Clinical trial NCT03287310
Conditions: Asthma
Keywords: eosinophils pharmacokinetics First time in Human GSK3511294 pharmacodynamics asthma
Sponsor: GlaxoSmithKline
Start date: 2017-10-17; Completion date: 2019-07-31
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
GSK3511294 is a humanized monoclonal antibody antagonist of Interleukin (IL)-5 which is known to block binding of IL-5 to the IL-5 receptor complex, causing a reduction in the circulating population of eosinophils. This is a single ascending dose FTIH study to investigate safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of GSK3511294, administered SC in subjects with mild to moderate asthma maintained on a low-medium daily dose of inhaled corticosteroids (ICS) or ICS/long acting beta-agonist (LABA), and short acting beta-agonist (SABA). The subjects will attend a pre-screen visit of up to 12 weeks before dosing for assessment of blood eosinophils. Eligible subjects with blood eosinophils \>=200 cells per microliter (cells/µL) will undergo a screening period of up to 4 weeks. The subjects will then be randomized into 5 cohorts. In each cohort, the subjects will be randomized to receive a single dose of GSK3511294 or placebo in a ratio of 3:1. The follow-up period will be up to 40 weeks post dose and will be dose-dependent. The scheduled maximum duration for each subject will be up to 44 weeks including up to 28 days of screening.

Detailed description:

Arms: arm 1: Six subjects in Cohort 1 will receive a single SC dose of 2 mg GSK3511294. arm 2: Two subjects in Cohort 1 will receive a single SC dose of placebo. arm 3: Six subjects in Cohort 2 will receive a single SC dose of 10 mg GSK3511294. arm 4: Two subjects in Cohort 2 will receive a single SC dose of placebo. arm 5: Nine subjects in Cohort 3 will receive a single SC dose of 30 mg GSK3511294. arm 6: Three subjects in Cohort 3 will receive a single SC dose of placebo. arm 7: Nine subjects in Cohort 4 will receive a single SC dose of 100 mg GSK3511294. arm 8: Three subjects in Cohort 4 will receive a single SC dose of placebo. arm 9: Six subjects in Cohort 5 will receive a single SC dose of 300 mg GSK3511294. arm 10: Two subjects in Cohort 5 will receive a single SC dose of placebo.
Interventions: intervention 1: GSK3511294 intervention 2: Placebo intervention 3: Salbutamol/albuterol
Intervention descriptions: intervention 1: GSK3511294 will be available as a clear or opalescent, colorless or yellow to brown solution for injection at unit dose strength of 150 milligrams per milliliter (mg/mL). GSK3511294 will be diluted in 0.9% weight by volume (w/v) sodium chloride to achieve the desired concentration for administration. GSK3511294 will be administered by SC injection. intervention 2: Matching Placebo will consist of 0.9% w/v sodium chloride which will be administered by the SC route. intervention 3: Salbutamol/albuterol will be supplied to all subjects for use as rescue medication during the study.

Protocol documents:
Prot_001.pdf: 
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C O N FI D E N TI A L
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TI T L E P A G E
Di visi o n: W orl d w i de De vel o p me nt
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U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d.
P P D
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N270529_00
2017-JUN-13
Original
2016N270529_01
2017-JUN-21
Amendment No. 1
To correct errors in the Secondary Medical Monitor’s email address and in the 
inflammatory marker tests to be performed at screening.
2016N270529_02
2017-AUG-04
Amendment No. 2
To amend the pharmacokinetic stopping criterion and clarify that saline for placebo will 
be an EU licensed product sourced locally by trial sites, in response to comments from 
the Medicines and Healthcare Products Regulatory Agency.
2016N270529_03
2017-SEP-04
Amendment No. 3
To correct errors and make minor clarifications.
2016N270529_04
2018-FEB-02
Amendment No. 4
To amend the timeframe for collection of PEF measurements. To clarify that 
demography, height, weight and BMI will be collected at the pre-screening visit if this 
visit is required. Alignment of ECG collection timeframe. Clarify timeframe for review 
of safety data from sentinel participants. Clarify that sentinel participants will be used at 
each escalating dose level.  To remove the necessity for evidence of airway 
hyperresponsiveness, airflow variation (peak flow rate or FEV1) or reversible airflow 
obstruction at inclusion.  Added live vaccines to prohibited concomitant medications list. 
Added Right Bundle Branch Block as an exclusion criteria.  Clarification of the study
halting criteria.  Clarification that each participants consent must be available, as well as 
obtained, before they are entered into the study. Added an exclusion criteria regarding 
vulnerable participants.  Clarify the definition of a pre-screening failure.  Added in 
country specific requirements for Germany, concerning the addition of Hepatitis B core 
antibody test screening and to increase the in-patient period to 8-days post dosing.  
Clarified that the PK sample information is located in the appropriate lab manual and not 
the study reference manual. To ensure there is no un-blinding that can occur for 
Eosinophil counts due to availability of other components and their contributions to WBC 
count.


2016N270529_06
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GlaxoSmithKline
Document Number
Date
Version
2016N270529_05
2018-JUN-18
Amendment No. 5
A raw QT interval change from baseline as one of the criteria for limiting dose escalation 
and for increased monitoring of individual participants has been included in error.  QTcF 
has been chosen as the most appropriate corrective measure of QT for this study and this 
is now reflected throughout.  Accordingly, one of the required criteria for limiting further 
dose escalation and increased monitoring of individuals is now a change in QTcF from 
baseline of > 60 msec.  To remove the requirement for reversibility testing at pre-
screening/screening, as evidence of reversibility is no longer a requirement for inclusion 
as per the previous amendment.  Consequently, participants who would not be a screen 
failure under the entry criteria in the current version of the protocol may be rescreened. 
Furthermore, participants that were not a screen failure but could not be dosed during the 
screening window due to logistical reasons may also be rescreened.  To extend the PK 
sampling period in the 2 mg and 10 mg cohorts, to better characterise the PK profile of 
GSK3511294.  To clarify that local labs are required for all sentinel participants at the 
48 hour time point to enable dosing of the rest of the cohort.  As the German in-patient 
stay is longer than the UK, local labs prior to discharge from the clinical site are required 
on Day 8 and not at 48 hours post dosing (Day 3).  Minor corrections of typos 
throughout.
2016N270529_06
2019-JAN-07
Amendment No. 6
Inclusion of additional interim analyses to better assess blood eosinophil count return 
towards baseline profiles at the highest dose levels investigated and better inform dose 
and dosing regimen to move forward into the next phase of development.  The earliest 
additional interim analysis is planned no earlier than once data is available at the 26-week 
time point after dosing Cohort 4 (planned 100 mg dose).


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M E DI C A L M O NI T O R/ S P O N S O R I N F O R M A T I O N P AG E
Me dic al M o nit or/ S A E C o nt act I nf or m ati o n: 
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M e dic al m o nit or as a b ov e
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I n s o me c o u ntries, t he cli nical trial s p o ns or ma y be t he l ocal Gla x o S mit h Kli ne Affiliate 
C o m pa n y  ( or desi g nee).  If a p plica ble, t he details of t he alter nati ve S p o ns or a n d c o ntact 
pers o n i n t he territ or y  will be pr o vi de d t o t he rele va nt re g ulat or y a ut h orit y as part of t he 
cli nical trial a p plicati o n.   
Re g ulat or y  A ge nc y Ide ntif y i n g N u m ber(s):  2 0 1 6- 0 0 4 2 5 6- 3 0
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number: 205722
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205722......................................................11
2.
INTRODUCTION....................................................................................................15
2.1.
Study Rationale ..........................................................................................15
2.2.
Brief Background ........................................................................................15
3.
OBJECTIVES AND ENDPOINTS...........................................................................18
4.
STUDY DESIGN ....................................................................................................19
4.1.
Overall Design ............................................................................................19
4.2.
Treatment Arms and Duration.....................................................................20
4.3.
Dose Escalation..........................................................................................21
4.4.
Type and Number of Participants................................................................22
4.5.
Design Justification and Choice of Population ............................................22
4.6.
Dose Justification........................................................................................23
4.7.
Benefit:Risk Assessment ............................................................................26
4.7.1.
Risk Assessment .........................................................................27
4.7.2.
Benefit Assessment.....................................................................33
4.7.3.
Overall Benefit:Risk Conclusion...................................................33
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............33
5.1.
Inclusion Criteria.........................................................................................34
5.2.
Exclusion Criteria........................................................................................36
5.3.
Pre-screening/Screening/Baseline/Run-in Failures.....................................39
5.4.
Study Withdrawal Criteria ...........................................................................39
5.4.1.
Individual participant withdrawal from the study ...........................39
5.4.1.1.
Lost to follow-up .........................................................39
5.4.2.
Criteria for follow up of potential Type III Hypersensitivity/ 
Immune Complex Disease...........................................................40
5.4.3.
Criteria for increased monitoring of individual participants ...........41
5.4.3.1.
Liver chemistry ...........................................................41
5.4.3.2.
QTc ............................................................................41
5.5.
Study halting criteria ...................................................................................42
5.6.
Participant and Study Completion...............................................................42
6.
STUDY TREATMENT ............................................................................................42
6.1.
Investigational Product and Other Study Treatment....................................42
6.2.
Treatment Assignment................................................................................44
6.3.
Blinding.......................................................................................................44
6.4.
Packaging and Labelling.............................................................................45
6.5.
Preparation/Handling/Storage/Accountability..............................................45
6.6.
Compliance with Study Treatment Administration.......................................46
6.7.
Treatment of Study Treatment Overdose....................................................46
6.8.
Treatment after the End of the Study ..........................................................46
6.9.
Lifestyle and/or Dietary Restrictions............................................................47
6.9.1.
Meals and Dietary Restrictions ....................................................47
6.9.2.
Caffeine, Alcohol, and Tobacco ...................................................47
6.9.3.
Activity .........................................................................................47
6.9.4.
Travel ..........................................................................................47
6.10.
Concomitant Medications and Non-Drug Therapies....................................47


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6.10.1.
Permitted Medications and Non-Drug Therapies..........................47
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................48
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................49
7.1.
Time and Events Table...............................................................................50
7.2.
Screening and Critical Baseline Assessments ............................................54
7.3.
Safety .........................................................................................................54
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........54
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................54
7.3.1.2.
Method of Detecting AEs and SAEs ...........................55
7.3.1.3.
Follow-up of AEs and SAEs........................................55
7.3.1.4.
Cardiovascular and Death Events ..............................55
7.3.1.5.
Regulatory Reporting Requirements for SAEs............55
7.3.2.
Pregnancy ...................................................................................56
7.3.3.
Physical Exams ...........................................................................56
7.3.4.
Vital Signs....................................................................................56
7.3.5.
Electrocardiogram (ECG).............................................................56
7.3.6.
Clinical Safety Laboratory Assessments ......................................57
7.3.7.
Lung function tests.......................................................................59
7.4.
Pharmacokinetics .......................................................................................59
7.4.1.
Blood Sample Collection..............................................................59
7.4.2.
Sample Analysis ..........................................................................59
7.5.
Immunogenicity...........................................................................................59
7.6.
Circulating Immune Complexes ..................................................................59
7.7.
Complement, IgE and inflammatory markers ..............................................60
7.8.
Pharmacodynamic and Exploratory Markers...............................................60
7.8.1.
Pharmacodynamic Biomarkers ....................................................60
7.8.2.
Exploratory Biomarkers of Asthma...............................................60
7.9.
Genetics .....................................................................................................60
8.
DATA MANAGEMENT ...........................................................................................61
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................61
9.1.
Hypotheses.................................................................................................61
9.2.
Sample Size Considerations.......................................................................61
9.2.1.
Sample Size Assumptions ...........................................................61
9.2.2.
Sample Size Re-estimation or Adjustment...................................62
9.3.
Data Analysis Considerations .....................................................................62
9.3.1.
Analysis Populations....................................................................62
9.3.2.
Interim Analyses ..........................................................................62
9.4.
Key Elements of Analysis Plan ...................................................................63
9.4.1.
Primary Analyses.........................................................................63
9.4.2.
Secondary Analyses ....................................................................63
9.4.2.1.
Raw Plasma PK Concentrations.................................63
9.4.2.2.
Derived Plasma Pharmacokinetic Parameters............63
9.4.2.3.
Blood eosinophil count ...............................................64
9.4.3.
Pharmacokinetic/Pharmacodynamic Analyses.............................64
10. STUDY GOVERNANCE CONSIDERATIONS........................................................65
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............65
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................65


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10.3.
Quality Control (Study Monitoring) ..............................................................66
10.4.
Quality Assurance.......................................................................................66
10.5.
Study and Site Closure ...............................................................................66
10.6.
Records Retention......................................................................................67
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................67
11. REFERENCES.......................................................................................................69
12. APPENDICES........................................................................................................70
12.1.
Appendix 1:  Abbreviations and Trademarks...............................................70
12.2.
Appendix 2:  Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................74
12.2.1.
References ..................................................................................75
12.3.
Appendix 3: Investigations and management in the event of immune 
related adverse events or relevant clinical concern.....................................76
12.4.
Appendix 4:  Genetic Research ..................................................................77
12.5.
Appendix 5:  Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events ............................80
12.5.1.
Definition of Adverse Events........................................................80
12.5.2.
Definition of Serious Adverse Events...........................................81
12.5.3.
Definition of Cardiovascular Events .............................................82
12.5.4.
Recording of AEs and SAEs ........................................................83
12.5.5.
Evaluating AEs and SAEs............................................................83
12.5.6.
Reporting of SAEs to GSK...........................................................85
12.6.
Appendix 6: Modified List of Highly Effective Methods of 
Contraception for post-menopausal females, who are taking 
Hormone Replacement Therapy, and Collection of Pregnancy 
Information..................................................................................................86
12.6.1.
References ..................................................................................87
12.7.
Appendix 7:  Asthma Control Test ..............................................................88
12.8.
Appendix 8:  Country Specific Requirements..............................................89
12.8.1.
Additional Hepatitis B Core Antibody test for inclusion of 
participants in Germany...............................................................89
12.8.2.
Additional In-patient stay period for participants from 
Germany......................................................................................89
12.8.2.1.
Time and Events Table...............................................90
12.9.
Appendix 9:  Anaphylaxis Criteria ...............................................................94
12.9.1.
References ..................................................................................94
12.10. Appendix 10: Protocol Changes..................................................................95
12.10.1. Protocol Amendment 1 ................................................................95
12.10.2. Protocol Amendment 2 ................................................................97
12.10.3. Protocol Amendment 3 – Protocol changes for 
Amendment 03 (04-SEP-2017), from amendment 02 (04-
Aug-2017)....................................................................................98
12.10.4. Protocol Amendment 4 – Protocol changes for 
Amendment 04 (02-FEB-2018), from amendment 03 (04-
Sep-2017)..................................................................................108
12.10.5. Protocol Amendment 5 – Protocol changes for 
Amendment 05 (18-Jun-2018), from amendment 04 (02-
Feb-2018)..................................................................................129


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12.10.6. Protocol Amendment 6 – Protocol changes for 
Amendment 06 (07-JAN-2019), from Amendment 05 (18-
JUN-2018) .................................................................................136


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1.
PROTOCOL SYNOPSIS FOR STUDY 205722
Rationale
GSK3511294 is a humanised monoclonal antibody (Immunoglobulin G1 [IgG1], kappa) 
antagonist of Interleukin (IL)-5 with an extended pharmacology.  It blocks IL-5 binding 
to the IL-5 receptor complex, causing a reduction in the circulating population of 
eosinophils.  Two antagonists of IL-5, mepolizumab and reslizumab, are approved in 
severe eosinophilic asthma, as an add-on treatment administered every 4 weeks.  
GSK3511294 is expected to confer efficacy over a dosing interval of up to 6 months.  
This single ascending dose first time in humans (FTIH) study will investigate safety, 
tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of 
GSK3511294, administered subcutaneously in participants with mild to moderate asthma 
maintained on a low–medium daily dose of inhaled corticosteroids (ICS) or ICS/long 
acting -agonist (LABA), and short acting -agonist (SABA).  To facilitate the 
investigation of blood eosinophil counts following single doses of GSK3511294, eligible 
participants will have a blood eosinophil count of ≥200 cells/μL at screening.  This 
should enable a quantification of the prolonged blood eosinophil reduction that is 
anticipated in humans resulting from the combination of the extended half-life and 
greater affinity to IL-5 of GSK3511294.
Objectives/Endpoints
Objectives
Endpoints
Primary

To assess the safety and tolerability of 
ascending single subcutaneous (SC) 
doses of GSK3511294 in participants 
with mild to moderate asthma 

Adverse events (AE), serious adverse 
events (SAE), including systemic 
reactions and local injection site 
reactions 

Vital signs, electrocardiograms (ECG), 
laboratory safety data – including liver 
and renal chemistry, high sensitivity 
C-reactive protein (hsCRP), and 
complement (C3 and C4) 
Secondary

To evaluate the plasma 
pharmacokinetics of ascending single 
subcutaneous doses of GSK3511294 in 
participants with mild to moderate 
asthma

Plasma pharmacokinetic parameters of 
GSK3511294 after single subcutaneous 
doses:  AUC(0-∞), AUC(0-t), 
AUC(0-Week4), AUC(0-Week12), 
AUC(0-Week26), %AUCex, Cmax, 
tmax, tlast, CL/F, Vd/F, λz and t½ 
when assessable*


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Objectives
Endpoints

To evaluate the dose response of blood 
eosinophil counts after ascending single 
subcutaneous doses of GSK3511294 in 
participants with mild to moderate 
asthma

Ratio to baseline in absolute blood 
eosinophil count

To assess the immunogenicity of 
GSK3511294

Frequency and titres of binding 
anti-drug antibodies (ADAs) to 
GSK3511294, before and after 
GSK3511294 administration
* PK parameter abbreviations:  AUC(0-∞) = area under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time; AUC(0-t) = area under the concentration-time curve from time zero 
(pre-dose) to last time of quantifiable concentration within a participant across all treatments; 
AUC(0-WeekN) = area under the concentration-time curve from time zero to Week N; %AUCex = 
percentage of AUC(0-∞) obtained by extrapolation; Cmax = maximum observed concentration; 
tmax = time of occurrence of Cmax; tlast = time of last quantifiable concentration; CL/F = apparent 
clearance following subcutaneous dosing; Vd/F = apparent volume of distribution after subcutaneous 
administration; λz = terminal elimination rate constant; t½ = terminal phase half-life.
Overall Design
This is a single ascending dose FTIH study to evaluate the safety, tolerability, 
immunogenicity, pharmacokinetics and pharmacodynamics of subcutaneously 
administered GSK3511294 in participants with mild to moderate asthma and blood 
eosinophils ≥ 200 cells/µL.
This study is a multi-center, randomised, double-blind (sponsor clinical pharmacology 
modelling and simulation [CPMS] and statistician representatives open), 
placebo-controlled, parallel-group study.  Each participant will receive a single dose of 
GSK3511294 or placebo, as shown in Figure 1.


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Figure 1
Summary of GSK3511294 first-time-in-human study design
Notes:  Planned single ascending SC doses of GSK3511294 are 2, 10, 30, 100 and 300 mg.  Actual dose 
levels beyond the 2 mg starting dose will be confirmed based on the emerging data.  Planned cohort sizes 
are shown; additional participants may be added to cohorts, if necessary to characterise the 
pharmacokinetics or pharmacodynamics of GSK3511294.  In each cohort, participants will be randomised 
3:1 to receive GSK3511294 or placebo.  Additional cohorts of up to 12 participants may be added to test 
additional dose levels or to repeat a dose level already tested, if deemed necessary; however, the dose will 
not exceed 300 mg.  The planned sample size is n=48 participants; the maximum sample size is n=72 
participants (excluding replacements for prematurely withdrawn participants).  

Sentinel participants:  In each cohort, one placebo and one GSK3511294 participant 
will be dosed before the remaining participants.  Providing no safety issues are 
identified in the sentinel participants over an observation period of at least 72 hours, 
the remaining participants in the cohort may be dosed.  The Investigator will discuss 
any safety concerns with the GlaxoSmithKline (GSK) medical monitor before dosing 
the remaining participants in a cohort.  Sentinel dosing is not required in cohorts 
investigating a dose lower than or equal to the highest dose tested to date.
Treatment Arms and Duration

Blood eosinophils pre-screen and screening:  a blood eosinophils pre-screen 
assessment will be performed.  Participants are eligible to skip the blood eosinophils 
pre-screening visit and go directly to the screening visit, if they have a documented 
blood test result within 12 weeks before dosing demonstrating a blood eosinophil 
level ≥200 cells/L.  Participants who fulfil the pre-screening criteria will then attend 
the clinic for a full screening visit.  Blood eosinophil level will be measured at 
screening to confirm eligibility.

In-patient period: Participants will be admitted the day before dosing, and the 
minimum post dose in-patient period for all participants will be 72 hours in the UK 
and 8 days in Germany (a longer in-patient stay is required in Germany to satisfy 
regulatory comments).  Participants will be monitored for local injection site reactions 
and allergic reactions for at least 72 hours post dose.  In the case of such reactions, 
appropriate medical treatment will be administered. Participants will be discharged
only if the Investigator deems it safe for the participant to leave the unit.


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
Follow up period:  Participants will receive post-dose assessments during the in-
patient period and attend the clinic for further post-dosing assessments.  The follow-
up period will be up to 40 weeks, and will be dose dependent, based on the predicted 
blood eosinophil profile.  Participants in cohorts receiving 2 and 10 mg GSK3511294 
will attend the clinic visits up to week 32, participants in cohorts receiving 30 mg and 
100 mg will attend clinic visits up to week 36, and participants in cohorts receiving 
300 mg will attend clinic visits up to week 40.  (For unplanned dose levels, the 
duration of follow-up will be documented in a Note to File.)  The follow-up period 
for any participant may be adjusted, if necessary, based on the anticipated duration of 
action or any safety concerns that may emerge during the study.

