
GlaxoSmithKline Document Number 2014N199359_00. Investigator Brochure. Effective 
date 2016
GlaxoSmithKline Document Number POL-WWD-0019. Enrolment of Human Subjects 
in Studies Which Involve Their Exposure to Ionising Radiation. Effective date 26 Nov 
2014
Kratz F. Albumin as a drug carrier. J. Cont. Release (2008) 132 (3), 171-83
O’Connor-Semmes RL, et al. GSK2374697, a novel albumin-binding domain antibody 
(AlbudAb), extends systemic exposure of exendin-4: first study in humans--PK/PD and 
safety. Clin Pharmacol Ther. (2014) 96(6), 704-712
Peters T. All About Albumin: biochemistry, genetic and medical applications. San Diego, 
CA: Academic Press Limited (1996(a))
Peters T. Jr Adv. Protein Chem. (1985) 37, 161–245
Peters T. Serum Albumin: Structure, Functions and Health Impact. Nova Science 
Publishers (1996(b))
Sepp A, Berges A, Sanderson A, Meno-Tetang G. Development of a physiologically 
based pharmacokinetic model for a domain antibody in mice using the two-pore theory. 
Journal of Pharmacokinetics and Pharmacodynamics (2015) 42(2), 97-109 
Vugts DJ, Visser GW, van Dongen GA. 89Zr-PET radiochemistry in the development 
and application of therapeutic monoclonal antibodies and other biologicals. Curr Top 
Med Chem. (2013) 13(4), 446-57

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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
ADA
Anti Drug Antibody
AE
Adverse Event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area Under the Curve
AUC[0-t]
Area under the concentration-time curve from time zero 
(pre-dose) to last time of quantifiable concentration within 
a subject 
AUC[0-∞]
Area under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CKI-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum observed plasma concentration
CONSORT
Consolidated Standards of Reporting Trials
CPN
Chronic Progressive Nephropathy
CT
Computed Tomography
C(T)
Tissue radioactivity concentration at a point in time
CRF
Case Report Form
dAb
Domain antibody
DICOM
Digital Imaging and Communications in Medicine
DMPK
Drug Metabolism and Pharmacokinetics
ECG
Electrocardiogram
ECL
Electrocheluminescent
eCRF
Electronic Case Report Form
eGFR
estimated Glomerular Filtration rate
FcRn
Neonatal Fc Receptor
FDA
Food and Drug Administration
FTiH
First Time in Human
GCP
Good Clinical Practice
g/L
Gram/Litre
GMP
Good Manufacturing Practice
GGT
Gamma Glutamyl Transpeptidase
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
Hep
Hepatitis
HIV
Human Immunodeficiency Virus
hr
Hour
HSA
Human Serum Albumin
IB
Investigator Brochure

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ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IV
Intra Venous
kDa
kiloDalton
kg
kilogram
LE
Liver Event
mAb
Monoclonal antibody
MBq
MegaBecquerel (SI unit of radioactivity)
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedRA
Medical Dictionary for Regulatory Agencies
µg/mL
Microgram/milliltre
min
minute
mM
millimolar
MS
Mass Spectroscopy
MSDS
Material Safety Data Sheet
mSv
milliSievert
NOAEL
No Adverse Effect Level
PBPK
Physiologically Based Pharmacokinetic
PET
Positron Emission Tomography
PK
Pharmacokinetics
QA
Quality Assurance
QC
Quality Control
QP
Quality Performance
QTc
Corrected QT interval
QTcB
QT interval corrected for heart rate according to Bazett’s 
formula 
QTcF
QT interval corrected for heart rate according to 
Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
ROI
Regions Of Interest
SAE
Serious Adverse Event
SGOT
Serum Glutamic Oxaloacetate Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SRM
Study Reference Manual
SUV
Standard Uptake Value
Tmax
Time at which maximum plasma concentration is observed
t 1/2
Apparent terminal phase half-life
ULN
Upper Limit Normal

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UPCR
Urine Protein Creatinine Ratio
WBC
White Blood cell
89Zr GSK3128349
GSK3128349 radiolabelled with zirconium
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
AlbudAb
Chiron RIBA
InForm

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12.2.
Appendix 2: Liver Safety – Required Actions and Follow up 
Assessments
Phase I liver chemistry increased monitoring criteria have been designed to assure subject 
safety and to evaluate liver event aetiology (in alignment with the FDA premarketing 
clinical liver safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I liver chemistry increased monitoring criteria and required follow up 
assessments
Liver Chemistry Increased Monitoring Criteria
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following 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, 
stabilise, or return to within baseline (see 
MONITORING below)

Viral hepatitis serology3

Blood sample for pharmacokinetic 
(PK) analysis, obtained within 72 hrs
of identified liver event.4

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening 
of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant 
medications on the concomitant 
medications report formincluding 
acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form

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MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to within 
baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin)  and perform liver 
event follow up assessments within  24-72 hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
If ALT≥3xULN AND bilirubin 2xULN 
or INR >1.5:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Assess history of acetaminophen 
usage in the past week. 

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 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 INR 
measurement is not required and the threshold value stated will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis 
CRNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
Record the date/time of the PK blood sample draw and the date/time of the dose of study treatment prior to blood 
sample draw on the CRF. Instructions for sample handling and shipping are in the SRM.

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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).
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 

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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 
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

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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.

Refer to Appendix 2 for the required liver chemistry follow-up instructions
12.3.3.
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.

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12.3.4.
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.

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.

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.

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
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
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.
12.3.5.
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.

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.

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12.4.
Appendix 4: Collection of Pregnancy Information

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 treatment.

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.