Total duration:  The scheduled maximum study duration for each participant who 
receives GSK3511294 or placebo will be up to 44 weeks (excluding pre-screening for 
blood eosinophils), including up to 28 days for screening, 4 days as an in-patient in 
the UK and 9 days in Germany, and up to 40 weeks post-dosing to investigate the PD; 
blood eosinophil count and safety profile. 

Dose escalation:  The dose escalation committee (DEC), comprised of members from 
the GSK Study Team and the Investigator(s), will review available data from all 
participants in each cohort before initiating each new dose level.  Dose escalation
may occur only after review of the following data at the highest dose level tested to 
date:  at least 4 weeks’ post-dose safety data and at least 2 weeks’ post-dose PK data 
from at least 4 participants on active treatment; and at least 72 hours’ post-dose safety 
data from the remaining participants in the cohort.  As the sponsor CPMS and 
statistician representatives will be unblinded, to minimise the risk of unblinding 
investigators and other sponsor representatives during DEC meetings, no individual 
PK or PD data will be discussed; only blinded summary statistics will be available to 
blinded DEC members. 
Type and Number of Participants
The total number of participants pre-screened/screened will meet the need to randomise a 
sufficient number of participants to fulfil the study objectives.  It is anticipated that after 
completion of successful screening, approximately 48 mild to moderate asthmatics, with 
blood eosinophils ≥200 cells/L at screening, will be randomised.  As the number of 
cohorts and number of participants per cohort are flexible, the protocol allows 
randomization of up to 72 participants (not including replacements for prematurely 
discontinued participants), split between about 6 clinical sites. 


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2.
INTRODUCTION
2.1.
Study Rationale
This is a single ascending dose FTIH study to investigate safety, tolerability, 
immunogenicity, PK and PD of GSK3511294, administered subcutaneously in 
participants with mild to moderate asthma, maintained on a low–medium daily dose of 
inhaled corticosteroids (ICS) or ICS/long acting -agonist (LABA), and short acting 
-agonist (SABA).  Eligible participants will be required to have a blood eosinophil
count of ≥200 cells/μL at screening, to facilitate investigation of reduction in blood 
eosinophil counts following single doses of GSK3511294, and to quantify the prolonged 
blood eosinophil reduction that is anticipated in humans given the expected extended 
half-life and greater IL-5 affinity of GSK3511294. 
In stream data review will occur during the study to support dose escalation decisions, 
and formal interim analyses are planned to ensure accumulated safety, PK and PD data is 
deemed sufficient to determine the doses, and dosing interval, to take forward to the next 
phase of development.
2.2.
Brief Background
Interleukin-5 (IL-5):  IL-5 mediates the growth and differentiation of eosinophils in the 
bone marrow and also their recruitment and activation within tissues [Corren, 2012].  
Eosinophils circulate in the blood with a half-life of 8 to 18 hours and can persist in 
tissues for longer (days to weeks) [Kovalszki, 2016].  Therefore, inhibiting IL-5 will 
remove a key eosinophil growth factor, and given the short half-life of eosinophils, will 
cause a rapid reduction in the circulating population. Reduction in eosinophils has been 
identified as a therapeutic strategy for numerous disorders, with monoclonal antibodies 
(mAbs) targeting IL-5, such as mepolizumab, currently approved in severe eosinophilic 
asthma and in development for other indications [Legrand, 2015].
GSK3511294:  GSK3511294 is an extended pharmacology humanised monoclonal 
antibody (Immunoglobulin G1 [IgG1], kappa).  It inhibits IL-5 signalling by blocking 
human IL-5 binding to the IL-5 receptor complex, which is expressed on the eosinophil 
cell surface.  Treatment with anti IL-5 monoclonal antibodies (mepolizumab and 
reslizumab) administered every 4 weeks appears well tolerated, and is approved as an 
add-on maintenance treatment in patients with severe refractory eosinophilic asthma.  
GSK3511294 is anticipated to confer a similar efficacy and benefit:risk profile as other 
IL-5 targeting monoclonal antibodies, while being administered with a longer dosing 
interval. 
GSK3511294 demonstrated an approximately 29-fold increase in IL-5 potency compared 
to mepolizumab in a cell based in vitro assay, and approximately 2-fold reduction in 
clearance in a single dose cynomolgus monkey pharmacokinetic (PK)/pharmacodynamic 
(PD) study.  Consistent with the in vitro data, in cynomolgus monkey, GSK3511294 
demonstrated an IL-5 binding affinity approximately 30-fold greater than mepolizumab, 
as evaluated by total IL-5 profile and duration of blood eosinophil suppression.  Return to 


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50% of the maximal blood eosinophil suppression effect was observed at around Day 169 
for GSK3511294 (1 mg/kg) and Day 29 for mepolizumab (1 mg/kg). 
The safety profile of GSK3511294 (10 and 100 mg/kg doses) has been evaluated in a 
4-week single dose and a 26-week repeat dose toxicity (2 doses 3 months apart given at 
Day-1 and Week-14) studies, administered by the subcutaneous (SC) route to 
cynomolgus monkeys. The off-dose phase of the 26-week study is ongoing so data 
generated during pretreatment through the end of the dosing period has been evaluated. 
An in vitro cross-reactivity study to evaluate the binding of GSK3511294 to human and 
cyno tissues has also been conducted.
GSK3511294 binding assessed by immunohistochemistry did not demonstrate specific 
positive staining in any of the tissues examined with staining restricted to the Positive 
Control Material (IL-5 coated coupled beads), suggesting little likelihood for non-
pharmacological effects. 
In the 26 week study, Anti-drug antibody (ADAs) were detected, at Week 26 and/or 
Week 13, in 3 males given 10 mg/kg/dose and in 1 male and 2 females given 
100 mg/kg/dose. 
GSK3511294 
plasma 
concentrations 
and 
serum 
total 
IL-5 
concentrations were decreased in one male given 10 mg/kg/dose that also had the highest 
titer for ADA.  ADAs were not detected in the 4 week study and quantifiable levels of 
GSK3511294 in plasma were demonstrated up to the end of collection intervals.  
In most animals, a trend towards reduced blood eosinophil counts was observed in both 
sexes given 100 and/or 10 mg/kg/dose; however, low pretreatment eosinophil values 
limited the detectable magnitude of the changes.  In addition, increases in serum total 
IL-5 concentrations (up to 70x control) were observed in males and females given 
100 and/or 10 mg/kg/dose. The serum total IL-5 concentrations were highly variable and 
did not exhibit dose-proportionality with increasing dose from 10 to 100 mg/kg/dose.
These changes reflect the expected pharmacological activity and extended half-life of 
GSK3511294.  
In the single dose 1 month study (n= 3/sex/grp), adverse vascular inflammation within 
the kidney, heart, pancreas, spleen, and liver was present in a female given 10 mg/kg: 
similarly, minimal focal inflammation of a bronchial artery was present in a female 
given 100 mg/kg. In the absence of detectable ADAs, while a direct effect of the test-
item is considered an unlikely cause of the adverse arterial changes in multiple organs, a 
potential exacerbation of spontaneous immune complex disease by GSK3511294 
administration cannot be excluded. Vascular inflammation was not observed in the 26 
week repeat dosing study given 2 doses 3 months apart of 10 and 100 mg/kg/dose. 
Furthermore, the pharmacological mechanism of GSK3511294 to attenuate the 
eosinophilic inflammatory pathway is precedented and appropriate clinical monitoring 
will be conducted in this study. Therefore, based on the weight of evidence and in the 
absence of microscopic findings in the 26 week study, these changes are considered to be 
of limited clinical relevance. 
Increases in QT (up to 55 msec) and QTc (up to 23 msec) observed in the 26 week study 
at 100 mg/kg are not consistent with the high specificity target interactions of 


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GSK3511294 to reduce circulating eosinophils by targeting the IL-5 pathway nor with its 
limited distribution or access to cellular targets, due to its physical size (~149 kilodalton 
[kDa]) [Vargas, 2013].  Furthermore, no binding to heart tissue was observed in the tissue 
cross reactivity studies using human and cyno tissue and no histopathological or 
functional (electrocardiogram [ECG] or heart rate) correlate was observed to explain 
these findings. 
In the 26 week study, as there were no adverse test item-related findings, the no observed 
adverse effect level (NOAEL) was considered to be 100 mg/kg, the highest dose tested. 
At this dose, mean Area under concentration-time curve
(AUC)0-2016
was 
1120000 µg.h/mL, range 898000 to 1290000 µg.h/mL; and mean Maximum observed 
concentration (Cmax) was 1390 µg/mL, range 1090 to 1610 µg/mL (gender averaged, 
Week 14). 
While the effect on safety and tolerability of increasing the affinity to IL-5 of 
GSK3511294 compared with other anti-IL-5 monoclonal antibodies is not known; 
precedented clinical experience of IL-5 targeting monoclonal antibodies indicate that the 
GSK3511294 mechanism of action is not anticipated to cause any particular safety 
concerns and will provide an alternative IL-5 targeting medicine with a longer duration of 
action.  Potential safety considerations with GSK3511294 include the effect on the 
degree and magnitude of eosinophil suppression, and immune-related non-clinical 
toxicology findings of unclear cause, and their unclear relevance to humans. Those data, 
along with pre-clinical data on GSK3511294, support progression of GSK3511294 into 
this First Time in Humans (FTIH) study of mild-moderate asthmatic patients.
For more information, please refer to the Investigator’s Brochure (IB; Section 5).


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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess the safety and tolerability of 
ascending single subcutaneous doses of 
GSK3511294 in participants with mild 
to moderate asthma 

Adverse events, serious adverse events, 
including systemic reactions and local 
injection site reactions 

Vital signs, ECGs, laboratory safety 
data – including liver and renal 
chemistry, high sensitivity C-reactive 
protein (hsCRP), and complement (C3 
and C4) 
Secondary

To evaluate the plasma 
pharmacokinetics of ascending single 
subcutaneous doses of GSK3511294 in 
participants with mild to moderate 
asthma

Plasma pharmacokinetic parameters of 
GSK3511294 after single SC doses:  
AUC(0-∞), AUC(0-t), AUC(0-Week4), 
AUC(0-Week12), AUC(0-Week26), 
%AUCex, Cmax, tmax, tlast, CL/F, 
Vd/F, λz and t½ when assessable*

To evaluate the dose response of blood 
eosinophil counts after ascending single 
subcutaneous doses of GSK3511294 in 
participants with mild to moderate 
asthma

Ratio to baseline in absolute blood 
eosinophil count 

To assess the immunogenicity of 
GSK3511294

Frequency and titers of binding ADAs 
to GSK3511294, before and after 
GSK3511294 administration
Exploratory 

To assess the effect of single SC doses 
of GSK3511294 on lung function

Change from baseline:  forced 
expiratory volume in 1 second (FEV1), 
forced vital capacity (FVC), peak 
expiratory flow (PEF)

Serum total IL-5 following single SC 
doses of GSK3511294 

Serum total IL-5 levels 

To explore drug specific circulating 
immune complexes (CIC) after single 
SC doses of GSK3511294

Levels of CICs

To determine the effect of single SC 
doses of GSK3511294 on serum 
markers of asthma

Change from baseline in asthma 
biomarkers

To explore the PK/PD (blood 
eosinophil count) relationship after 
single SC doses of GSK3511294, if 
deemed appropriate

GSK3511294 plasma concentration and 
blood eosinophil count for 
determination of Half maximal 
effective concentration (EC50) and 
maximum effect, if deemed appropriate


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* PK parameter abbreviations:  AUC(0-∞) = area under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time; AUC(0-t) = area under the concentration-time curve from time zero 
(pre-dose) to last time of quantifiable concentration within a participant across all treatments; 
AUC(0-WeekN) = area under the concentration-time curve from time zero to Week N; %AUCex = 
percentage of AUC(0-∞) obtained by extrapolation; Cmax = maximum observed concentration; 
tmax = time of occurrence of Cmax; tlast = time of last quantifiable concentration; CL/F = apparent 
clearance following subcutaneous dosing; Vd/F = apparent volume of distribution after subcutaneous 
administration; λz = terminal elimination rate constant; t½ = terminal phase half-life.
4.
STUDY DESIGN
4.1.
Overall Design
This is a single ascending dose FTIH study to evaluate the safety, tolerability, 
immunogenicity, pharmacokinetics and pharmacodynamics of subcutaneously 
administered GSK3511294 in participants with mild to moderate asthma and blood 
eosinophils ≥200 cells/µL.
This study is a multi-center, randomised, double-blind (sponsor clinical pharmacology 
modelling and simulation [CPMS] and statistician representatives open), 
placebo-controlled, parallel-group study.  Each participant will receive a single dose of 
GSK3511294 or placebo, as shown in Figure 2.
Figure 2
Summary of GSK3511294 first-time-in-human study design
Notes:  Planned single ascending SC doses of GSK3511294 are 2, 10, 30, 100 and 300 mg.  Actual dose 
levels beyond the 2 mg starting dose will be confirmed based on the emerging data.  Planned cohort sizes 
are shown; additional participants may be added to cohorts, if necessary to characterise the 
pharmacokinetics or pharmacodynamics of GSK3511294.  In each cohort, participants will be randomised 
3:1 to receive GSK3511294 or placebo.  Additional cohorts of up to 12 participants may be added to test 
additional dose levels or to repeat a dose level already tested, if deemed necessary; however, the dose will 
not exceed 300 mg.  The planned sample size is n=48 participants; the maximum sample size is n=72 
participants (excluding replacements for prematurely withdrawn participants).  

Sentinel participants:  In each cohort, one placebo and one GSK3511294 participant 
will be dosed before the remaining participants.  Providing no safety issues are 
identified in the sentinel participants over an observation period of at least 72 hours, 


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the remaining participants in the cohort may be dosed.  The Investigator will discuss 
any safety concerns with the GlaxoSmithKline (GSK) medical monitor before dosing 
the remaining participants in a cohort.  Sentinel dosing is not required in cohorts 
investigating a dose lower than or equal to the highest dose tested to date.
4.2.
Treatment Arms and Duration

Cohorts:  Planned cohort sizes are as follows:  

Cohorts 1 (2 mg), 2 (10 mg) and 5 (300 mg): 
8 participants per cohort –
6 receiving GSK3511294 and 2 receiving placebo

Cohorts 3 (30 mg) and 4 (100 mg):  12 participants per cohort – 9 receiving 
GSK3511294 and 3 receiving placebo   

The dose levels, number of cohorts and number of participants per cohort may be 
adjusted during the course of the study to achieve study objectives based on 
emerging data from the ongoing analysis.  The ratio of active to placebo participants 
in each cohort will be 3:1.  

Blood eosinophils pre-screen and screening:  It is anticipated that a high proportion of 
the defined asthma population may have blood eosinophil levels that do not meet the 
inclusion criteria of ≥200 eosinophil cells/L, therefore a blood eosinophils 
pre-screen assessment will be performed.  Participants are eligible to skip the blood 
eosinophils pre-screening visit and go directly to the screening visit, if they have a 
documented blood test result within 12 weeks before dosing demonstrating a blood 
eosinophil level ≥200 cells/L.  If blood eosinophil levels within the prior 12 weeks 
are not available, participants will provide written informed consent at a pre-
screening visit followed by a pre-screen assessment of blood eosinophil level.  
Participants who fulfil the pre-screening criteria will then attend the clinic for a full 
screening visit.  Blood eosinophil level will be measured at screening to confirm 
eligibility. 

In-patient period: Participants will be admitted the day before dosing, and the 
minimum post dose in-patient period for all participants will be 72 hours in the UK 
and 8 days in Germany (Appendix 8).  Participants will be monitored for local 
injection site reactions and allergic reactions for at least 72 hours post dose.  In the 
case of such reactions, appropriate medical treatment will be administered.  
Participants will be discharged only if the Investigator deems it safe for the 
participant to leave the unit (For further information regarding the in-patient period in 
Germany, please refer to Section 12.8.2).

Follow up period:  Participants will receive post-dose assessments during the in-
patient period and attend the clinic for further post-dosing assessments, as outlined in 
the Time and Events Table (Section 7.1).  The follow-up period will be up to 
40 weeks after dosing, and will be dose dependent, based on the predicted blood 
eosinophil profile.  Participants in cohorts receiving 2 and 10 mg GSK3511294 will 
attend the clinic visits up to week 32, participants in cohorts receiving 30 mg and 
100 mg will attend clinic visits up to week 36, and participants in cohorts receiving 
300 mg will attend clinic visits up to week 40.  (For unplanned dose levels, the 
duration of follow-up will be documented in Note to File.)  The follow-up period for 


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any participant may be adjusted, if necessary, based on the anticipated duration of 
action or any safety concerns that may emerge during the study.

Total duration: The scheduled maximum study duration for each participant who 
receives GSK3511294 or placebo will be up to 44 weeks (excluding pre-screening for 
blood eosinophils), including up to 28 days for screening, 4 days as an in-patient in 
the UK and 9 days in Germany (Appendix 8), and up to 40 weeks post-dosing to 
investigate the PD (blood eosinophil count) and safety profile. 
4.3.
Dose Escalation

The Dose Escalation Committee (DEC) will consist of the Principal Investigator(s) 
(or appropriate designee), GSK Medical Monitors, GSK Study Team Leader, GSK 
Clinical Pharmacology Modelling and Simulation (CPMS) representative, a GSK 
Global Clinical Safety and Pharmacovigilance (GCSP) representative and GSK 
Statistician representative.  The GSK CPMS and statistician representatives will 
remain unblinded throughout the course of the study.

The DEC will select and approve doses throughout the study, and will review 
available data from all participants in each cohort before initiating each new dose 
level.  Dose escalation may occur only after review of the following data at the 
highest dose level tested to date: at least 4 weeks’ post-dose safety data and at least 
2 weeks’ post-dose PK data from at least 4 participants on active treatment; and at 
least 72 hours’ post-dose safety data from the remaining participants in the cohort.  In 
the unlikely event that one or more of the remaining participants discontinued the 
study within 72 hours after dosing, all available safety data from that/those 
participants will be reviewed.

Owing to the mechanism of action of GSK3511294, blood eosinophil results have the 
potential to unblind.  Therefore, study personnel will be blinded to post-dose blood 
eosinophil results for individual participants.  The sponsor CPMS and statistician 
representatives will review individual data, but summary statistics for the active 
group only will be provided to the remaining members of the DEC for the purposes of 
dose selection.  Similarly, to minimise the risk of unblinding during DEC meetings, 
no individual PK data will be discussed; summary statistics only will be provided to 
blinded members of the DEC.  If ongoing analyses are based on an incomplete cohort, 
to avoid unblinding, the DEC (except the GSK CPMS and statistician representatives) 
will be blinded to the number of participants included in the summaries of PK and 
blood eosinophils for that cohort. 

This protocol allows some alteration from the currently outlined dosing schedule, but 
the maximum single dose will not exceed 300 mg.

The dose will be increased only if safety and tolerability at previous dose levels are 
acceptable, and also if the predicted exposure (upper 95% prediction interval for Cmax
and AUC) at the next dose level does not exceed the mean exposure observed at the 
NOAEL in monkey in the 26 week toxicity study (100 mg/kg).
mean Cmax:  1390 µg/mL
mean AUC0–2016   1120000 µg.h/mL

The dose will not be escalated, nor will a dose level be repeated, if, at that dose level:


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
one or more of the study halting criteria are met (see Section 5.5)

one or more participants has experienced at least one of the criteria for potential 
type III hypersensitivity/immune complex disease, and there is ongoing clinical 
concern about the participant’s condition (see Section 5.4.2)

one or more participants has a QTcF > 500 msec or uncorrected QT > 600 msec, 
or an increase in QTcF > 60 msec, in the absence of any other identifiable reason 
(e.g. concomitant medication). In such a scenario, if after review of all clinical 
safety data for the participant(s), the increased QT is considered to be isolated and 
not clinically significant in the opinion of the medical monitor and investigators, 
dose escalation and/or dosing of further patients at the dose level at which the 
event was observed can occur only after ethics and regulatory approval of a 
substantial amendment.
4.4.
Type and Number of Participants
The total number of participants pre-screened/screened will meet the need to randomise a 
sufficient number of participants in order to meet the study objectives.  It is anticipated 
that after completion of successful screening, approximately 48 mild to moderate 
asthmatic participants, with blood eosinophils ≥200 cells/µL at screening, will be 
randomised.  As the number of cohorts and number of participants per cohort are flexible, 
the protocol allows randomization of up to 72 participants (excluding replacements for 
prematurely withdrawn participants), split between about 6 clinical sites. 
If participants prematurely discontinue the study, replacement participants may be 
recruited at the discretion of the Sponsor in consultation with the investigator in order to 
achieve the objectives of the study. 
4.5.
Design Justification and Choice of Population
The current study is a double-blind (sponsor CPMS and statistician representatives open), 
placebo controlled, parallel group, single ascending dose, FTIH study of GSK3511294, 
with safety and tolerability as the primary objective.  A key secondary objective is to 
confirm if the extended pharmacology of GSK3511294 observed preclinically translates 
into humans.  Hence, the magnitude and duration of reduction in blood eosinophils in a 
disease setting of eosinophilic asthma will be assessed.  In order to fully assess the 
GSK3511294 PK/PD profile, data will be collected for various follow up periods post 
dose (dependent on dose level) up to approximately 40 weeks.
FTIH population selected:  Mild to moderate asthmatics with an eosinophilic phenotype 
have been selected based on the following considerations.

Although GSK3511294 is a new molecular entity, and this study represents its first 
investigation in humans, its mechanism of action of IL-5 antagonism is precedented. 
Anti IL-5 mAbs, mepolizumab and reslizumab, have been investigated in the clinic in 
severe eosinophilic asthma, and were shown to have an overall favourable safety 
profile. As of 23 September 2016, approximately 2000 people have been exposed to 


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at least one dose of mepolizumab in completed GSK-sponsored clinical studies across 
various eosinophilic-mediated indications.  

Mepolizumab dose response for blood eosinophil reduction is consistent between 
participants with mild to moderate asthma and those with severe asthma.  Also, blood 
eosinophils and IL-5 are elevated in mild-moderate asthmatics relative to healthy 
participants.  Therefore, a study in mild-moderate asthmatics with blood eosinophils 
≥200 cells/µL at screening, provides an opportunity to investigate the effect of 
GSK3511294 on the blood eosinophil profile, to better inform dose selection and the 
dosing interval in later phase studies.  However, based on the data with mepolizumab, 
treatment benefit is not expected in a mild-moderate asthma patient population.
Overall, a FTIH study of participants with mild to moderate controlled asthma (defined in 
Section 5), on prn SABA, and regular ICS or an ICS/LABA combination, is considered 
justified to achieve the objectives of this FTIH study with GSK3511294.
4.6.
Dose Justification
Pharmacokinetics:  Mepolizumab and GSK3511294 plasma concentration data, generated 
from a single dose cynomolgus monkey PK/PD study, were modelled simultaneously 
along with the toxicokinetics (TK) data from the one month toxicity study, and showed 
that only systemic clearance differed between the two molecules.  The volume of 
distribution of the central and peripheral compartment, as well as the inter-compartmental 
clearance, were similar.  Clearance decreased by an estimated 1.9-fold with GSK3511294 
compared to mepolizumab, and this fold reduction is expected to be preserved between 
monkey and human.    Predicted human exposure following single GSK3511294 SC 
administration at the proposed doses in the study were estimated using the known 
mepolizumab PK in human adjusted by the predicted fold difference in clearance 
determined from the pre-clinical studies (Table 1 and Figure 3).  Absolute bioavailability 
was assumed to be 75%, similar to mepolizumab.  The predicted human systemic 
clearance (CL) is 0.00465 L/h or 0.112 L/day and the plasma elimination half-life is 
approximately 37 days.  
IL-5 binding affinity:  Due to the limitation of various in vitro assays, GSK3511294 
binding affinity is difficult to measure, but is anticipated to be 20-30 fold more potent 
than mepolizumab. Simulations to reproduce the total IL-5 and blood eosinophil profiles 
observed in the cynomolgus monkey PK/PD study were generated using a PK/PD model 
developed previously based on mepolizumab pharmacology data.  Whilst acknowledging 
the uncertainty due to the small sample size in the cynomolgus monkey study, 
simulations seem to support a minimum of a 30-fold higher binding affinity of 
GSK3511294 compared with mepolizumab.
Estimation of GSK3511294 therapeutic dose and frequency of administration:  The 
approved mepolizumab therapeutic dose in severe eosinophilic asthma is 100 mg SC 
administered every 4 weeks.  It is hypothesised that if the blood eosinophil reduction 
observed at GSK3511294 trough concentrations in steady-state conditions is similar to 
that observed at mepolizumab 100 mg SC trough concentrations, it is likely that similar 
‘clinical efficacy’ (reduction in asthma exacerbations) to mepolizumab will also be 


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observed in relevant clinical populations.  Therefore, simulations using a semi-
mechanistic stochastic model were generated, incorporating the clearance (1.9-fold) and 
binding affinity (30-fold) improvements observed in monkeys, assuming the findings in 
monkey will translate into humans.  The GSK3511294 simulations showed that a SC 
dose of GSK3511294 between 30−100 mg administered every 6 months could be a 
plausible therapeutic dose and dosing interval.
GSK3511294 starting dose:  Given the clinical experience with IL-5 antagonism as a 
mechanism of action, a 2 mg SC dose of GSK3511294 is justified as a starting dose.  The 
2 mg SC dose is anticipated to correspond to an average maximum reduction in blood 
eosinophils of approximately 75% (occurring approximately 2 weeks post-dosing), with a 
return to approximately 50% of the maximum response at around 150 days post dose 
(Figure 4). This level of blood eosinophil reduction is less than that previously observed 
in the clinic with repeat dosing of mepolizumab that was well tolerated.  Therefore, this 
sub-therapeutic GSK3511294 2 mg starting dose is anticipated to:  be well tolerated; 
offer the possibility to evaluate the blood eosinophil return towards baseline over an 
operationally reasonable period of time; and hence the opportunity to assess the in vivo
potency of GSK3511294 in human.  The proposed starting dose of 2 mg is 3500-fold 
lower than the NOAEL dose established in the 26-week toxicity monkey study (dose 
expressed in mg/kg and assuming a 70 kg participant) and the predicted AUC 3470-fold 
lower than the exposure observed at the NOAEL dose (Table 1).
SAD increments:  The proposed SC single doses to be investigated in this FTIH study are 
2, 10, 30, 100 and 300 mg.  These doses correspond to dose increments of 5-fold, 3-fold, 
3.3-fold and 3-fold, respectively, and are considered acceptable considering the 
precedence of the IL-5 antagonism mechanism of action.  Furthermore, sentinel 
participants are planned for each escalating dose level. 
Maximum GSK3511294 dose:  In this single ascending dose FTIH study, the maximum 
proposed GSK3511294 SC dose is 300 mg which is 23-fold lower than the NOAEL dose 
established in the 26-week toxicity monkey study (dose expressed in mg/kg and assuming 
a 70 kg participant).  This dose will provide safety data at a dose 3-fold above the upper 
limit of the predicted therapeutic GSK3511294 SC dose range of 30–100 mg for severe 
asthma (predicted based on the GSK3511294 monkey PK/PD data).  A dose of 300 mg 
remains operationally feasible and is expected to be tolerated by participants with regard 
to number of injections (3x100 mg SC injections).  Furthermore, the proposed 300 mg 
maximum GSK3511294 SC dose, with an estimated average maximum reduction in 
blood eosinophils of approximately 93% (Figure 4), is anticipated to be tolerable given 
that 750 mg Intravenous (IV) mepolizumab administered every 4 weeks for at least 12 
months (average 88% blood eosinophil reduction at lowest concentration of a drug just 
before the next dose [Ctrough]) was found to be well tolerated.  Redundancy mechanisms 
exist to promote eosinophil production and therefore a complete (100%) suppression of 
blood eosinophils is not expected even at the maximum proposed 300 mg SC dose of 
GSK3511294.  The predicted AUC at this dose is 23-fold lower than the exposure 
observed at the NOAEL dose of 100 mg /kg in the 26 week toxicity monkey study
(Table 1).


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Figure 3
Predicted mean with 95% CI GSK3511294 plasma concentration-time 
profiles at the planned single SC doses of 2, 10, 30, 100 and 300 mg 
(with mepolizumab as a reference)
Figure 4
Predicted mean with 95% CI GSK3511294 blood eosinophil ratio-
time profiles at the planned single SC doses of 2, 10, 30, 100 and 
300 mg (with mepolizumab as a reference)


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Table 1
Safety margins when comparing monkey NOAEL data 
(cross-reactive species) with predicted human data at the proposed 
doses of GSK3511294 administered SC (‘safety cover’)
Predicted Human Cmax and AUC
Safety cover (vs. Monkey NOAEL)
Dose 
(mg)
Dose 
(mg/kg)1
Cmax 
(µg/mL)
AUC 
(µg*h/mL)
Dose 
cover2
Cmax 
Cover
Cover 
AUC 
2
0.03
0.226
323
3500x
6156x
3471x
10
0.14
1.13
1613
700x
1231x
694x
30
0.43
3.39
4840
233x
410x
231x
100
1.43
11.3
16132
70x
123x
69x
300
4.29
33.9
48396
23x
41x
23x
1.
assuming a 70 kg participant
2.
dose (expressed in mg/kg) cover
4.7.
Benefit:Risk Assessment
Summaries of findings from non-clinical studies conducted with GSK3511294 can be 
found in the Investigator’s Brochure.  The following section outlines the risk assessment 
and mitigation strategy for this protocol:  


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4.7.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK3511294] 

Systemic reactions including allergic 
reactions.

Systemic reactions including allergic 
reactions, with the most severe form being 
anaphylaxis (see Appendix 9), are potential 
risks associated with mAbs.

Acute and delayed systemic reactions, 
including hypersensitivity reactions (e.g. 
anaphylaxis, urticaria, angioedema, rash, 
bronchospasm or hypotension) have 
occurred following mepolizumab 
administration in asthma patients.  

Sentinel participants will be used at all 
escalating dose levels and monitored for at 
least 72 hours post dose before dosing the 
remainder of the cohort.

All participants in the UK will have a 
minimum 72 hour post dose in-patient 
monitoring period at experienced phase 1 
study sites to ensure any late reactions are 
captured. In Germany this post dose in-
patient monitoring period will be 8 days 
(Appendix 8).

Participants with a history of an allergic 
sensitivity to biologic agents are excluded.

Any observed reactions will also be treated 
based on investigator medical judgement 
(with medical monitor consult as needed).

Investigators will be asked to assess events 
they consider to represent systemic 
reactions and events of anaphylaxis against 
Sampson diagnostic criteria for anaphylaxis
(Appendix 9)

Type III Hypersensitivity (Immune complex 
deposition in kidney, heart, pancreas, 
spleen, liver and lung)

Adverse effects of vascular inflammation 
consistent with immune complex disease 
were observed in 1 female monkey in the 
1-month toxicity study after administration 
of 10 mg/kg.  A further monkey had a 

Participants with history of renal disease, 
evidence of protein or blood on urinalysis or 
abnormal kidney function will be excluded, 
as will be patients with history or signs of 
immunologically active disease (defined by 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
minimal focal inflammation after 
administration of 100 mg/kg. Immune 
complex disease was not observed in the
6-month repeat dose (2 doses) study at the 
same doses. It is unknown whether 
immunogenicity in humans after dosing will 
result in the formation of pathogenic 
immune complexes as data from preclinical 
models is not necessarily predictive of 
immune complex disease in human effects.
low C3 or low C4), previous history of 
vasculitis and patients with a significantly 
elevated Alanine aminotransferase (ALT) or 
history of liver disease. 

Safety evaluation of individual participants 
will be in place, with data being reviewed 
on an ongoing basis by the Sponsor and 
Investigators.  Any clinical signs that might 
indicate immune complex disease will be 
reported to the sponsor’s medical monitor 
within 24 hours of the investigator 
becoming aware of the event, regardless 
whether the event is considered serious or 
non-serious.  Participants will be 
investigated and treated as clinically 
indicated (Appendix 3).  

Targeted monitoring of laboratory data 
(tests shown in Section 7.3.6 and time 
points shown in Section 7.1) will include 
urinalysis to detect haematuria and 
microalbuminuria and clinical chemistry 
parameters.  ADA and immune complex 
concentrations, trends in C3 and C4, 
platelets and inflammatory markers, over 
time will also be assessed. 

Halting and monitoring rules, based on the 
clinical findings, are defined to minimise 
the risk to participants (Section 5.4 and 
Section 5.5).


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

Immunogenicity, ADAs

Biopharmaceutical products may elicit 
ADAs, which have the potential to modulate 
PK or PD, or to produce adverse reactions.  
This is the GSK3511294 FTIH study, hence 
the ADA response in humans is unknown.  

A single dose of GSK3511294 will be 
administered to a participant.

Binding ADAs to GSK3511294 will be 
measured, and adverse event profile will be 
compared between ADA-positive and 
ADA-negative participants.

Local injection site reactions

A potential risk of any drug delivered via 
injection. 

No injection site reactions were noted in the 
preclinical studies.

In the placebo-controlled severe asthma 
studies, an increase in the incidence of local 
injection site reactions has been observed 
with SC mepolizumab administration 
compared with placebo (8% vs. 3%). There 
have been no reports of severe reactions.  
Pain, erythema, swelling, itching, and 
burning sensation were the most common 
symptoms reported.

Routine monitoring of participants for at 
least 72 hours after dosing in the UK and 
8 days in Germany (Appendix 8).

QTc prolongation

Four monkeys in the 6-month repeat dose 
monkey study administered 
100 mg/kg/week were observed to have 
QTc prolongation (mean change of 18 msec 
relative to vehicle control value) during 
Week 14.

relative to control) at week 14 in the 
100 mg/kg dose group only. 

ECGs will be performed on a regular basis 
and should there be any QTc abnormality 
patients will be monitored more frequently 
and management instituted as deemed 
relevant by the Investigator in liaison with 
the medical monitor.

Participants with QTc prolongation on 
screening will be excluded.
Participants with a history of cardiac 
disease, Left Bundle Branch Block, Right 
Bundle Branch Block, severe hypertension, 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
QTc abnormality or arrhythmia will be 
excluded as will participants with a relevant 
family history.

Alterations in immune response, potentially 
leading to increase in infections

This is a theoretical concern with drugs that 
affect the immune system.  The known 
biology of IL-5 and eosinophils suggest that 
inhibiting IL-5 is unlikely to induce an 
immunosuppressive effect.

Eosinophils may be involved in the 
immunological response to some helminth 
infections.

Individuals with a recent history of an 
opportunistic infection, a current respiratory 
or other latent/chronic infection, or positive 
history or test for hepatitis B/C or human 
immunodeficiency virus (HIV) are 
excluded.

Receipt of a live vaccine within 4 weeks of 
screening is exclusionary, and live vaccines 
are contraindicated during the study period.

Major surgery within 90 days of screening 
and/or planned surgery during the study are 
exclusionary.

Current study will be conducted in countries 
where gastro-intestinal parasitic infections 
are rare.  Patients with parasitic (helminth) 
infections within 6 months of screening are 
excluded, along with those who have 
travelled to (within the 6 months before 
dosing) or intend to travel to (within 1 year 
after dosing) countries with a high 
prevalence of parasitic disease.

Risk of GSK3511294 affecting an unborn 
baby.

Reproductive studies have not been 
conducted with GSK3511294; however, in 
the 6-month repeat dose monkey study no 
changes were observed in reproductive 
organs. Seminiferous tubules were 
evaluated with respect to their stage in the 

Females of reproduction potential will be 
excluded from the study.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
spermatogenic cycle and the integrity of the 
various cell types present within the 
different stages in sexually mature males. 
No cell or stage specific abnormalities were 
noted.  In addition, there is a low 
reproductive risk associated with the IL-5 
target mechanism (as shown in pre-clinical 
reproductive toxicology studies of 
mepolizumab and  reslizumab), a low 
genotoxic concern for mAbs in general, and 
a low transfer of monoclonal antibody 
(mAbs) into semen due to the inability of 
large molecular weight proteins such as 
GSK3511294 to access pivotal cells in the 
testes [Setchell, 1975; Pollanen, 1995; 
Pollanen, 1989; Setchell, 2001; Sohn, 
2015], the risk of adverse effects on 
spermatogenesis is considered minimal.  

It is expected that spermatogenesis will not 
be affected by GSK3511294, so males will 
not be required to use contraception during 
the study.
Study Design

Duration of in-patient stay after dosing

Tmax of GSK3511294 is expected at 
7−10 days after dosing.  However, any 
significant side effect of GSK3511294 in 
the time to Tmax is most likely to be an 
anaphylactic reaction, which would occur in 
the first 72 hours after dosing.  The 
predicted PK profile indicates 
approximately 80% of Cmax at 72 hours 
after dosing.  Participants will have a 
minimum 72 hour in patient monitoring 
period at experienced phase 1 study.  

In the UK, Investigators will review 
available safety data up to 72 hours to 
confirm participants are well enough to 
leave the clinical unit.  In Germany, in 
response to regulatory comments, 
participants will be in-patient until at least 
8 days after dosing.

Participants will receive a medical alert 
card, with details of the study, clinical site 
and Investigator, when they are discharged 
from the unit.  They will be instructed to 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Therefore, to minimise the inconvenience to 
participants, they may be discharged from 
the clinical unit 72 hours (or longer) after 
dosing, provided that the Investigator 
considers them well enough to leave.
contact the unit with any safety concerns 
they might have, and to show the medical 
alert card to any other medical professional 
they might consult. 

Duration of the study

Final follow-up at all dose levels is 
scheduled to exceed 5 terminal t½ of 
GSK3511294 (predicted t½ is about 
37 days; shortest time to follow-up after 
dosing is 225 days).  Owing to the increased 
affinity of GSK3511294 for IL-5, blood 
eosinophils levels may still be reduced at 
the final scheduled follow-up visit, 
particularly at higher dose levels.  However, 
reduction in blood eosinophils is not 
considered to be a safety concern – residual 
levels of blood eosinophils are expected to 
be present, and there have been no safety 
signal from chronic dosing with 
mepolizumab, reslizumab or benralizumab.

Follow-up will be extended in any 
participant for whom there are safety 
concerns, until that concern is discharged.


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4.7.2.
Benefit Assessment

No clinical benefit is expected for the mild to moderate asthmatics who are to be 
enrolled into this FTIH study, as evidence for clinical benefits using mepolizumab 
and reslizumab have been demonstrated in the severe asthmatic population.

This single ascending dose, FTIH study in mild to moderate asthmatics (with blood 
eosinophils
≥200 cells/L) will not only provide initial safety, tolerability, 
immunogenicity, and pharmacokinetic data, but also an understanding of the 
relationship between GSK3511294 dose and blood eosinophil reduction, to better 
inform dose selection and dosing interval in the subsequent studies of the clinical 
development program.
4.7.3.
Overall Benefit:Risk Conclusion
Although no clinical benefit is expected for recruited participants, overall the benefit:risk 
balance for this FTIH study to be performed in mild to moderate asthmatics is considered 
acceptable.  The study provides the opportunity to generate key PK and PD data, as well 
as safety and tolerability information, in an eosinophilic population, thereby supporting 
subsequent progression into the targeted severe eosinophilic asthma population.  Close 
monitoring of participants for standard safety concerns in FTIH studies of biologics will 
be performed. 
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact participant eligibility is provided in the IB (Section 3).
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardise the scientific integrity of the study, regulatory acceptability or 
participant safety.  Therefore, adherence to the criteria as specified in the protocol is 
essential.


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5.1.
Inclusion Criteria
A participant will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Between 18 and 65 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2. Blood eosinophils of ≥200 cells/µL at screening.
3. Asthma:  A physician diagnosis of asthma (mild or moderate, as defined by the 
Global Initiative for Asthma (GINA), 2017) at least 12 months prior to the start of the 
study.  The reason for diagnosis of asthma should be documented in the participant’s 
source data, including relevant history.  If available, investigations – specifically 
evidence of airway hyperresponsiveness, airflow variation (peak flow rate or FEV1) 
or reversible airflow obstruction, should also be documented in the participant’s 
source data.
NOTE:

Airway hyper-responsiveness is defined by a methacholine or histamine 
concentration of <8 mg/mL producing a ≥ 20% fall in FEV1.

Airflow variation is defined as a variation in peak flow rate (the difference 
between the highest and lowest peak expiratory flow rate expressed as a 
percentage of the average peak expiratory flow rate) of > 20% over a series of 
measurements or a variation in FEV1 > 15% when measured on separate 
occasions.

Reversible airway obstruction is defined as increase in FEV1 of ≥ 12% over 
baseline AND an absolute change of ≥ 200 mL, following 4 inhalations of 
albuterol/salbutamol inhalation aerosol/spacer (or equivalent nebulised treatment 
with albuterol/salbutamol solution).
4. Asthma status:  A screening pre-bronchodilator FEV1 60% of predicted normal 
value.

NOTE: Predicted values based upon European Respiratory Society guidelines 
[Quanjer, 2012].
5. Asthma control:  Asthma Control Test score > 19.
6. hsCRP of < 10 mg/L at screening.
7. Otherwise healthy (other than the acceptable conditions of asthma and other atopic 
diseases, including allergic rhinitis and atopic dermatitis) based on a screening 
medical history, physical examination, vital signs, ECG assessment, pulmonary 
function testing, and clinical laboratory results.
NOTE:  A participant with abnormal clinical laboratory parameter(s), which is/are 
not specifically listed in the inclusion or exclusion criteria, outside the reference 
range for the population being studied may be included only if the investigator (in 
consultation with the Medical Monitor) agree and document that the finding is 


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unlikely to introduce additional risk factors and will not interfere with the study 
procedures.  In the event of out-of-range results of safety tests, the tests may be 
repeated once within the screening window.  If a retest result is again outside the 
reference range and considered clinically significant by the investigator and GSK 
medical monitor, the participant will be considered a screen failure.
8. Asthma therapy:

Maintained controlled on as needed SABA and one of the following:

stable dose of ICS 

stable dose of combination therapy:  ICS/LABA 
NOTE:  the ICS dose should be up to a maximum daily dose shown in Table 2, 
and stable for at least 12 weeks prior to the study treatment.
Table 2
Maximum Allowed Daily Doses of Inhaled Corticosteroid (ICS)
Inhaled Corticosteroid
Max Daily Dose (g)
Beclomethasone dipropionate (CFC)
1000
Beclomethasone dipropionate (HFA)
400
Budesonide (DPI)
800
Ciclesonide (HFA)
320
Fluticasone priopionate (DPI)
500
Fluticasone furoate (DPI)
100
Mometasone furoate
440
Triamcinolone acetonide
2000
CFC –Chorofluorocarbonate, DPI – Dry Powder inhaler, HFA-: hydrofluoroalkane propellant
WEIGHT
9. Body weight 50 kg, and body mass index (BMI) of 19-32 kg/m2 inclusive.
SEX
10. Male and female participants. 
a. Females:  a female participant is eligible to participate if she is not pregnant (see 
Appendix 6), not breastfeeding, and not a woman of childbearing potential as 
defined in Appendix 6.
b. Males:  as GSK3511294 is a monoclonal antibody that is not anticipated to 
interact directly with Deoxyribonucleic acid (DNA) or other chromosomal 
material with minimal exposure through semen expected, male participants will 
not be required to use contraception during the study, nor are they prohibited from 
donating sperm.  


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INFORMED CONSENT
11. Capable of giving signed informed consent as described in Section 10.2, which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A participant will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Asthma exacerbation:  Any asthma exacerbation requiring systemic corticosteroids 
within 12 weeks of screening, or that resulted in overnight hospitalization requiring 
additional treatment for asthma within 6 months prior to screening.
2. A history of life-threatening asthma.  Defined as an asthma episode that required 
intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic 
seizures within the last 5 years.
3. Significant pulmonary diseases, other than asthma, including (but not limited 
to):  pneumonia previously requiring hospital admission, pulmonary fibrosis, 
bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive 
pulmonary disease, or other significant respiratory abnormalities.
4. Respiratory Infection:  Suspected or confirmed bacterial or viral infection 
(including tuberculosis) of the upper or lower respiratory tract, sinus or middle ear 
that occurred within and/or has not resolved within 4 weeks of screening that:

led to a change in asthma management
OR

in the opinion of the Investigator, is expected to affect the participant’s asthma 
status or the participant’s ability to participate in the study.
NOTE: Participants can be rescreened once to allow for an adequate time period 
between resolution of the infection and randomisation.
5. Positive for hepatitis B surface antigen (HBsAg) at screening. (Please refer to 
Appendix 8 for country specific requirements for Germany)
6. Positive hepatitis C antibody test result at screening, or within 3 months prior to first 
dose of study treatment.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA) 
Polymerase chain reaction (PCR) test is obtained.  Test is optional and participants 
with negative Hepatitis C antibody test are not required to also undergo Hepatitis C 
RNA testing. 
7. Known immunodeficiency (other than that explained by the use of corticosteroids), 
including a positive test for HIV antibody at screening.


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8. Latent or chronic infections (e.g., genital herpes, urinary tract infections) or at risk 
of infection (e.g., significant trauma or infection within the 90 days before screening).
9. Opportunistic infection within 6 months prior to screening (e.g., a non-tuberculous 
mycobacterial infection or cytomegalovirus, pneumocystosis, aspergillosis).
10. Parasitic infestation within 6 months prior to screening, or have travelled to a 
country with a high prevalence of such infections in the 6 months before screening, or 
intend to do so in the year after dosing.
11. Live vaccine within 4 weeks prior to screening, or intention to receive live vaccine 
during the study. 
NOTE: Attenuated or non-live vaccines are acceptable, if > 5 days before dosing.
12. QTcF > 450 msec.
NOTES: 

The QTc is the QT interval corrected for heart rate, for the purposes of 
standardisation, QTc corrected by Fridericia’s formula (QTcF) will be used 
across sites with central over-read to limit variability.

For purposes of data analysis, QTcF or a composite of available values of QTc 
will be used as specified in the Reporting and Analysis Plan (RAP).
13. A personal history of severe hypertension, arrhythmia, Right Bundle Branch 
Block, or Left Bundle Branch Block, or a family history of sudden unexplained 
death, long QT, familial cardiac syndrome, or cardiomyopathy.
14. Alanine aminotransferase (ALT) >1.5xUpper limit of normal (ULN).
15. Bilirubin >1.5xULN.  Isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%.
16. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
17. Any history or presence of clinically relevant cardiac or cardiovascular, 
gastrointestinal, hepatic, renal, metabolic, haematological, neurological, 
osteomuscular, articular, psychiatric, systemic, ocular, or infectious disease or 
immunodeficiency, or signs of acute illness, or any other illness or condition that, in 
the opinion of the investigator (in consultation with the medical monitor), would 
adversely affect the participant's participation in this study.  
Note:  Atopic diseases, like allergic rhinitis or atopic dermatitis, are not exclusionary.
18. History of cancer:  a previous history of cancer in remission for less than 5 years 
prior to screening (except for localised carcinoma of the skin that had been resected 
for cure) or current malignancy.
19. A positive drug/alcohol test before dosing, OR any history of drug abuse OR regular 
alcohol consumption within 6 months of the study defined as: 

An average weekly intake of > 14 units alcohol.  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. 


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20. Current smokers or ex-smokers who have given up smoking for < 12 months 
and/or have a smoking pack history of > 5 pack years (1 pack year = 20 cigarettes per 
day for 1 year or 5 cigarettes per day for 4 years).
21. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 6 months prior to screening. 
22. Anticipated non-availability and/or risk of non-compliance with study visits and
procedures, or unwillingness or inability to follow the procedures outlined in the 
protocol.
NOTE: Vulnerable Subjects (e.g those in detention) and those not able to 
communicate in the native language of the attending study site would be excluded.
23. The participant 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:  3 months, 5 half-lives or twice the duration of the biological 
effect of the investigational product (whichever is longer).
24. Exposure to more than 4 investigational medicinal products within 12 months 
prior to the first dosing day.
25. History of sensitivity to any of the study medications, or its components, or a 
history of drug reaction or other allergy that, in the opinion of the investigator or 
Medical Monitor, contraindicates their participation.  
NOTE:  This includes any previous allergic reaction to biologic agents.
26. Major surgery within 90 days prior to screening, or planned in-patient surgery or 
hospitalisation during the study period
27. Donation or loss of blood or blood products in excess of 500 mL within the 
3 months before dosing.
28. History of renal disease, abnormal kidney function or evidence of persisting or 
clinically relevant protein or blood on urinalysis.
29. History or signs of immunologically active disease (including the presence of low 
C3 or low C4) or thrombocytopenia.
30. History of vasculitis.
CONCOMITANT MEDICATIONS
31. Prohibited Medications:  Participants are excluded if they are undergoing 
desensitization therapy, or have received any of the following medications as 
indicated prior to screening: 

anti- Immunoglobulin E (IgE) therapy (within 6 months)

anti-IL5 (within 6 months)

oral or injectable corticosteroids (within 8 weeks)

long acting muscarinic antagonist (LAMA) or leukotriene receptor antagonist 
(LTRA) therapy (within 8 weeks)

drugs that can prolongate the QT interval (see Table 3)


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OTHER
32. Employment:  participants who are employees of the sponsor or clinical unit are 
excluded.
33. Vulnerable subjects, e.g., participants kept in detention, protected adults under 
guardianship, trusteeship and soldiers, or participants committed to an institution by 
governmental or juridical order.
5.3.
Pre-screening/Screening/Baseline/Run-in Failures
Pre-screening failures are defined as participants who consent to participate in a clinical 
trial, attend the Pre-screening visit but do not meet the criteria for the screening visit 
(blood eosinophils ≥200 cells/µL).  Screen failures are defined as participants who 
consent to participate in the clinical trial but are never subsequently randomised. To
ensure transparent reporting of screen failure participants, meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements, and respond to 
queries from Regulatory authorities, a minimal set of screen failure information is 
required including Demography, Screen Failure details, Eligibility Criteria, and Serious 
Adverse Events (see Section 7.3.1.5).  Participants who would not have been a screen 
failure on the basis of the entry criteria in the current version of the protocol may be 
rescreened for entry into the study.  Participants who could not be dosed for logistical 
reasons within the permissible screening window after passing screening for a cohort, 
may be rescreened for entry into a subsequent cohort.  Rescreened participants should be 
assigned a new participant number.
5.4.
Study Withdrawal Criteria
5.4.1.
Individual participant withdrawal from the study 

A participant may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons.

If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

Procedures planned for the participant’s last visit should be done at the time of early 
withdrawal.  Furthermore, if a PK sample was not planned at the participant’s last 
visit, it should be taken at early withdrawal.
5.4.1.1.
Lost to follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 


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The following actions must be taken in relation to a participant who fails to attend the 
clinic for a required study visit:

The site must attempt to contact the participant and re-schedule the missed visit as 
soon as possible. 

The site must counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study. 

In cases where the participant is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the participant (where 
possible, 3 telephone calls and if necessary a certified letter to the participant’s last 
known mailing address or local equivalent methods).  These contact attempts should 
be documented in the participant’s medical record. 

Should the participant continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost to 
Follow-up”. 
5.4.2.
Criteria for follow up of potential Type III Hypersensitivity/ 
Immune Complex Disease
Owing to the adverse effects consistent with immune complex disease, that were 
observed in the 1-month, but not 6-month, monkey studies, events consistent with type III 
hypersensitivity/immune complex disease will be reported to the GSK medical monitor 
within 24 hours of the Investigator becoming aware of the event, regardless whether the 
event is considered serious or non-serious.  Treatment for the event will be given as 
medically required (see Appendix 3 regarding proposed management).  If possible, PK, 
ADA and CIC samples should be taken at the time of the event.  

A combination of general symptoms associated with hypersensitivity or other 
potential clinical manifestations of immune complex disease.  Symptoms include but 
are not limited to: 

persistent* fever 

persistent* muscle and joint pain 

persistent* rash

symptoms of peripheral neuropathy, like numbness or weakness, and associated 
with progressive decrease in complement markers (C3, C4) 

* Persistent is considered to be longer than 2 days.

Urticaria.

Clinical symptoms suggestive of serum sickness (e.g., fever, general ill feeling, 
hives, itching, joint pain, rash, swollen lymph nodes).

Persistent thrombocytopenia, elevated hsCRP, or kidney or liver function tests 
indicative of organ damage:


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
reduced platelet count 

elevated hsCRP

elevated serum creatinine 

urinary albumin-creatinine ratio > 3 mg/mmol in the absence of a urinary 
tract infection 

persisting urinalysis abnormality for longer than 1 week 

macroscopic haematuria, without a clear cause (such as trauma)

Participants who experience any of the above events will be withdrawn from the 
study (ie they won’t take part in further study procedures, if clinically indicated; 
however, they will be followed up for safety, as required).  If the participant is well 
enough to do so, they may continue in the study.
5.4.3.
Criteria for increased monitoring of individual participants
5.4.3.1.
Liver chemistry
Liver chemistry increased monitoring criteria and required actions and follow-up 
assessments have been designed to assure participant safety and evaluate liver event 
aetiology. Since this is a single dose study liver chemistry stopping criteria do not apply.
If the following criteria are met increased liver chemistry monitoring is required:

ALT≥3xULN

ALT≥3xULN AND bilirubin ≥2xULN (>35% direct bilirubin) or (International 
Normalized Ratio) INR >1.5
See Appendix 2 for guidance regarding increased monitoring of liver chemistry and 
required actions and follow-up assessments.
5.4.3.2.
QTc
A detailed assessment including a concomitant assessment for PK, renal chemistry and 
electrolytes (potassium, calcium and magnesium), toxicology screen and clinical 
evaluation (e.g. continuous cardiac monitoring, admission for direct observation or 
referral) and discussion with the GSK medical monitor will be triggered in the following 
scenarios:
Refer for hospital admission & cardiology consult

Arrhythmia or evidence of clinical impact e.g. syncope. 
Direct observation for 24 hours before discharge with 48 hour ambulatory Holter monitor 
and subsequent repeat assessment at 48 hours *.

QTcF change from baseline > 60 msec and no clinical impact.  (Baseline is the 
average of triplicate readings at pre-dose on Day 1).

QTcF > 500 msec or uncorrected QT > 600 msec and no clinical impact.


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* To remain under observation if QTcF (or QT if > 600 msec) remains the same/increases 
on assessment at 24 (end of direct observation) and 72 hours periods (after 48 hour Holter 
monitor) and for consideration of cardiology consult.
Notes:  the QTcF should be based on averaged QTcF values of triplicate 
electrocardiograms obtained over a brief (up to 10 minutes) recording period.
5.5.
Study halting criteria
If one or more of the following criteria are met, the study will be halted and all available 
safety data will be reviewed by the sponsor and investigator(s):

one or more participants has:

a Serious Adverse Event (SAE) that is at least possibly related to study drug

an episode of acute renal failure requiring renal replacement therapy that is at 
least possibly related to study drug

an episode of anaphylaxis that is at least possibly related to study drug 

an episode of angioedema that is at least possibly related to study drug

a biopsy showing features of immune complex disease 

2 or more participants have severe Adverse Event (AEs) at least possibly related
to study drug
Participants who have been dosed at the time of the study halt will continue in the study, 
as planned.  Further participants may be dosed only if, after review, the sponsor and 
investigators consider it safe to do so and only after ethics and regulatory approval of a 
substantial amendment.
5.6.
Participant and Study Completion
A completed participant is one who has completed all phases of the study including the 
follow-up visit.  The end of the study/clinical trial is defined as the last visit of the last 
participant in the trial globally.  If the study is terminated early, the end of study/clinical 
trial is defined as the last visit of the last participant in the trial globally, or the date on 
which the sponsor decides to end the study, whichever is later.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the participant as per the protocol design. 


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Study Treatment
Product name:
GSK3511294 Injection, 150 mg/mL
0.9% w/v Sodium Chloride 
Injection (placebo)
Formulation description:
The GSK3511294 drug product is 
formulated with L-Histidine, 
monohydrochloride, monohydrate; L-
Histidine; Trehalose dihydrate; L-
Arginine hydrochloride; Disodium 
Edetate Ethylenediaminetetraacetic acid 
(EDTA); L-Methionine; and polysorbate 
80
0.9% w/v Sodium Chloride
Dosage form:
Solution for injection
Solution for injection
Unit dose strength(s)/Dosage 
level(s):
150 mg/mL (1 mL nominal volume) in a 
3 mL glass vial; 
Dosage levels vary per cohort.
Volume to match active dose
Route of Administration
Subcutaneous Injection. 1 mL solution 
per injection.  
For dose levels below 100 mg:
The study medication must be diluted in 
0.9% w/v sodium chloride to a 
concentration equivalent to the dose so 
that the entire dose can be administered 
using a single 1 mL injection (e.g. 1 mL 
administration of diluted 2 mg/mL 
concentration for 2 mg dose).
For dose level at 100 mg:
The study medication must be diluted in 
0.9% w/v sodium chloride to 100 mg/mL. 
One 1 mL injection of the diluted 
100 mg/mL study medication will be 
administered per participant to achieve 
100 mg dose.
For dose levels above 100 mg:
The study medication must be diluted in 
0.9% w/v sodium chloride to a 
concentration between 50-100 mg/mL 
such that one to three 1 mL injections of 
the diluted study medication can be 
administered per participant to achieve 
above 100 mg to 300 mg dose (e.g. two 
1 mL injections of diluted 65 mg/mL 
concentration for 130 mg dose). The 
multiple dose injection can be injected in 
the upper arm, up to 3 per arm at least 
5 cm apart.
To match active (i.e. the 
same volume and number of 
injections as the participants 
on GSK3511294 in that 
cohort)
Dosing instructions:
Details can be found in the Study 
Reference Manual
To match active
Physical description:
Clear or opalescent, colourless or yellow 
to brown liquid. Essentially free from 
visible particulates.
Refer to product insert


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Study Treatment
Manufacturer/ Source 
of procurement:
GSK
Locally sourced by trial site
Rescue medication (salbutamol/albuterol) shall be supplied to participants at Screening 
for use during the study.  This should be stored and administered in accordance with the 
manufacturer’s recommended instructions.  Replacement rescue medication will be 
supplied to participants, as required.
6.2.
Treatment Assignment
Participants will be randomised in accordance with the randomization schedule generated 
by Clinical Statistics, prior to the start of the study, using validated internal software.
Participants in each cohort will be allocated in a 3:1 ratio (active:placebo). 
In each cohort, dosing will be staggered:  one participant will receive GSK3511294 and 
one participant will receive placebo at least 72 hours before the remaining participants in 
that cohort are dosed.  Providing no safety issues are identified in the sentinel participants 
over an observation period of at least 72 hours, the remaining participants in the cohort 
may be dosed.  Sentinel dosing is not required in cohorts investigating a dose lower than 
or equal to the highest dose tested to date.
A separate randomisation schedule will be created for each cohort.  Two strata will be 
created within each randomisation schedule; to capture the randomisation for the sentinel 
participants and the randomisation for the remaining participants in each cohort.
6.3.
Blinding
This will be a double blind (sponsor CPMS and statistician representatives open).  The 
following will apply. 

The investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of an emergency OR in the event of a serious medical 
condition when knowledge of the study treatment is essential for the appropriate 
clinical management or welfare of the participant as judged by the investigator. 

Investigators have direct access to the participant’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded participant, unless that information is 
important for the safety of participants currently in the study. 

The date and reason for the unblinding must be fully documented in the case report 
form (CRF). 


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A participant may continue in the study if that participant’s treatment assignment is 
unblinded.  
GSK’s GCSP staff may unblind the treatment assignment for any participant with an 
SAE.  If the SAE requires that an expedited regulatory report be sent to one or more 
regulatory agencies, a copy of the report, identifying the participant’s treatment 
assignment, may be sent to investigators in accordance with local regulations and/or GSK 
policy.
In addition, the bioanalytical laboratory, and pharmacy staff involved in preparation of 
SC administration syringes, will have access to the randomisation code.  As there is a 
difference between active and placebo, where possible, administration syringes will be 
blinded by pharmacy staff using amber syringes or coloured, see through, tape to cover 
the full length of the syringe cylinder.  If blinding isn’t possible, participants will be 
dosed by independent staff, who will not be involved in any other procedures for any 
participant in a cohort that they dose.  
Formal unblinded interim analyses will be performed by GSK (see Section 9.3.2).
6.4.
Packaging and Labelling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK3511294 will 
be detailed in the Study Reference Manual (SRM), which will be accompanied by a 
Quality Agreement.

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorised site staff may supply or administer study treatment.  All study treatments 
must be stored in a secure environmentally controlled and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access 
limited to the investigator and authorised site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose a significant safety risks to site staff.  Adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists are advised.  


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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.
6.6.
Compliance with Study Treatment Administration
When the individual dose for a participant is prepared from a bulk supply, the preparation 
of the dose will be confirmed by a second member of the study site staff. 
When participants are dosed with GSK3511294 subcutaneously at the site, they will 
receive study treatment directly from the investigator or designee, under medical 
supervision.  The date and time of each dose administered in the clinic will be recorded in 
the source documents and reported in the CRF.  The dose of study treatment and study 
participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study treatment.  
6.7.
Treatment of Study Treatment Overdose
For this study, any dose of GSK3511294 greater than the specified dose for that cohort 
will be considered an overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose the investigator should:
1. contact the Medical Monitor immediately
2. closely monitor the participant for AEs/ SAEs and laboratory abnormalities until 
GSK3511294 has reached a systemic level at a time point at which there were no 
safety concerns in previous participants 
3. obtain a plasma sample for PK analysis within 4 weeks from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis).  If beyond 4 weeks, then collect as soon as feasible
Document the quantity of the excess dose as well as the duration of the overdosing in the 
CRF.
6.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study.  Mild to moderate asthmatics in this FTIH study aren’t expected to benefit from 
GSK3511294.  Other treatment options are available, and participants will remain on 
their standard of care during the study.
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the participant’s medical condition.


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6.9.
Lifestyle and/or Dietary Restrictions
6.9.1.
Meals and Dietary Restrictions

Participants should arrive fasted for the screening visit only, and will be allowed to 
eat during the screening visit after blood draw for clinical chemistry has been 
completed. 
6.9.2.
Caffeine, Alcohol, and Tobacco

Participants will abstain from ingesting caffeine- or xanthine-containing products 
(e.g., coffee, tea, cola drinks and chocolate) for 6 hours prior to the visits that 
include a spirometry and/or ECG assessments, and during those visits. 

Participants will abstain from alcohol for 24 hours prior to each visit to the clinic 
and during the in-patient period. 
6.9.3.
Activity

Participants will abstain from strenuous exercise for 72 hours prior to each blood 
collection for clinical laboratory tests.  
6.9.4.
Travel

Participants must not have travelled to a country with a high prevalence of parasitic 
infections in the 6 months before screening, or intend to do so in the year after 
dosing.  
6.10.
Concomitant Medications and Non-Drug Therapies
6.10.1.
Permitted Medications and Non-Drug Therapies
Paracetamol, at doses of 2 g/day, is permitted for use any time during the study.  
Hormone replacement therapy (HRT) is also permitted in females.  Other concomitant 
medication may be considered on a case-by-case basis by the investigator in consultation 
with the Medical Monitor.  Special consideration should be given for those medications 
that might impact blood eosinophil counts.
The following asthmatic ‘standard of care’ will be used throughout the study, as 
prescribed by a treating physician. 

SABA i.e. albuterol, salbutamol prn. (Provided to participants in the form of 
‘rescue medication’.)
AND

ICS alone, or inhaled ICS/LABA combination.  The ICS dose should be up to the 
maximum allowed daily dose (see Table 2) and stable for at least 12 weeks prior to 
study treatment.


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Asthma medication will be temporarily withheld before spirometry assessments at 
screening and on Day –1:  SABAs will be withheld for 6 hours; LABAs will be withheld 
for 12 hours; and LABAs with ultra-long activity will be withheld for 24 hours.  
Given that participants have mild-moderate asthma and are controlled with stable therapy 
on entering the study, maintenance asthma therapy should remain unchanged for the 
duration of the study. In the event of asthma exacerbations, participants should however 
be treated as per standard practice, which may include short bursts of systemic 
corticosteroids. Any changes to maintenance asthma therapy should be documented and 
communicated to the sponsor.
6.10.2.
Prohibited Medications and Non-Drug Therapies
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 7 days or 5 half-lives (whichever is 
longer) prior to study medication administration and until completion of the follow-up 
visit, unless in the opinion of the Investigator and sponsor the medication will not 
interfere with the study.  This excludes the background asthma standard of care defined 
in Section 6.10.1, which are permitted based on the established inclusion/exclusion 
criteria. 
The following asthma medications are prohibited during the study and within the 
timeframe indicated in brackets before screening:

Immunotherapy (at any time)

Desensitization therapy (ongoing)

anti-IgE therapy (within 6 months)

anti-IL5 (within 6 months)

oral or injectable corticosteroids (within 8 weeks)

LAMA or LTRA therapy (within 8 weeks)

Live vaccines
Medications that are known to prolong QT interval are also excluded.  Some of the more 
commonly encountered drugs that are known to prolong QT interval are listed in Table 3.


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Table 3
Drugs that can prolong the QT interval
Antimicrobial
s
Antipsychotics 
(all have some 
risk)
Antiarrhythmic
s
Antidepressant
s
Antiemetics
Others
Erythromycin
Clarithromycin
Moxifloxacin
Fluconazole
Ketoconazole
Risperidone
Fluphenazine
Haloperidol
Pimozide
Chlorpromazin
e
Quetiapine
Clozapine
Dronedarone
Sotalol
Quinidine
Amiodarone
Flecainide
Citalopram/
escitalopram
Amitriptyline
Clomipramine
Dosulepin
Doxepin
Imipramine
Lofepramine
Ondansetron/
Granisetron
Droperidol
Domperidon
e
Methadone
Protein 
kinase 
inhibitors e.g. 
sunitinib
Some 
antimalarials
Some 
antiretroviral
s
Telaprevir
Boceprevir
Notes:  list taken from http://www.ggcprescribing.org.uk/media/uploads/ps_extra/pse_21.pdf. 
Attenuated or non-live vaccines are prohibited within 5 days before and after dosing.
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). 
The following points must be noted: 

The timing and number of planned study assessments, including safety, PK, 
PD/biomarker, immunogenicity or other assessments may be altered during the 
course of the study based on newly available data (e.g., to obtain data closer to the 
time of peak plasma concentrations) to ensure appropriate monitoring. 

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File which is approved by the relevant GSK study 
team member and then archived in the study sponsor and site study files, but this 
will not constitute a protocol amendment. 

The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form. 

No more than 500 mL of blood will be collected over any 3-month period during 
the study, including any extra assessments that may be required.


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7.1.
Time and Events Table
Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 5
253 5
281 5
Informed consent
X 6
Pre-screening 
Blood eosinophils 
X7
Inclusion & 
exclusion criteria
X
X
X
Demography
X
Medical history 10
X
Concomitant 
medication
HIV, Hep B and 
Hep C screen 
X
FSH and estradiol
8
X
Pregnancy test 9
X
X
X
X
X
X
X
X 5
X 5
X 5
Drug, alcohol and 
cotinine screen
X
X
Genetic sample
X 11
Administer IP
X
ACT 12
X
X
X
X 5
X 5
X 5
Height, weight and 
BMI
X 13
X 13
X 5,13
X 5,13
X 5,13
Full phys exam
X
X 5
X 5
X 5
Brief phys exam
X
X
X
X
X
Dispense rescue 
SABA
X
Resupply, as required.


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Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 5
253 5
281 5
Haematology 
(including blood 
eosinophil count), 
Clin. Chem., 
Urinalysis and 
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Serum save (for 
immunological 
analysis, if 
needed)
X
Ad hoc, as required by symptoms – see Appendix 3.
Inflammatory 
markers
X
Ad hoc, as required by symptoms – see Appendix 3.
Complement (C3 
& C4)
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Total IgE
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
PK Blood Samples
See Table 4.
Immunogenicity
X
X
X
X
X
X
X
X
X 5
X 5
X 5
CICs
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
12-lead ECG 14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Vital signs 15
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
AE/SAE review 
(inc local ISR up to 
72 h after dosing)
X 16
IL-5 sample
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Exploratory 
biomarkers of 
asthma in blood 
X
X
X
Spirometry
X
X
X
X
X
X
X
X 5
X 5
X 5
PEF Training 17
X
PEF 17
X 17
Diary review 17
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5


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Abbreviations:  ACT = Asthma Control Test; AE = adverse event; BMI = body mass index; CICs = circulating immune complexes; CRP = C-reactive protein; ECG = 
electrocardiogram; FSH = follicle stimulating hormone; h = hour(s); Hep B = Hepatitis B; Hep C = Hepatitis C; HIV = human immunodeficiency virus; IgE = 
immunoglobulin E; IL-5 = interleukin-5; IP = Investigational Product; ISR = injection site reactions; PEF = peak expiratory flow; PK = pharmacokinetic; SABA = 
short acting -agonist; SAE = serious adverse event.
Notes:
1.
Pre-screen up to 12 weeks before dosing.  Blood eosinophils must be ≥200 cells/µL for participants to proceed to screening.  Blood eosinophil count may be 
existing data or obtained at a pre-screen visit.
2.
Screening up to 4 weeks before randomisation.  Screening procedures may be done at one or more visits, within the screening window.
3.
In the UK, all participants will be in-patient for at least 72 h after dosing.  In Germany, all participants will be in-patient for at least 8 days after dosing (see 
Appendix 8 for the German-specific time and events table).
4.
Allowed time deviations will be documented in the Study Reference Manual.
5.
All participants will have all out-patient visits up to Week 26 after dosing.  Each cohort will also have out-patient visits after week 26, depending on the dose, as 
follows:  

2 and 10 mg:  Week 32 only

30 mg and 100 mg:  Week 36 only 

300 mg:  Weeks 32 and 40
(For unplanned dose levels, the timing of out-patient visits will be documented in a Note to File.) 
6.
Informed consent will be taken either at the pre-screen visit, for participants who don’t have an existing eosinophil count, or at screening, for those who do.
7.
Blood eosinophils will be included in the haematology panel at all time points other than the pre-screen visit.  
8.
If required to confirm postmenopausal status.
9.
Women on hormone replacement therapy, whose post-menopausal status cannot be confirmed, only.
10. Including cardiovascular (CV) disease, asthma exacerbation, and drug, alcohol and smoking history.
11. If the participant consents, an optional, genetic sample will be collected once during the study.  
12. At each applicable visit, ACT should be done before any other assessment.
13. Height at pre-screening or screening only.
14. ECGs triplicate at all time points.  ECGs should be time-matched to baseline (i.e. pre-dose on Day 1) from Day 2 onwards.
15. Blood pressure and heart rate in triplicate before dosing; single measurements after dosing.  Single temperature and respiratory rate measurements at all time 
points.
16. Only SAEs are collected before dosing (see Section 7.3.1).
17. PEF will be recorded in the evening before bedtime on the day of the screening visit, then twice each day (once in the morning upon waking and once in the 
evening before bedtime) from the day after screening until the end of the study.  Training of the participant in how to take measurements will occur at screening.  
PEF measurements will be taken and results will be recorded by the site while the participant is in-patient at the clinical site (ie from the evening of Day –1 until 
the morning of discharge).  At all other time points, the participant will record their PEF as instructed, on their diary card, along with any rescue medication use
and adverse events.  Site staff will review the diary cards at each out-patient visit.


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Table 4
Pharmacokinetic sampling time points
Dose level
Pre-dose
Post-dose
Hours
Days
2
8
24
48
5
8
15
29
57
85
127
169
183
225
253
281
2 mg and 10 mg 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
30 mg and 100 mg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
300 mg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Notes:  For unplanned dose levels, PK sampling time points will be documented in a Note to File.


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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured:  year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the participant’s routine clinical management and 
obtained prior to signing of informed consent may be utilised for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Time and Events Schedule.
The Asthma Control Test (Appendix 7) should be completed by participants before any 
other assessment at a clinic visit, in the order specified.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 5.
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

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 participant consents to participate in the 
study up to dosing, and all SAEs will be documented after dosing, including any 
follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up contact 
(see Section 7.3.1.3), at the time points specified in the Time and Events Table 
(Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5.


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
Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant 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 5.
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 participant 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 
participant at subsequent visits/contacts.  All AEs will be followed until resolution, until 
the condition stabilises, until the event is otherwise explained, or until the participant is 
lost to follow-up (as defined in Section 5.4). Further information on follow-up procedures 
is given in Appendix 5.
7.3.1.4.
Cardiovascular and Death Events
For any CV events detailed in Appendix 5 and all deaths, whether or not they are 
considered SAEs, specific CV and Death sections of the CRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden 
cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.3.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 


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ethical responsibilities towards the safety of participants 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, IRB/ 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
Only women of non-childbearing potential are eligible for this study, so pregnancies are 
not expected. However, if a pregnancy does occur then:  details of all pregnancies in 
females will be collected after the start of dosing and until the end of the mandated 
contraceptive period.  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 6.
7.3.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Skin, Eyes and Cardiovascular, Respiratory, Gastrointestinal and Neurological 
systems. Height (screening only) and weight will also be measured and recorded. 

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses
7.3.4.
Vital Signs

Vital signs will be measured in supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, heart rate and respiratory rate. 
7.3.5.
Electrocardiogram (ECG)

12-lead ECGs will be obtained using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals.  Refer to Section 
5.4.3.2 for QTc increased monitoring criteria and additional QTc readings that may 
be necessary.
The 12-lead ECG will be performed in the supine position.  At all time points, after a 
5 minutes rest, triplicate ECGs will be obtained over a brief recording period (up to 


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10 minutes).  The ECGs will be time-matched to baseline assessment (ie pre-dose on 
Day 1) from Day 2 onwards.  For QT interval corrected for heart rate (QTc), for the 
purposes of standardisation, Fridericia’s correction formula (QTcF) was selected and will 
be used across sites with central over-read to limit variability.
7.3.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 5, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the participant number, protocol number, site/centre number, and visit date. Details 
for the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM.  Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.
If additional, non-protocol specified, laboratory assessments are performed at the 
institution’s local laboratory and result in a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory, 
except for pre-screen eosinophils, which, if required, may be performed at the local 
laboratory.
NOTE:  Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed – for example:  on Day –1, when results should be available before dosing on 
Day 1; at 48 h post-dose for all sentinel participants; at 48 h post-dose when results 
should be available before the participant is discharged from the clinical unit in the UK; 
on Day 8, when results should be available before the participant is discharged from the 
clinical unit in Germany; or at any other time when a participant is unwell and results are 
required urgently. If a local sample is required it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
CRF.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 5. 


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Table 5
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
(post-dose results blinded as 
described in footnote 1)
RBC Count
MCV
WBC
Neutrophils
Haemoglobin
MCH
Lymphocytes
Haematocrit
Monocytes 
Eosinophils 
Basophils 
Clinical 
Chemistry 
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
(fasted at 
screening)
Calcium
Alkaline phosphatase
Albumin
Magnesium
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination and UACR (if blood or protein is 
abnormal [evidence of microalbuminuria or haematuria of ≥ 1+])
Other tests

hsCRP
Other 
Screening 
Tests

HIV

Hepatitis B (HBsAg; in Germany only, anti-HBc will also be tested 
[Appendix 8])

Hepatitis C (Hep C antibody)

FSH and estradiol (if required to confirm postmenopausal status)

Alcohol, cotinine and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)
Abbreviations:  ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST 
(SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); BUN = blood urea 
nitrogen; FSH = follicle stimulating hormone; HBsAg = hepatitis B surface antigen; anti-HBc = hepatitis B 
core antibody; hsCRP = highly sensitive C-reactive protein; MCH = mean corpuscular haemoglobin; MCV 
= mean corpuscular volume; RBC = red blood cell; UACR = urinary albumin-creatinine ratio; WBC = 
white blood cell, pH= hydrogen ion concentration.
1.
The following post-dose results will be blinded to Investigators and blinded Sponsor 
representatives:  total WBCs; absolute and percentage eosinophils; and percentage neutrophils, 
lymphocytes, monocytes and basophils.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within the defined in clinic follow up periods 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.


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7.3.7.
Lung function tests
FEV1, FVC and PEF will be measured, as described in the SRM.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples for determination of GSK3511294 plasma concentration will be collected 
at the time points indicated in Table 4.
The actual date and time of each blood sample collection will be recorded.  The timing of 
PK samples may be altered and/or PK samples may be obtained at additional time points 
to ensure thorough PK monitoring.  
Processing, storage and shipping procedures are provided in the appropriate lab manual. 
7.4.2.
Sample Analysis
Plasma analysis will be performed under the control of Platform Technology and Science 
(PTS), GlaxoSmithKline, the details of which will be included in the SRM.
Concentrations of GSK3511294 will be determined in plasma samples using the currently 
approved bioanalytical methodology. Raw data will be archived at the bioanalytical site 
(detailed in the SRM).
Once the plasma has been analysed for parent compound any remaining plasma may be 
analysed for other compound-related material and the results reported under a separate 
PTS, GlaxoSmithKline protocol.
7.5.
Immunogenicity
Samples for testing binding antibodies against GSK3511294 will be collected at the time 
points indicated in the Time and Events Tables. The actual date and time of each blood 
sample collection will be recorded.  Processing, storage and shipping procedures are 
provided in the SRM. 
Sample analysis will be performed under the control of PTS, GlaxoSmithKline.  The 
presence of anti-GSK3511294 binding antibodies will be determined in serum samples 
using a validated bioanalytical method, which includes a screening assay, confirmation 
assay and titre analysis.  If necessary, further immune response characterization may be 
performed as needed.
7.6.
Circulating Immune Complexes
Samples for circulating immune complexes (CIC) will be collected at the time points 
indicated in the Time and Events Tables. The actual date and time of each blood sample 
collection will be recorded.  Processing, storage and shipping procedures are provided in 
the SRM. 


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Sample analysis will be performed under the control of PTS, GlaxoSmithKline.  The 
presence of CICs will be determined in serum samples using a validated bioanalytical 
assay, using immunoglobulin detection.  Further characterization with drug specific 
detection may be performed as needed.
7.7.
Complement, IgE and inflammatory markers
Blood samples will be collected during the study to measure complement (C3 and C4) 
and total IgE.  Assessments will be performed by a central laboratory.
Inflammatory markers at screening will comprise Tumour necrosis factor-alpha (TNF-α), 
IL-2, IL-6, IL-10, Interferon-gamma (IFN-γ) and C3a.  A screening serum sample will 
also be stored for assay of Antinuclear antibodies (ANA), Anti-neutrophil cytoplasmic 
antibody (ANCA) and anti-DNA antibodies, if required at a later date based on 
symptoms.  After dosing, additional inflammatory markers and tests will be considered 
on an ad hoc basis should there be clinical concerns regarding an immune mediated AE 
(see Section 5.4.2 and Appendix 3).
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
7.8.
Pharmacodynamic and Exploratory Markers
7.8.1.
Pharmacodynamic Biomarkers
Serum samples will be collected during this study to measure total IL-5 levels as a 
marker of target engagement.  Additionally, blood eosinophil levels will be measured as 
part of the haematology panel as a marker of pharmacological response.  Samples will be 
collected at the time points indicated in Section 7.1, Time and Events Tables. The timing 
of the collections may be adjusted on the basis of emerging PK or PD data from this 
study or other new information in order to ensure optimal evaluation of the biomarker 
endpoints.
7.8.2.
Exploratory Biomarkers of Asthma
Serum samples will be collected during this study and may be used for the purposes of 
measuring biomarkers to identify factors that may influence the development of asthma 
and/or medically related conditions or the development of asthma treatments, as well as 
the biological and clinical responses to GSK3511294.  Samples will be collected at the 
time points indicated in Section 7.1, Time and Events Table. 
All exploratory biomarker samples will be retained for a maximum of 15 years after the 
last participant completes the trial.
7.9.
Genetics
Information regarding genetic research is included in Appendix 4.  Participant 
participation is optional. Participants who do not wish to participate in the genetic 
research may still participate in the study.


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8.
DATA MANAGEMENT

For this study participant data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

AEs and concomitant medications terms will be coded using MedDRA and an 
internal validated medication dictionary, GSK Drug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Participant initials 
will not be collected or transmitted to GSK according to GSK policy.

Participant initials and full date of birth will not be collected in the CRF or 
transmitted to GSK, according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
Given this study is the FTIH for GSK3511294, there are no formal statistical hypotheses 
to be tested.  The assessment of safety and tolerability of single SC doses of 
GSK3511294 in this study will not include any formal comparisons.  For the 
pharmacokinetic and pharmacodynamic data, where appropriate, an estimation approach 
will be adopted and point estimates with corresponding confidence intervals will be 
provided.  In addition, for the analysis of blood eosinophils, posterior means and 
corresponding 95% credible intervals will be constructed for each dose and time point. 
Furthermore, posterior probabilities that the placebo adjusted ratio is less than various 
thresholds of interest will be constructed.
9.2.
Sample Size Considerations
No formal statistical techniques were used to calculate the sample size for this study.  The 
number of participants included is primarily determined by feasibility and is deemed an 
adequate number to provide an assessment of safety and tolerability, pharmacokinetics 
and pharmacodynamic measurements, and thereby to allow progression to larger clinical 
studies.  More participants are planned in cohorts to be given doses in the expected 
therapeutic range to gain more information on those dose levels.
9.2.1.
Sample Size Assumptions
Although the sample size is not based on statistical criteria, general probabilities can be 
determined on the likelihood of seeing adverse events.  For example, with 6 participants 
receiving each dose of active drug, if the true adverse outcome rate is 5%, the chance of 
seeing at least one adverse outcome at a given dose is 26%.  Similarly, if the true adverse


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outcome rate is 20%, the chance of seeing at least one adverse outcome at a given dose is 
74%.  The corresponding figures for 9 participants with true event rates of 5% and 20% 
are 37% and 87%, respectively.  This level of predictivity is deemed adequate within this 
FTIH setting, prior to progression to larger studies.
9.2.2.
Sample Size Re-estimation or Adjustment
No formal sample size re-estimation will be performed.  However, upon ongoing review 
of data, it is possible that the size of a cohort may be increased. 
9.3.
Data Analysis Considerations
Statistical analysis will be performed by, or under the direct auspices of Clinical
Statistics, GlaxoSmithKline.
Complete details of the planned statistical analyses will be provided in the RAP.
9.3.1.
Analysis Populations
For purposes of analysis, the following populations are defined:

Screened:  All participants who were screened.

Safety:  All randomised participants who take at least 1 dose of study treatment. 
Participants will be analysed according to the treatment they actually received.

Pharmacokinetic:  Participants in the ‘Safety’ population for whom a 
pharmacokinetic sample was obtained and analysed.

Pharmacodynamic: Participants in the ‘Safety’ population for whom a post-dose 
pharmacodynamic (i.e. blood eosinophil) sample was obtained and analysed.
9.3.2.
Interim Analyses
In stream data review will occur during the study to support dose escalation decisions, 
and formal interim analyses are planned to ensure accumulated safety, PK and PD data 
are deemed sufficient to determine the doses and dosing interval to move forward into the 
next phase of development but is not expected to affect the progression of this FTIH 
study.
Currently, the first interim analysis is projected to occur once data is available at the 
12-week time point after dosing in Cohort 4 (planned 100 mg dose).  The primary focus 
of this interim analysis will be reduction in blood eosinophil counts.  The ratio to baseline 
will be derived for each dose and time point and will be compared to corresponding data 
from the placebo arm.  Posterior means and corresponding 95% credible intervals will be 
constructed for each of the available doses and time points. Furthermore, posterior 
probabilities that the placebo adjusted ratio is less than various thresholds of interest will 
be constructed. 
The earliest next interim analysis is planned no earlier than once data is available at the 
26-week time point after dosing Cohort 4 (planned 100 mg dose).  The primary focus of 


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this and potential subsequent interim analyses will be the same as the first interim 
analysis (described above).
The interim analyses will be performed by GSK Clinical Statistics and only the 
responsible statistician (and Quality control [QC] statistician) and the CPMS 
representative will have access to individual participant data.  However, the findings of 
the interim analyses will be shared with the entire GSK study team. 
9.4.
Key Elements of Analysis Plan
On-going PK analyses will be performed on plasma concentration-time data available 
prior to dose escalation decisions in subsequent cohorts.  
For these on-going analyses, plasma concentration-time data will be analysed by 
non-compartmental methods using nominal times.  The decision to proceed to higher 
doses will be made by the Dose Escalation Committee based on assessment of 
safety/tolerability and PK data at lower dose levels, together with any available PD data 
if deemed appropriate. 
9.4.1.
Primary Analyses
All safety analyses will be performed on the Safety Population.  Safety data will be 
presented in tabular and/or graphical format and summarised descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards.
9.4.2.
Secondary Analyses
All pharmacokinetic analyses will be conducted on the Pharmacokinetic Population.
9.4.2.1.
Raw Plasma PK Concentrations
Blood sampling time will be related to the start of dosing.  Linear and semi-logarithmic 
individual plasma concentration-time profiles and mean and median profiles by 
GSK3511294 dose will be plotted. Plasma concentrations of GSK3511294 will be listed 
and summarised by dose and nominal time.
9.4.2.2.
Derived Plasma Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation Department, QSci, GSK. Plasma concentration-time data for 
GSK3511294 will be analysed by non-compartmental methods according to 
GlaxoSmithKline guidance document, GUI_00000051487 and using WinNonlin.
Calculations will be based on the actual sampling times recorded during the study.
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit, for each dose of GSK3511294 and for each participant:

Cmax


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
tmax

AUC(0-t), AUC(0-week4), AUC(0-week12) AUC(0-week26) and AUC(0-∞)

%AUCextrapolated

tlast

CL/F

Vd/F

λz

the number of points used to determine λz

t1/2
Pharmacokinetic data will be presented in graphical and/or tabular form and will be listed 
and summarised descriptively by treatment group.
All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline 
Pharmaceuticals, Research and Development (R&D).
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Clinical Statistics, GlaxoSmithKline.
Assessment of Dose Proportionality
An initial assessment of dose proportionality will be explored for AUC(0-∞) and Cmax 
following single SC doses of GSK3511294 using graphical presentations, if data permits.  
Further exploratory statistical analysis to assess dose proportionality may be performed, 
to be detailed in the Reporting Analysis Plan (RAP).
9.4.2.3.
Blood eosinophil count
Blood eosinophil count will be log transformed prior to analysis and the ratio to baseline 
for each dose and time point will be summarised using appropriate descriptive statistics 
and will be compared to corresponding data from the placebo arm.  The primary intent 
will be to analyse this data by fitting a Bayesian dose response model. The 4-parameter 
Emax model will be fitted by first intent; however, should the data not allow for a 
suitable model fit, then other models may be attempted. Posterior means and 
corresponding 95% credible intervals will be constructed for each dose and time point. 
Furthermore, posterior probabilities that the placebo adjusted ratio is less than various 
thresholds of interest will be constructed. 
9.4.3.
Pharmacokinetic/Pharmacodynamic Analyses
The relationship between plasma concentration and blood eosinophil count after single 
subcutaneous doses of GSK3511294 will be explored, if data permits, by population PK 
methods using for example an indirect response model.  Full details of the analysis to be 
performed will be provided in the RAP.


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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 enrolment of participants begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH GCP, all applicable participant 
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 favourable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained and available for each participant prior 
to participation in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments 
is being deferred and the study, with the exception of the optional assessments, can 
be initiated.


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10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of participants are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues or 
severe non-compliance. For multicentre 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.


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
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for those 
required by local regulations to be maintained elsewhere), in a safe and secure 
location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator must 
ensure there is an acceptable back-up of these reproductions and that an acceptable 
quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly 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 


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opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study participants, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.  The procedures and timing for public 
disclosure of the results summary and for development of a manuscript for publication 
will be in accordance with GSK Policy.


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11.
REFERENCES
Corren J. Inhibition of Interleukin-5 for the Treatment of Eosinophilic Diseases. Discov. 
Med. 2012;13(71):305-312. 
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention. www.ginaasthma.org. 2017;1:1-155. 
Kovalszki A, Weller PF. Primary Care: Clinics in Office Practice. Eosinophilia. 
2016;43(4):607-617. 
Legrand F, Klion AD. Biologic therapies targeting eosinophils: current status and future 
prospects. J Allergy Clin Immunol Pract. 2015;3(2):167-174. 
Pollanen P, Cooper TG. Vascular permeability to effectors of the immune system in the 
male rat reproductive tract at puberty. J Reprod Immunol. 1995;28(2):85-109. 
Pollanen P, Setchell BP. Microvascular permeability to IgG in the rat testis at puberty. Int 
J Androl. 1989;12(3):206-218. 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson 
JL, Ip MS, Zheng J, Stocks J; ERS Global Lung Function Initiative. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-1343. 
Setchell BP, Waites GMB. The blood-testis barrier. In: Hamilton DW, Greep RO, editor. 
The Handbook of Physiology, Section 7, Vol. V. Male Reproductive System. Washington, 
DC:American Physiological Society, 1975:143-172. 
Setchell BP. La barriere sang-testicule. Andrologie. 2001;11:15-20. 
Sohn W, Lee E, Kankam MK, Egbuna O, Moffat G, Bussiere J, Padhi D, Ng E, Kumar S, 
Slatter JG. An open-label study in healthy men to evaluate the risk of seminal fluid 
transmission of denosumab to pregnant partners. British Journal of Clinical 
Pharmacology. 2015;81(2):362-369. 
Vargas HM, Amouzadeh HR, Engwall MJ. Nonclinical strategy considerations for safety 
pharmacology: evaluation of biopharmaceuticals. Expert Opinion on Drug Safety. 
2013;12:91-102. 


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12.
APPENDICES
12.1.
Appendix 1:  Abbreviations and Trademarks
Abbreviations
ACT
Asthma Control Test
ADA
Anti-drug antibody
AE
Adverse Event
ALT
Alanine aminotransferase
AMD
Age-related macular degeneration
ANA
Antinuclear antibodies
ANCA
Anti-neutrophil cytoplasmic antibody
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under concentration-time curve
AUC(0-∞)
Area under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time
%AUCex
Percentage of AUC(0-) obtained by extrapolation
AUC(0-t)
Area under the concentration-time curve from time zero 
(pre-dose) to last time of quantifiable concentration 
within a participant across all treatments
AUC(0-Week x)
Area under the concentration-time curve from time zero 
to Week x
Anti-HBc
Hepatitis B core Antibody
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
CI
Confidence interval
CIC
Circulating immune complex
CFC
Chorofluorocarbonate
CL
Clearance
CL/F
Apparent clearance following subcutaneous dosing
cm
Centimeter
Cmax
Maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacology Modelling and Simulation
CRF
Case Report Form
CRP
C-reactive protein
Ctrough
Lowest concentration of a drug just before the next dose
CV
Cardiovascular
DEC
Dose Escalation Committee
DNA
Deoxyribonucleic acid
DPI
Dry Powder inhaler
EC50
Half maximal effective concentration
ECG
Electrocardiogram


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eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
ESR
Erythrocyte sedimentation rate
FAAN
Food Allergy and Anaphylaxis Network
FEV1
Forced expiratory volume in 1 second
FSH
Follicle stimulating hormone
FTIH
First Time in Humans
FVC
Forced vital capacity
g
Grams 
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GINA
Global Initiative for Asthma 
GSK
GlaxoSmithKline
h
Hours
HBsAg
Hepatitis B Surface Antigen
HFA
Hydrofluoroalkane propellant
HIV
Human immunodeficiency virus
HPLC
High-performance liquid chromatography
HRT
Hormone replacement therapy
hsCRP
High sensitivity C-reactive protein
IB
Investigator’s Brochure
ICH
International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
ICS
Inhaled corticosteroid
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IFN-γ
Interferon-gamma
Ig
Immunoglobulin 
IgG1
Immunoglobulin G1
IgE
Immunoglobulin E
IgM
Immunoglobulin M
IL
Interleukin
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
ISR
Injection site reactions
IV
Intravenous
kDa
kilodalton
kg
kilogram
L
Litre
LABA
Long acting -agonist
LAMA
Long acting muscarinic antagonist 
LAMBDAz
Terminal phase rate constant 
LDH
Lactate dehydrogenase
LTRA
Leukotriene receptor antagonist


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mAb
Monoclonal antibody
MCH
Mean corpuscular haemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Millilitres
mm Hg
Millimetre of mercury
mol
Mole
MSDS
Material Safety Data Sheet
msec
Milliseconds
NIAID
National Institute of Allergy and Infectious Disease
NOAEL
No Observed Adverse Effect Level
PCR
Polymerase chain reaction
PD
Pharmacodynamics
PEF
Peak expiratory flow
pH
Hydrogen ion concentration
PK
Pharmacokinetics
PTS
Platform Technology and Science
QC
Quality control
QTcF
QTc corrected by Fridericia’s formula
R&D
Research and Development
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RNA
Ribonucleic acid
SABA
Short acting -agonist
SAE
Serious Adverse Event
SC
Subcutaneous
SGPT
Serum glutamic pyruvic transaminase
SGOT
Serum glutamic oxaloacetic transaminase
SRM
Study Reference Manual
t
Time of last observed quantifiable concentration
t½
Terminal phase half-life
TK
Toxicokinetics
tlast
Time of last quantifiable concentration
tmax
Time of occurrence of Cmax
TNF-α 
Tumour necrosis factor-alpha
TTS
Study Specific Technical Terms of Supply 
Agreement/Memo
UACR
Urinary albumin-creatinine ratio 
UK
United Kingdom
ULN
Upper Limit of Normal
Vd/F
Apparent volume of distribution after subcutaneous 
administration
WBC
White blood cell
W/V
Weight/volume
μL
Microlitre


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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
WinNonlin


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12.2.
Appendix 2:  Liver Safety Required Actions and Follow up 
Assessments
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 participant until liver chemistries 
resolve, stabilise, or return to within baseline (see 
MONITORING below)

Viral hepatitis serology3

Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show 
downward trend

Obtain blood sample for 
pharmacokinetic (PK) analysis, 
obtained within a week of meeting 
increased liver monitoring criteria4

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia 
Note:The mechanism of action of 
GSK3511294 leads to lowering of 
eosinophils.  Investigators should be 
blinded to those results, unless 
unblinding is required for participant 
safety.

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 


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acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
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 hours

Monitor participants 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:
1.
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within 24-72 hours 

Monitor participants weekly until liver chemistries 
resolve, stabilise or return to within baseline
If ALT≥3xULN AND bilirubin 2xULN 
or INR >1.5:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct High-
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week [James, 2009]). 

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 (excluding 
studies of hepatic impairment or cirrhosis).
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.
PK sample may not be required for participants known to be receiving placebo. Record the date/time of the PK 
blood sample draw and the date/time of the last dose of study treatment prior to blood sample draw on the CRF. If 
a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for 
sample handling and shipping are in the appropriate lab manual. 
12.2.1.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.3.
Appendix 3: Investigations and management in the event of 
immune related adverse events or relevant clinical concern
The early recognition of immune-related AEs and initiation of treatment are important in 
reducing the clinical impact, as the majority of these AEs are reversible with the use of 
steroids and other immunosuppressants; however, the symptoms and clinical features are 
often non-specific and heterogenous in regards to the time course over which they 
develop, organ involvement and indeed the constellation of symptoms and severity.  The 
precise management will depend on the clinical evaluation at the time of presentation and 
ongoing assessment including consideration of relevant differential diagnoses.  Given 
that there is often a differential for presenting symptoms such as infection, and indeed 
such factors may also precipitate immune related adverse events, these factors should be 
given due consideration and ruled out, especially as infection may be at risk of 
deterioration with empirical immunosuppression.
If an immune-related AE is suspected, the participant should contact the study site as 
soon as possible, instead of waiting for his/her next scheduled visit.  A thorough 
evaluation should be conducted in an effort to properly diagnose an immune-related AE 
and rule out other potential causes (infectious, neoplastic, metabolic, toxic).  Serological, 
immunological, and histological (biopsy) data should be considered to support the 
diagnosis and consultation with the GSK medical monitor, and an appropriate medical 
specialist should be considered when investigating a possible immune-related AE.
PK, ADA and CIC samples will be taken at the time of the event and samples will be 
taken for additional biomarkers in the setting of clinical concern regarding the possibility 
of immune complex disease; suggested additional samples will comprise coagulation 
parameters (Activated partial thromboplastin time [APTT] and INR), Erythrocyte 
sedimentation rate (ESR) and C3a, should there be clinical features as indicated in 
Section 5.4.2.  Furthermore, samples for ANA, ANCA and anti-DNA antibodies will be 
taken as biomarkers of autoimmune disease and these same antibodies will be measured 
on frozen serum samples taken and stored before dosing to identify any interval change. 
Other possible causative or differential factors for abnormal clinical or laboratory 
observations will also be investigated including testing to exclude infection. Suspected 
immune complex disease should be reported as an AE or SAE, whichever appropriate, 
within 24 hours as indicated in Section 5.4.2.
Where no alternative cause is established in the setting of inflammatory signs and/ or 
symptoms, or there be ongoing clinical concern, the patient will be referred to a specialist 
for further management. In the setting of clinically relevant pathology, target organ 
biopsy should be considered after consultation with an appropriate clinical specialist.  
Specifically, given the relative ease of performing a skin biopsy, if a rash is observed, 
consultation with a dermatologist with a view to performing skin biopsies should be 
considered.    


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12.4.
Appendix 4:  Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including GSK3511294 or any concomitant medicines;

Asthma susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilise data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a RAP prior to initiation of the 
analysis. Planned analyses and results of genetic investigations will be reported either as 
part of the clinical RAP and study report, or in a separate genetics RAP and report, as 
appropriate.
Study Population
Any participant who is enrolled in the study can participate in genetic research.  Any 
participant who has received an allogeneic bone marrow transplant must be excluded 
from the genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 


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identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 mL blood sample will be taken for DNA extraction. A blood sample is collected 
after the participant has been dosed and provided informed consent for genetic 
research. Instructions for collection and shipping of the genetic sample are described 
in the laboratory manual. The DNA from the blood sample may undergo quality 
control analyses to confirm the integrity of the sample. If there are concerns 
regarding the quality of the sample, then the sample may be destroyed. The blood 
sample is taken on a single occasion unless a duplicate sample is required due to an 
inability to utilise the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the participant by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last 
participant completes the study, or GSK may destroy the samples sooner.  GSK or those 
working with GSK (for example, other researchers) will only use samples collected from 
the study for the purpose stated in this protocol and in the informed consent form.  
Samples may be used as part of the development of a companion diagnostic to support 
the GSK medicinal product.
Participants can request their sample to be destroyed at any time.
Informed Consent
Participants who do not wish to participate in the genetic research may still participate in 
the study.  Genetic informed consent must be obtained prior to any blood being taken.
Participant Withdrawal from Study
If a participant who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the participant will be 
given a choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a participant withdraws consent for genetic research or requests sample destruction for 
any reason, the investigator must complete the appropriate documentation to request 
sample destruction within the timeframe specified by GSK and maintain the 
documentation in the site study records. 


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Genotype data may be generated during the study or after completion of the study and 
may be analysed during the study or stored for future analysis. 

If a participant withdraws consent for genetic research and genotype data has not 
been analysed, it will not be analysed or used for future research.  

Genetic data that has been analysed at the time of withdrawn consent will continue to 
be stored and used, as appropriate. 
Provision of Study Results and Confidentiality of Participant’s Genetic Data
GSK may summarise the genetic research results in the clinical study report, or separately 
and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the 
participant, family members, insurers, or employers of individual genotyping results that 
are not known to be relevant to the participant’s medical care at the time of the study, 
unless required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
Reference
Chen H, Yu K-D, Xu G-Z.  Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis.  PLOS ONE.  2012;7:e42464.
Gorin MB.  Genetic insights into age-related macular degeneration: controversies 
addressing risk, causality, and therapeutics.  Mol Aspects Med.  2012;33:467-86.


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12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events 
12.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a participant, 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 unfavourable 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 (haematology, 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 participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is 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.
12.5.2.
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 
participant was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are AEs.  
If a complication prolongs hospitalization or fulfils 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, diarrhoea, 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 jeopardise 
the participant 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 
participants 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
12.5.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization


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12.5.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in the 
CRF

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all participant identifiers, with the exception of 
the participant 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.

Participant-completed Value Evidence and Outcomes questionnaires and the 
collection of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.5.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the participant, 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 utilised 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.


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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 IB and/or Product Information, for marketed 
products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
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 participant dies during participation in the study or during a recognised 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.


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12.5.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable, the site will use the paper SAE data collection 
tool in order to report the event within 24 hours  and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the Electronic case report form (eCRF) page 
within 72 hours of submission of the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the site can report this information on a paper SAE form or to the 
Medical Monitor or the SAE coordinator] 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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12.6.
Appendix 6: Modified List of Highly Effective Methods of 
Contraception for post-menopausal females, who are taking 
Hormone Replacement Therapy, and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
Women in the following categories are not considered to be Woman of Childbearing 
Potential
1.
Premenarchal
2.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female participants
Post-menopausal females, under 60 years of age, who are taking HRT and have not had 
their menopausal status confirmed, must use one of the follow methods of contraception, 
from dosing until the final visit.
1.
Male partner sterilization with documentation of azoospermia prior to the female 
participant's entry into the study, and this male is the sole partner for that participant 
[Hatcher, 2011]. The documentation on male sterility can come from the site 


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personnel’s: review of participant’s medical records or medical history interview 
provided by her or her partner.
The investigator is responsible for ensuring that participants understand how to properly 
use these methods of contraception.
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
2 weeks of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 5. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 

Any female participant who becomes pregnant while participating will continue to 
attend all follow-up visits.
12.6.1.
References
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50. Table 3-2.


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12.7.
Appendix 7:  Asthma Control Test
Country-specific, commercially available versions of the ACT will be used.


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12.8.
Appendix 8:  Country Specific Requirements
12.8.1.
Additional Hepatitis B Core Antibody test for inclusion of 
participants in Germany
In order to comply with German requirements for Hepatitis B virus testing in Germany, 
participants will be tested for the hepatitis B core antibody (anti-HBc) at screening.  The 
German-specific exclusion criterion 5 is as follows:
Positive for hepatitis B surface antigen (HBsAg) and core antibody (anti-HBc) at 
screening.
Table 5 has been updated accordingly.
12.8.2.
Additional In-patient stay period for participants from Germany
In Germany, participants will remain in-patient for a minimum of 8 days post dosing, as 
noted in Section 4.2, Section 4.7.1, Section 7.1.  For clarity, the time and events table for 
Germany is provided below.


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12.8.2.1.
Time and Events Table
Procedure
Pre-
Screen 1
Screen 
2
In-patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2 Day 3 Day 4
Week
NA
1
NA
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
9
15
29
57
85
127 169 183
225 5
253 5
281 5
Informed consent
X 6
Pre-screening 
Blood eosinophils 
X 7
Inclusion & 
exclusion criteria
X
X
X
Demography
X
Medical history 10
X
Concomitant 
medication
HIV, Hep B and 
Hep C screen 
X
FSH and 
estradiol 8
X
Pregnancy test 9
X
X
X
X
X
X
X
X 5
X 5
X 5
Drug, alcohol and
cotinine screen
X
X
Genetic sample
X 11
Administer IP
X
ACT 12
X
X
X
X 5
X 5
X 5
Height, weight 
and BMI
X 13
X 13
X 5,13
X 5,13
X 5,13
Full phys exam
X
X 5
X 5
X 5
Brief phys exam
X
X
X
X
X
Dispense rescue 
SABA
X
Resupply, as required.


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Procedure
Pre-
Screen 1
Screen 
2
In-patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2 Day 3 Day 4
Week
NA
1
NA
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
9
15
29
57
85
127 169 183
225 5
253 5
281 5
Haematology 
(including blood 
eosinophil count), 
Clin. Chem., 
Urinalysis and 
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Serum save (for 
immunological 
analysis, if 
needed)
X
Ad hoc, as required by symptoms – see Appendix 3.
Inflammatory 
markers
X
Ad hoc, as required by symptoms – see Appendix 3.
Complement (C3 
& C4)
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Total IgE
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
PK Blood 
Samples
See Table 4.
Immunogenicity
X
X
X
X
X
X
X
X
X 5
X 5
X 5
CICs
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
12-lead ECG 14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Vital signs 15
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
AE/SAE review 
(inc local ISR up 
to 72 h after 
dosing)
X 16
IL-5 sample
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Exploratory 
biomarkers of 
asthma in blood 
X
X
X
Spirometry
X
X
X
X
X
X
X
X 5
X 5
X 5
PEF Training 17
X


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Procedure
Pre-
Screen 1
Screen 
2
In-patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2 Day 3 Day 4
Week
NA
1
NA
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
9
15
29
57
85
127 169 183
225 5
253 5
281 5
PEF 17
X 17
Diary review 17
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Abbreviations:  ACT = Asthma Control Test; AE = adverse event; BMI = body mass index; CICs = circulating immune complexes; CRP = C-reactive protein; ECG = 
electrocardiogram; FSH = follicle stimulating hormone; h = hour(s); Hep B = Hepatitis B; Hep C = Hepatitis C; HIV = human immunodeficiency virus; IgE = 
immunoglobulin E; IL-5 = interleukin-5; IP = Investigational Product; ISR = injection site reactions; PEF = peak expiratory flow; PK = pharmacokinetic; SABA = 
short acting -agonist; SAE = serious adverse event.
Notes:
1.
Pre-screen up to 12 weeks before dosing.  Blood eosinophils must be ≥200 cells/µL for participants to proceed to screening.  Blood eosinophil count may be 
existing data or obtained at a pre-screen visit.
2.
Screening up to 4 weeks before randomisation.  Screening procedures may be done at one or more visits, within the screening window.
3.
All participants will be in-patient for at least 8 days after dosing.  
4.
Allowed time deviations will be documented in the Study Reference Manual.
5.
All participants will have all out-patient visits up to Week 26 after dosing.  Each cohort will also have out-patient visits after week 26, depending on the dose, as 
follows:  

2 and 10 mg:  Week 32 only

30 mg and 100 mg:  Week 36 only 

300 mg:  Weeks 32 and 40
(For unplanned dose levels, the timing of out-patient visits will be documented in a Note to File.) 
6.
Informed consent will be taken either at the pre-screen visit, for participants who don’t have an existing eosinophil count, or at screening, for those who do.
7.
Blood eosinophils will be included in the haematology panel at all time points other than the pre-screen visit.  
8.
If required to confirm postmenopausal status.
9.
Women on hormone replacement therapy, whose post-menopausal status cannot be confirmed, only.
10. Including cardiovascular (CV) disease, asthma exacerbation, and drug, alcohol and smoking history.
11. If the participant consents, an optional, genetic sample will be collected once during the study.  
12. At each applicable visit, ACT should be done before any other assessment.
13. Height at pre-screening or screening only.
14. ECGs triplicate at all time points.  ECGs should be time-matched to baseline (i.e. pre-dose on Day 1) from Day 2 onwards.
15. Blood pressure and heart rate in triplicate before dosing; single measurements after dosing.  Single temperature and respiratory rate measurements at all time 
points.
16. Only SAEs are collected before dosing (see Section 7.3.1).


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17. PEF will be recorded in the evening before bedtime on the day of the screening visit, then twice each day (once in the morning upon waking and once in the 
evening before bedtime) from the day after screening until the end of the study.  Training of the participant in how to take measurements will occur at screening.  
PEF measurements will be taken and results will be recorded by the site while the participant is in-patient at the clinical site (ie from the evening of Day –1 until 
the morning of discharge).  At all other time points, the participant will record their PEF as instructed, on their diary card, along with any rescue medication use 
and adverse events.  Site staff will review the diary cards at each out-patient Visit.


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12.9.
Appendix 9:  Anaphylaxis Criteria
Joint National Institute of Allergy and Infectious Disease (NIAID)/ Food Allergy and 
Anaphylaxis Network (FAAN) Second Symposium on Anaphylaxis [Sampson, 2006].  
The criteria do not make a distinction based on underlying mechanism. These criteria are 
summarised as follows:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalised hives, pruritus or flushing, swollen 
lipstongue-uvula), and at least one of the following:
a) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)
b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(e.g., hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)
b) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)
c) Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)
d) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):
a) Adults:  systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline
12.9.1.
References
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson Jr NF, Bock SA, Branum A et 
al. Second symposium on the definition and management of anaphylaxis: summary 
report—Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117:391-397.


2 0 1 6 N 2 7 0 5 2 9 _ 0 6
C O N FI D E N TI A L
2 0 5 7 2 2
9 5
1 2. 1 0.
A p p e n di x 1 0: Pr ot o c ol C h a n g e s
1 2. 1 0. 1.
Pr ot o c ol A m e n d m e nt 1
Pr ot oc ol A me n d me nt 1 a p plies t o all sites.  
Descri pti o n of c h a n ges
C h a n ge 1:  Me dic al M o nit or/ S A E C o nt act I nf or m ati o n:  Sec o n d ar y Me dic al 
M o nit or
C h a n ge fr o m: 
R ol e
N a m e
D a y Ti m e P h o n e 
N u m b er a n d e m ail 
a d dr e s s
Aft er -h o ur s 
P h o n e/ C ell/
P a g er N u m b er
F a x 
N u m b er
Sit e A d dr e s s
S ec o n d ary 
M e dic al 
M o nit or
G S K
G u n n els W o o d 
R o a d
St ev e n a g e 
H ertf or ds hir e
S G 1 2 N Y 
U K
T o: 
R ol e
N a m e
D a y Ti m e P h o n e 
N u m b er a n d e m ail 
a d dr e s s
Aft er -h o ur s 
P h o n e/ C ell/
P a g er N u m b er
F a x 
N u m b er
Sit e A d dr e s s
S ec o n d ary 
M e dic al 
M o nit or
G S K
G u n n els W o o d 
R o a d
St ev e n a g e
H ertf or ds hir e
S G 1 2 N Y 
U K
R ati o n ale:   
P P D
t o c orrect t he sec o n dar y Me dical M o nit or’s e mail a d dress
P P D
P P D
P P D
P P D
P P D


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Change 2:  Section 7.1, Time and Events Table, Inflammatory markers sample collection row
Change from: 
Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Outpatient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 
5
253 5
281 5
Inflammatory 
markers
X
Ad hoc, as required by symptoms – see Appendix 3.
To: 
Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Outpatient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 
5
253 5
281 5
Serum save (for 
immunological 
analysis, if 
needed)
X
Ad hoc, as required by symptoms – see Appendix 3.
Inflammatory 
markers
X
Ad hoc, as required by symptoms – see Appendix 3.
Rationale:  to clarify blood sampling needed for inflammatory markers


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Change 3:  Section 7.7, Complement, IgE and inflammatory markers, Paragraph 2
Change from: 
Inflamatory markers at screening will comprise Tumour necrosis factor-alpha (TNF-α), 
IL-2, IL-6, IL-10, Interferon-gamma (IFN-γ), C3a/C3d, Antinuclear antibodies (ANA), 
Anti-neutrophil cytoplasmic antibody (ANCA) and anti-DNA antibodies.  After dosing, 
additional inflammatory markers and tests will be considered on an ad hoc basis should 
there be clinical concerns regarding an immune mediated AE (see Section 5.4.2 and 
Appendix 3).
To: 
Inflamatory markers at screening will comprise Tumour necrosis factor-alpha (TNF-α), 
IL-2, IL-6, IL-10, Interferon-gamma (IFN-γ) and C3a.  A screening serum sample will 
also be stored for assay of Antinuclear antibodies (ANA), Anti-neutrophil cytoplasmic 
antibody (ANCA) and anti-DNA antibodies, if required at a later date based on 
symptoms.  After dosing, additional inflammatory markers and tests will be considered 
on an ad hoc basis should there be clinical concerns regarding an immune mediated AE 
(see Section 5.4.2 and Appendix 3).
Rationale:  to correct the markers to be measured at screening and those for which 
samples will be taken and stored for analysis later in the study, if required
12.10.2.
Protocol Amendment 2
Protocol Amendment 2 applies to all sites.  
Description of changes
Change 1:  Section 4.3, Dose Escalation, PK stopping criterion
Change from: 

The dose will be increased only if safety and tolerability at previous dose levels are 
acceptable, and also if the predicted exposure (mean Cmax and mean AUC) at the next 
dose level does not exceed exposure observed at the NOAEL in monkey in the 26 
week toxicity study (100 mg/kg).
mean Cmax:  1390 µg/mL
mean AUC0–2016   1120000 µg.h/mL
To: 

The dose will be increased only if safety and tolerability at previous dose levels are 
acceptable, and also if the predicted exposure (upper 95% prediction interval for 
Cmax and AUC) at the next dose level does not exceed the mean exposure observed at 
the NOAEL in monkey in the 26 week toxicity study (100 mg/kg).
mean Cmax:  1390 µg/mL
mean AUC0–2016   1120000 µg.h/mL


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Rationale:  the MHRA commented that the use of mean PK data for a stopping criterion 
is unacceptable and this should be amended in the protocol to the maximum clinical 
exposure in an individual subject.  As the study is using a parallel design, it is not 
possible to predict the exposure (Cmax and AUC) at the next dose level for a particular 
individual, so the upper 95% prediction interval at the next dose was used instead.
Change 2:  Section 6.1, Investigational Product and Other Study Treatment, Study 
treatment table, Manufacturer/Source of procurement row
Change from: 
Study Treatment
Product name:
GSK3511294 Injection, 150 mg/mL
0.9% w/v Sodium Chloride 
Injection (placebo)
Manufacturer/ Source 
of procurement:
GSK
Provided by trial site
To: 
Study Treatment
Product name:
GSK3511294 Injection, 150 mg/mL
0.9% w/v Sodium Chloride 
Injection (placebo)
Manufacturer/ Source 
of procurement:
GSK
Locally sourced by trial site
Rationale:  to clarify that saline for placebo will be an EU licensed product sourced 
locally by sites.
12.10.3.
Protocol Amendment 3 – Protocol changes for Amendment 03
(04-SEP-2017), from amendment 02 (04-Aug-2017)
Protocol Amendment 3 applies to all sites.
Description of changes
Change 1:  Synopsis, Rationale
Change from:
GSK3511294 is a humanised monoclonal antibody (Immunoglobulin G1 [IgG1], kappa) 
antagonist of Interleukin (IL)-5 with an extended pharmacology.  It blocks IL-5 binding 
to the IL-5 receptor complex, causing a reduction in the circulating population of 
eosinophils.  Two antagonists of IL-5, mepolizumab and reslizumab, are approved in 
severe eosinophilic asthma, as an add-on treatment administered every 4 weeks.  
GSK3511294 is expected to confer efficacy over a dosing interval of up to 6 months.  
This single ascending dose first time in humans (FTIH) study will investigate safety, 
tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of 
GSK3511294, administered subcutaneously in participants with mild to moderate asthma 
maintained on a low–medium daily dose of inhaled corticosteroids (ICS) or ICS/long 


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acting -agonist (LABA), and short acting -agonist (SABA)..  To facilitate the 
investigation of blood eosinophil counts following single doses of GSK3511294, eligible 
participants will have a blood eosinophil count of ≥200 cells/μL at screening.  This 
should enable a quantification of the prolonged blood eosinophil reduction that is 
anticipated in humans resulting from the combination of the extended half-life and 
greater affinity to IL-5 of GSK3511294.
To:
GSK3511294 is a humanised monoclonal antibody (Immunoglobulin G1 [IgG1], kappa) 
antagonist of Interleukin (IL)-5 with an extended pharmacology.  It blocks IL-5 binding 
to the IL-5 receptor complex, causing a reduction in the circulating population of 
eosinophils.  Two antagonists of IL-5, mepolizumab and reslizumab, are approved in 
severe eosinophilic asthma, as an add-on treatment administered every 4 weeks.  
GSK3511294 is expected to confer efficacy over a dosing interval of up to 6 months.  
This single ascending dose first time in humans (FTIH) study will investigate safety, 
tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of 
GSK3511294, administered subcutaneously in participants with mild to moderate asthma 
maintained on a low–medium daily dose of inhaled corticosteroids (ICS) or ICS/long 
acting -agonist (LABA), and short acting -agonist (SABA).  To facilitate the 
investigation of blood eosinophil counts following single doses of GSK3511294, eligible 
participants will have a blood eosinophil count of ≥200 cells/μL at screening.  This 
should enable a quantification of the prolonged blood eosinophil reduction that is 
anticipated in humans resulting from the combination of the extended half-life and 
greater affinity to IL-5 of GSK3511294.
Rationale:  to correct a typographical error.
Change 2:  Synopsis, Treatment Arms and Duration
Change from:

Blood eosinophils pre-screen and screening:  a blood eosinophils pre-screen 
assessment will be performed.  Participants are eligible to skip the blood eosinophils 
pre-screening visit and go directly to the screening visit, if they have a documented 
blood test result within 12 weeks before screening demonstrating a blood eosinophil 
level ≥ 200 cells/L.  Participants who fulfil the pre-screening criteria will then attend 
the clinic for a full screening visit.  Blood eosinophil level will be measured at 
screening to confirm eligibility.
To: 

Blood eosinophils pre-screen and screening:  a blood eosinophils pre-screen 
assessment will be performed.  Participants are eligible to skip the blood eosinophils 
pre-screening visit and go directly to the screening visit, if they have a documented 
blood test result within 12 weeks before dosing demonstrating a blood eosinophil 
level ≥ 200 cells/L.  Participants who fulfil the pre-screening criteria will then attend 


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the clinic for a full screening visit.  Blood eosinophil level will be measured at 
screening to confirm eligibility.
Rationale:  to correct an error.
Change 3:  Section 4.2, Treatment Arms and Duration
Change from:

Blood eosinophils pre-screen and screening:  It is anticipated that a high 
proportion of the defined asthma population may have blood eosinophil levels that 
do not meet the inclusion criteria of ≥200 eosinophil cells/L, therefore a blood 
eosinophils pre-screen assessment will be performed.  Participants are eligible to 
skip the blood eosinophils pre-screening visit and go directly to the screening visit, if 
they have a documented blood test result within 12 weeks before screening
demonstrating a blood eosinophil level ≥200 cells/L.  If blood eosinophil levels 
within the prior 12 weeks are not available, participants will provide written 
informed consent at a pre-screening visit followed by a pre-screen assessment of 
blood eosinophil level.  Participants who fulfil the pre-screening criteria will then 
attend the clinic for a full screening visit.  Blood eosinophil level will be measured at 
screening to confirm eligibility.
To: 

Blood eosinophils pre-screen and screening:  It is anticipated that a high 
proportion of the defined asthma population may have blood eosinophil levels that 
do not meet the inclusion criteria of ≥200 eosinophil cells/L, therefore a blood 
eosinophils pre-screen assessment will be performed.  Participants are eligible to 
skip the blood eosinophils pre-screening visit and go directly to the screening visit, if 
they have a documented blood test result within 12 weeks before dosing
demonstrating a blood eosinophil level ≥200 cells/L.  If blood eosinophil levels 
within the prior 12 weeks are not available, participants will provide written 
informed consent at a pre-screening visit followed by a pre-screen assessment of 
blood eosinophil level.  Participants who fulfil the pre-screening criteria will then 
attend the clinic for a full screening visit.  Blood eosinophil level will be measured at 
screening to confirm eligibility. 
Rationale:  to correct an error.
Change 4:  Section 5.4.2, Criteria for follow up of potential Type III 
Hypersensitivity/ Immune Complex Disease
Change from:

urinary albumin-creatinine ratio > 3 mg/mol in the absence of a urinary tract 
infection


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To:

urinary albumin-creatinine ratio > 3 mg/mmol in the absence of a urinary 
tract infection
Rationale:  to correct an error in the units for urinary albumin-creatinine ratio.
Change 5:  Section 5.4.3.2, QTc criteria for increased monitoring of individual 
participants 
Change from:
Direct observation for 24 hours before discharge with 48 hour ambulatory Holter monitor 
and subsequent repeat assessment at 48 hours *.

QT or QTc change from baseline ≥ 60 msec and no clinical impact.  (Baseline is 
the average of triplcaite readings at pre-dose on Day 1.)

QTc > 500 msec or uncorrected QT > 600 msec and no clinical impact.
* To remain under observation if QT/QTc remains the same/increases on assessment at 
24 (end of direct observation) and 72 hours periods (after 48 hour Holter monitor) and for 
consideration of cardiology consult.
For participants with underlying bundle-branch block, follow the evaluation criteria 
listed below:

Baseline < 450 msec, increase monitoring at > 500 msec

Baseline between 450 to 480 msec, increase monitoring at ≥530 msec
To:
Direct observation for 24 hours before discharge with 48 hour ambulatory Holter monitor 
and subsequent repeat assessment at 48 hours *.

QT or QTc change from baseline ≥ 60 msec and no clinical impact.  (Baseline is 
the average of triplicate readings at pre-dose on Day 1.)

QTc > 500 msec or uncorrected QT > 600 msec and no clinical impact.
* To remain under observation if QT/QTc remains the same/increases on assessment at 
24 (end of direct observation) and 72 hours periods (after 48 hour Holter monitor) and for 
consideration of cardiology consult.
For participants with underlying bundle-branch block, follow the evaluation criteria 
listed below:

Baseline QTc < 450 msec, increase monitoring at QTc > 500 msec

Baseline QTc between 450 to 480 msec, increase monitoring at QTc ≥530 msec
Rationale:  to correct a spelling mistake and clarify that evaluation criteria relate to QTc.


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Change 6:  Section 6.5, Investigational Product Preparation/Handling/Storage/
Accountability
Change from:
A description of the methods and materials required for preparation of GSK3511294 will 
be detailed in a Study Specific Technical Agreement/Memo (TTS) or Pharmacy Manual
which will be accompanied by a Quality Agreement.

Further guidance and information for final disposition of unused study treatment 
are provided in the Study Reference Manual (SRM). 
To:
A description of the methods and materials required for preparation of GSK3511294 will 
be detailed in the Study Reference Manual (SRM), which will be accompanied by a 
Quality Agreement.

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 
Rationale:  to correct an error.
Change 7:  Section 6.10.1, Permitted medications and non-drug therapies
Change from:
Asthma medication will be temporarily withheld before the reversibility test at screening, 
and spirometry assessments on Day –1:  SABAs will be withheld for 6 hours; LABAs 
will be withheld for 12 hours; and LABAs with ultra-long activity will be withheld for 
24 hours.
To:
Asthma medication will be temporarily withheld before the reversibility test at pre-
screening or screening, and spirometry assessments at screening and on Day –1:  
SABAs will be withheld for 6 hours; LABAs will be withheld for 12 hours; and LABAs 
with ultra-long activity will be withheld for 24 hours.
Given that participants have mild-moderate asthma and are controlled with stable 
therapy on entering the study, maintenance asthma therapy should remain 
unchanged for the duration of the study.  In the event of asthma exacerbations, 
participants should however be treated as per standard practice, which may include 
short bursts of systemic corticosteroids.  Any changes to maintenance asthma 
therapy should be documented and communicated to the sponsor.
Rationale:  to clarify rescue medication restrictions in relation to reversibility testing and 
spirometry, and to account for treatment of possible asthma exacerbations and to ensure 
that any changes in maintenance asthma therapy during the study are documented and 
communicated to the sponsor.  The latter is because asthma exacerbations and changes in 
asthma therapy could affect the PD results.


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Change 8:  Section 7.1, Time and Events Table, Spirometry and PEF rows, and footnotes 2 and 18
Change from:
Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Outpatient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 
5
253 5
281 5
Spirometry
X
X
X
X
X
X
X 5
X 5
X 5
PEF 18
X
X
X
X
X
X 18
2.
Screening up to 4 week before randomisation.  Screening procedures may be done at one or more visits, within the screening window.
18.
PEF will be recorded each day during the study from Day −1 onwards.  On Days −1 to 3, results will be recorded by the site; on all other days, results will be 
recorded by the participant, along with any rescue medication use, on diary cards provided by the site.  Site staff will review the diary cards at each outpatient 
visit.
To:
Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Outpatient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 
5
253 5
281 5
Spirometry
X
X
X
X
X
X
X
X 5
X 5
X 5
PEF 18
X 18
2.
Screening up to 4 weeks before randomisation.  Screening procedures may be done at one or more visits, within the screening window.
18. PEF will be recorded twice each day (once in the morning upon waking and once in the evening before bedtime) during the study from Day −1 onwards.  On 
Days −1 to 3, results will be recorded by the site; on all other days, results will be recorded by the participant, along with any rescue medication use, on diary
cards provided by the site.  Site staff will review the diary cards at each outpatient visit.


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Rationale:  to correct a typographical error and to clarify that spirometry will be done at 
screening, in line with the study eligibility criteria, and that PEF should be measured 
twice daily.
Change 9:  Section 7.7, Complement, IgE and inflammatory markers
Change from:
Inflamatory markers at screening will comprise Tumour necrosis factor-alpha (TNF α), 
IL 2, IL 6, IL 10, Interferon-gamma (IFN γ) and C3a.  A screening serum sample will 
also be stored for assay of Antinuclear antibodies (ANA), Anti-neutrophil cytoplasmic 
antibody (ANCA) and anti-DNA antibodies, if required at a later date based on 
symptoms.  After dosing, additional inflammatory markers and tests will be considered 
on an ad hoc basis should there be clinical concerns regarding an immune mediated AE 
(see Section 5.4.2 and Appendix 3).
To:
Inflammatory markers at screening will comprise Tumour necrosis factor-alpha (TNF 
α), IL 2, IL 6, IL 10, Interferon-gamma (IFN γ) and C3a.  A screening serum sample will 
also be stored for assay of Antinuclear antibodies (ANA), Anti-neutrophil cytoplasmic 
antibody (ANCA) and anti-DNA antibodies, if required at a later date based on 
symptoms.  After dosing, additional inflammatory markers and tests will be considered 
on an ad hoc basis should there be clinical concerns regarding an immune mediated AE 
(see Section 5.4.2 and Appendix 3).
Rationale:  to correct a typographical error.
Change 10:  Section 9.1, Hypotheses
Change from:
Given this study is the FTIH for GSK3511294, there are no formal statistical hypotheses 
to be tested.  The assessment of safety and tolerability of single SC doses of 
GSK3511294 in this study will not include any formal comparisons.  For the 
pharmacokinetic and pharmacodynamic data, where appropriate, an estimation approach 
will be adopted and point estimates with corresponding confidence intervals will be 
provided.  In addition for the analysis of blood esoinophils, posterior means and 
corresponding 95% credible intervals will be constructed for each dose and time point. 
Furthermore, posterior probabilities that the placebo adjusted ratio is less than various
thresholds of interest will be constructed.
To:
Given this study is the FTIH for GSK3511294, there are no formal statistical hypotheses 
to be tested.  The assessment of safety and tolerability of single SC doses of 
GSK3511294 in this study will not include any formal comparisons.  For the 
pharmacokinetic and pharmacodynamic data, where appropriate, an estimation approach 
will be adopted and point estimates with corresponding confidence intervals will be 


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provided.  In addition for the analysis of blood eosinophils, posterior means and 
corresponding 95% credible intervals will be constructed for each dose and time point. 
Furthermore, posterior probabilities that the placebo adjusted ratio is less than various 
thresholds of interest will be constructed.
Rationale:  to correct a typographical error.
Change 11:  Section 9.3.2, Interim analysis
Change from:
The interim analysis will be performed by GSK Clinical Statistics and only the 
responsible statistician (and Quality contol
[QC] statistician) and the CPMS 
representative will have access to individual participant data.  However, the findings of 
the interim analysis will be shared with the entire GSK study team. 
To:
The interim analysis will be performed by GSK Clinical Statistics and only the 
responsible statistician (and Quality control
[QC] statistician) and the CPMS 
representative will have access to individual participant data.  However, the findings of 
the interim analysis will be shared with the entire GSK study team. 
Rationale:  to correct a typographical error.
Change 12:  Appendix 6, Contraception guidance for female participants
Change from:
Post-menopausal females, under 60 years of age, who are taking HRT and have not had 
their menopausal status confirmed, must use one of the follow methods of contraception, 
from dosing until the final visit.
1.
A condom, with spermicide.
2.
Male partner sterilization with documentation of azoospermia prior to the female 
participant's entry into the study, and this male is the sole partner for that participant
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of participant’s medical records or medical history interview 
provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that participants understand how to properly use these methods of contraception.
To:
Post-menopausal females, under 60 years of age, who are taking HRT and have not had 
their menopausal status confirmed, must use one of the follow methods of contraception, 
from dosing until the final visit.


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1.
Male partner sterilization with documentation of azoospermia prior to the female 
participant's entry into the study, and this male is the sole partner for that participant
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of participant’s medical records or medical history interview 
provided by her or her partner.
The investigator is responsible for ensuring that participants understand how to properly 
use these methods of contraception.
Rationale:  to remove condom with spermicide as it is not considered an acceptable 
method of contraception.


2 0 1 6 N 2 7 0 5 2 9 _ 0 6
C O N FI D E N TI A L
2 0 5 7 2 2
1 0 7
C h a n ge 1 3 :  A p pe n di x 7, Asth m a C o ntr ol Test
C h a n ge fr o m :
T o:
C o u ntr y -s pecific, c o m merci all y a v ail a ble versi o ns of t he A C T will be use d.
R ati o n ale:   
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
t o c orrect t he versi o n of t he A C T t o be use d i n t he st u d y.


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12.10.4.
Protocol Amendment 4 – Protocol changes for Amendment 04 (02-FEB-2018), from amendment 03 (04-
Sep-2017)
Protocol Amendment 4 applies to all sites
Change 1: Section 7.1, Time and Events Table, PEF rows and footnote 18
Change from:
Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 
5
253 5
281 5
PEF 18
X 18
18. PEF will be recorded twice each day (once in the morning upon waking and once in the evening before bedtime) during the study from Day −1 onwards.  On 
Days −1 to 3, results will be recorded by the site; on all other days, results will be recorded by the participant, along with any rescue medication use, on diary 
cards provided by the site.  Site staff will review the diary cards at each outpatient visit.
Change to:
Procedure
Pre-
Screen 
1
Screen 
2
In-patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 
5
253 5
281 5
PEF Training 18
X 18
PEF 18
X 18
18. PEF will be recorded in the evening before bedtime on the day of the screening visit, then twice each day (once in the morning upon waking and once in the 
evening before bedtime) from the day after screening until the end of the study.  Training of the participant in how to take measurements will occur at screening.  
PEF measurements will be taken and results will be recorded by the site while the participant is in-patient at the clinical site (ie from the evening of Day –1 until 


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the morning of discharge).  At all other time points, the participant will record their PEF as instructed, on their diary card, along with any rescue medication use 
and adverse events.  Site staff will review the diary cards at each out-patient Visit.
Rationale: To acquire a better baseline, additional PEF measurements will be recorded from the evening of screening onwards.
Change 2: Section 5.4.3.2, ECG collection timeframe to align with Section 7.3.5
Change from:
Notes:  the QTc should be based on averaged QTc values of triplicate electrocardiograms obtained over a brief (e.g., 5–10 minute) 
recording period.
Change to:
Notes:  the QTc should be based on averaged QTc values of triplicate electrocardiograms obtained over a brief (up to 10 minutes) 
recording period.
Rationale: To align Section 5.4.3.2 and Section 7.3.5 of the protocol to allow QTc values to be obtained from electrocardiograms in a 10 
minute time period.
Change 3: Section 6.2, Timeframe for review of available safety data to align with Section 4.1
Change from:
In each cohort, dosing will be staggered:  one participant will receive GSK3511294 and one participant will receive placebo at least 
72 hours before the remaining participants in that cohort are dosed.  If the review of all safety data up to 72 hours after dosing of the first 
two participants in each cohort is satisfactory, the remaining participants will be dosed.  Sentinel dosing is not required in cohorts 
investigating a dose lower than or equal to the highest dose tested to date.
Change to:
In each cohort, dosing will be staggered:  one participant will receive GSK3511294 and one participant will receive placebo at least 
72 hours before the remaining participants in that cohort are dosed.  Providing no safety issues are identified in the sentinel participants 


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over an observation period of at least 72 hours, the remaining participants in the cohort may be dosed.  Sentinel dosing is not required in 
cohorts investigating a dose lower than or equal to the highest dose tested to date.
Rationale: To align Section 4.1 and Section 6.2 of the protocol, regarding the observation of sentinel participants in each cohort, prior to 
dosing the remaining participants in the cohort.
Change 4: Section 4.7.1, Risk Assessment, Risk Mitigation strategy
Change from:
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK3511294] 

Systemic reactions including allergic 
reactions.

Systemic reactions including allergic 
reactions, with the most severe form being 
anaphylaxis (see Appendix 9), are potential 
risks associated with mAbs.

Acute and delayed systemic reactions, 
including hypersensitivity reactions (e.g. 
anaphylaxis, urticaria, angioedema, rash, 
bronchospasm or hypotension) have 
occurred following mepolizumab 
administration in asthma patients.  

Sentinel participants will be used at all dose 
levels and monitored for at least 72 hours 
post dose before dosing the remainder of the 
cohort.

All participants in the UK will have a 
minimum 72 hour post dose in-patient 
monitoring period at experienced phase 1 
study sites to ensure any late reactions are 
captured. In Germany this post dose in-
patient monitoring period will be 8 days 
(Appendix 8).

Participants with a history of an allergic 
sensitivity to biologic agents are excluded.

Any observed reactions will also be treated 
based on investigator medical judgement 
(with medical monitor consult as needed).

Investigators will be asked to assess events 
they consider to represent systemic 
reactions and events of anaphylaxis against 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Sampson diagnostic criteria for anaphylaxis
(Appendix 9).

QTc prolongation

Four monkeys in the 6-month repeat dose 
monkey study administered 
100 mg/kg/week were observed to have 
QTc prolongation (mean change of 18 msec 
relative to vehicle control value) during 
Week 14.

relative to control) at week 14 in the 
100 mg/kg dose group only. 

ECGs will be performed on a regular basis 
and should there be any QTc abnormality 
patients will be monitored more frequently 
and management instituted as deemed 
relevant by the Investigator in liaison with 
the medical monitor.

Participants with QTc prolongation on 
screening will be excluded.

Participants with a history of cardiac 
disease, severe hypertension, QTc 
abnormality or arrhythmia will be excluded 
as will participants with a relevant family 
history.
Change to:
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK3511294] 

Systemic reactions including allergic 
reactions.

Systemic reactions including allergic 
reactions, with the most severe form being 
anaphylaxis (see Appendix 9), are potential 
risks associated with mAbs.

Acute and delayed systemic reactions, 
including hypersensitivity reactions (e.g. 
anaphylaxis, urticaria, angioedema, rash, 
bronchospasm or hypotension) have 

Sentinel participants will be used at all 
escalating dose levels and monitored for at 
least 72 hours post dose before dosing the 
remainder of the cohort.

All participants will have a minimum 
72 hour in patient monitoring period at 
experienced phase 1 study sites to ensure 
any late reactions are captured. 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
occurred following mepolizumab 
administration in asthma patients.  

Participants with a history of an allergic 
sensitivity to biologic agents are excluded.

Any observed reactions will also be treated 
based on investigator medical judgement 
(with medical monitor consult as needed).

Investigators will be asked to assess events 
they consider to represent systemic 
reactions and events of anaphylaxis against 
Sampson diagnostic criteria for anaphylaxis 
(Appendix 9).

QTc prolongation

Four monkeys in the 6-month repeat dose
monkey study administered 
100 mg/kg/week were observed to have 
QTc prolongation (mean change of 18 msec 
relative to vehicle control value) during 
Week 14.

relative to control) at week 14 in the 
100 mg/kg dose group only. 

ECGs will be performed on a regular basis 
and should there be any QTc abnormality 
patients will be monitored more frequently 
and management instituted as deemed 
relevant by the Investigator in liaison with 
the medical monitor.

Participants with QTc prolongation on 
screening will be excluded.

Participants with a history of cardiac 
disease, Left Bundle Branch Block, Right 
Bundle Branch Block, severe hypertension, 
QTc abnormality or arrhythmia will be 
excluded as will participants with a relevant 
family history.
Rationale: To clarify that sentinel participants will be used at escalating dose levels only.


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Change 5: Section 7.1, Time and Events Table; Demography and Height, Weight and BMI rows
Change from:
Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 5
253 5
281 5
Demography
X
Medical history 10
X
Concomitant 
medication
HIV, Hep B and 
Hep C screen 
X
FSH and estradiol
8
X
Pregnancy test 9
X
X
X
X
X
X
X
X 5
X 5
X 5
Drug, alcohol and 
cotinine screen
X
X
Asthma 
reversibility test
X 11
Genetic sample
X 12
Administer IP
X
ACT 13
X
X
X
X 5
X 5
X 5
Height, weight and 
BMI
X 14
X 14
X 5,14
X 5,14
X 5,14
14. Height at screening only.


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Change to:
Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 5
253 5
281 5
Demography
X
Medical history 10
X
Concomitant 
medication
HIV, Hep B and 
Hep C screen 
X
FSH and estradiol
8
X
Pregnancy test 9
X
X
X
X
X
X
X
X 5
X 5
X 5
Drug, alcohol and 
cotinine screen
X
X
Asthma 
reversibility test
X 11
Genetic sample
X 12
Administer IP
X
ACT 13
X
X
X
X 5
X 5
X 5
Height, weight and 
BMI
X 14
X 14
X 5,14
X 5,14
X 5,14
14. Height at pre-screening or screening only.
Rationale: To clarify that Demography, Height, Weight and BMI will be collected at the pre-screening visit if this visit is required.


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Change 6: Section 5.1, Inclusion criterion #3 and #4
Change from:
3. Asthma:  A physician diagnosis of asthma (mild or moderate, as defined by the 
Global Initiative for Asthma (GINA), 2017) at least 12 months prior to the start of the 
study.  The reason for diagnosis of asthma should be documented in the participant’s 
source data, including relevant history and investigations – specifically evidence of 
airway hyperresponsiveness, airflow variation (peak flow rate or FEV1) or reversible 
airflow obstruction.
4. Historical evidence of airway hyperresponsiveness, airflow variation (peak flow 
rate or FEV1) or reversible airflow obstruction should be recorded in the 
participant’s source data.  If historical evidence of airway hyperresponsiveness, 
airflow variation (peak flow rate or FEV1) or reversible airflow obstruction is not 
available the patient may be included if there is evidence of reversibility on 
pre-screening or screening.
NOTE:

Airway hyper-responsiveness is defined by a methacholine or histamine 
concentration of <8 mg/mL producing a ≥ 20% fall in FEV1.

Airflow variation is defined as a variation in peak flow rate (the difference 
between the highest and lowest peak expiratory flow rate expressed as a 
percentage of the average peak expiratory flow rate) of > 20% over a series of 
measurements or a variation in FEV1 > 15% when measured on separate 
occasions.

Reversible airway obstruction is defined as increase in FEV1 of ≥ 12% over 
baseline AND an absolute change of ≥ 200 mL within 30 minutes following 
4 inhalations of albuterol/salbutamol inhalation aerosol/spacer (or equivalent 
nebulised treatment with albuterol/salbutamol solution).
Change to:
3. Asthma:  A physician diagnosis of asthma (mild or moderate, as defined by the 
Global Initiative for Asthma (GINA), 2017) at least 12 months prior to the start of the 
study.  The reason for diagnosis of asthma should be documented in the participant’s 
source data, including relevant history.  If available, investigations – specifically 
evidence of airway hyperresponsiveness, airflow variation (peak flow rate or FEV1) 
or reversible airflow obstruction, should also be documented in the participant’s 
source data.  

NOTE: Airway hyper-responsiveness is defined by a methacholine or histamine 
concentration of <8 mg/mL producing a ≥ 20% fall in FEV1.

Airflow variation is defined as a variation in peak flow rate (the difference 
between the highest and lowest peak expiratory flow rate expressed as a 
percentage of the average peak expiratory flow rate) of > 20% over a series of 
measurements or a variation in FEV1 > 15% when measured on separate 
occasions.

Reversible airway obstruction is defined as increase in FEV1 of ≥ 12% over 
baseline AND an absolute change of ≥ 200 mL following 4 inhalations of 


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albuterol/salbutamol inhalation aerosol/spacer (or equivalent nebulised treatment 
with albuterol/salbutamol solution).
Rationale: To remove the necessity for evidence of airway hyperresponsiveness, airflow 
variation (peak flow rate or FEV1) or reversible airflow obstruction.  
Change 7: Section 5.3, Screening/Baseline/Run-in Failures
Change from:
Screening/Baseline/Run-in Failures
Screen failures are defined as participants who consent to participate in the clinical trial 
but are never subsequently randomised. In order to ensure transparent reporting of screen 
failure participants, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.3.1.5).
Change to:
Pre-screening/Screening/Baseline/Run-in Failures
Pre-screening failures are defined as participants who consent to participate in a clinical 
trial, attend the Pre-screening visit but do not meet the criteria for the screening visit 
(blood eosinophils ≥200 cells/µL).  Screen failures are defined as participants who 
consent to participate in the clinical trial but are never subsequently randomised. In order 
to ensure transparent reporting of screen failure participants, meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements, and respond to 
queries from Regulatory authorities, a minimal set of screen failure information is 
required including Demography, Screen Failure details, Eligibility Criteria, and Serious 
Adverse Events (see Section 7.3.1.5).
Rationale: To clarify the definition of a pre-screening failure.
Change 8: Section 6.10.2, Added live vaccines to the prohibited concomitant 
medication list
Change from:
The following asthma medications are prohibited during the study and within the 
timeframe indicated in brackets before screening:

Immunotherapy (at any time)

Desensitization therapy (ongoing)

anti-IgE therapy (within 6 months)

anti-IL5 (within 6 months)

oral or injectable corticosteroids (within 8 weeks)

LAMA or  LTRA therapy (within 8 weeks)


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Change to:
The following asthma medications are prohibited during the study and within the 
timeframe indicated in brackets before screening:

Immunotherapy (at any time)

Desensitization therapy (ongoing)

anti-IgE therapy (within 6 months)

anti-IL5 (within 6 months)

oral or injectable corticosteroids (within 8 weeks)

LAMA or  LTRA therapy (within 8 weeks)

Live vaccines
Rationale: To clarify that no patient is allowed to receive a live vaccine at any point 
during study participation.
Change 9: Section 5.2, addition of Right Bundle Branch Block as an exclusion 
criteria. Section 5.4.3.2, QTc
Change from:
Section 5.2:
12. QTc > 450 msec or QTc > 480 msec in participants with Right Bundle Branch Block.  
NOTES: 

The QTc is the QT interval corrected for heart rate, for the purposes of 
standardisation, QTc corrected by Fridericia’s formula (QTcF) will be used 
across sites with central over-read to limit variability.

For purposes of data analysis, QTcF or a composite of available values of QTc 
will be used as specified in the Reporting and Analysis Plan (RAP).
13. A personal history of severe hypertension, arrhythmia or Left Bundle Branch
Block, or a family history of sudden unexplained death, long QT, familial cardiac 
syndrome, or cardiomyopathy.
Section 5.4.3.2:
Direct observation for 24 hours before discharge with 48 hour ambulatory Holter monitor 
and subsequent repeat assessment at 48 hours *.

QT or QTc change from baseline ≥ 60 msec and no clinical impact.  (Baseline is 
the average of triplicate readings at pre-dose on Day 1.)

QTc > 500 msec or uncorrected QT > 600 msec and no clinical impact.
* To remain under observation if QT/QTc remains the same/increases on assessment at 
24 (end of direct observation) and 72 hours periods (after 48 hour Holter monitor) and for 
consideration of cardiology consult.
For participants with underlying bundle-branch block, follow the evaluation criteria 
listed below:

Baseline QTc < 450 msec, increase monitoring at QTc > 500 msec

Baseline QTc between 450 to 480 msec, increase monitoring at QTc ≥530 msec


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Change to:
Section 5.2
12. QTc > 450 msec.  
NOTES: 

The QTc is the QT interval corrected for heart rate, for the purposes of 
standardisation, QTc corrected by Fridericia’s formula (QTcF) will be used 
across sites with central over-read to limit variability.

For purposes of data analysis, QTcF or a composite of available values of QTc 
will be used as specified in the Reporting and Analysis Plan (RAP).
13. A personal history of severe hypertension, arrhythmia, Right Bundle Branch 
Block, or Left Bundle Branch Block, or a family history of sudden unexplained 
death, long QT, familial cardiac syndrome, or cardiomyopathy.
Section 5.4.3.2:
Direct observation for 24 hours before discharge with 48 hour ambulatory Holter monitor 
and subsequent repeat assessment at 48 hours *.

QT or QTc change from baseline ≥ 60 msec and no clinical impact.  (Baseline is 
the average of triplicate readings at pre-dose on Day 1.)

QTc > 500 msec or uncorrected QT > 600 msec and no clinical impact.
* To remain under observation if QT/QTc remains the same/increases on assessment at 
24 (end of direct observation) and 72 hours periods (after 48 hour Holter monitor) and for 
consideration of cardiology consult.
Rationale: To safely exclude all participants with Right Bundle Branch Block
Change 10: Section 5.5, Study halting criteria
Change from:
The study may continue, if, after review, the sponsor and investigators consider it safe to 
do so.  However, the study may re-start only after ethics and regulatory approval of a 
substantial amendment.
Change to:
Participants who have been dosed at the time of the study halt will continue in the study, 
as planned.  Further participants may be dosed only if, after review, the sponsor and 
investigators consider it safe to do so and only after ethics and regulatory approval of a 
substantial amendment.
Rationale: To clarify the study halting criteria


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Change 11: Section 10.2, Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Change from:

Signed informed consent must be obtained for each participant prior to participation 
in the study
Change to:

Signed informed consent must be obtained and available for each participant prior 
to participation in the study
Rationale: To clarify the informed consent process and that informed consent must be 
available prior to inclusion in the study
Change 12: Section 5.2, Exclusion Criteria, Other
Addition of participants who are institutionalised on regulatory or court order as an 
exclusion criteria
33. Vulnerable subjects, e.g., participants kept in detention, protected adults under 
guardianship, trusteeship and soldiers, or participants committed to an institution by 
governmental or juridical order.
Rationale: To ensure exclusion of such participants from the study as this may hinder 
their ability to comply with study procedures/requirements.
Change 13: Section 12.8.1, Country Specific Requirements
Addition of:
13.8.2 Additional Hepatitis B Core Antibody test for inclusion of 
participants in Germany
In order to comply with German requirements for Hepatitis B virus testing in Germany, 
participants will be tested for the hepatitis B core antibody (anti-HBc) at screening.  The 
German-specific exclusion criterion 5 is as follows:
Positive for hepatitis B surface antigen (HBsAg) and core antibody (anti-HBc) at 
screening.
Table 5 has been updated accordingly.


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Table 5
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
(post-dose results blinded as 
described in footnote 1)
WBC
Hemoglobin
MCH
Neutrophils
Haematocrit
Lymphocytes
Monocytes 
Eosinophils 
Clinical 
Chemistry 
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
(fasted at 
screening)
Calcium
Alkaline 
phosphatase
Albumin
Magnesium
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination and UACR (if blood or protein is 
abnormal [evidence of microbalbinumaemia or haematuria of ≥ 
1+])
Other tests

hsCRP
Other 
Screening 
Tests

HIV

Hepatitis B (HBsAg; in Germany only, anti-HBc will also be 
tested [Appendix 8])

Hepatitis C (Hep C antibody)

FSH and estradiol (if required to confirm postmenopausal status)

Alcohol, cotinine and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)
Abbreviations:  ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST 
(SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); BUN = blood urea 
nitrogen; FSH = follicle stimulating hormone; HBsAg = hepatitis B surface antigen; anti-HBc = hepatitis 
B core antibody; hsCRP = highly sensitive C-reactive protein; MCH = mean corpuscular haemoglobin; 
MCV = mean corpuscular volume; RBC = red blood cell; UACR = urinary albumin-creatinine ratio; 
WBC = white blood cell, pH= hydrogen ion concentration.
1.
The following post-dose results will be blinded to Investigators and blinded Sponsor 
representatives:  total WBCs; absolute and percentage eosinophils; and percentage neutrophils, 
lymphocytes, monocytes and basophils.


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12.8.2 Additional In-patient stay period for participants from Germany
In Germany, participants will remain in-patient for a minimum of 8 days post dosing, as 
noted in Section 4.2, Section 4.7.1 and Section 7.1.  For clarity, the time and events table 
for Germany is provided below:
Section 4.2, Treatment Arms and Duration

In-patient period: Participants will be admitted the day before dosing, and the 
minimum post dose in-patient period for all participants will be 72 hours in the UK 
and 8 days in Germany (Appendix 8).  Participants will be monitored for local 
injection site reactions and allergic reactions for at least 72 hours post dose.  In the 
case of such reactions, appropriate medical treatment will be administered.  
Participants will be discharged only if the Investigator deems it safe for the 
participant to leave the unit (For further information regarding the in-patient period in 
Germany, please refer to Section 12.8.2).

Total duration: The scheduled maximum study duration for each participant who 
receives GSK3511294 or placebo will be up to 44 weeks (excluding pre-screening for 
blood eosinophils), including up to 28 days for screening, 4 days as an in-patient in 
the UK and 9 days in Germany (Appendix 8), and up to 40 weeks post-dosing to 
investigate the PD (blood eosinophil count) and safety profile. 
Rationale: To accommodate the requirements of the Regulators and Ethics Committee 
from Germany.


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4.7.1 Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK3511294] 
Duration of in-patient stay after dosing
Tmax of GSK3511294 is expected at 7−10 days 
after dosing.  However, any significant side effect of 
GSK3511294 in the time to Tmax is most likely to 
be an anaphylactic reaction, which would occur in 
the first 72 hours after dosing.  The predicted PK 
profile indicates approximately 80% of Cmax at 
72 hours after dosing.  Participants will have a 
minimum 72 hour in patient monitoring period at 
experienced phase 1 study.  Therefore, to minimise 
the inconvenience to participants, they may be 
discharged from the clinical unit 72 hours (or 
longer) after dosing, provided that the Investigator 
considers them well enough to leave.

In the UK, Investigators will review 
available safety data up to 72 hours to 
confirm participants are well enough to 
leave the clinical unit.  In Germany, in 
response to regulatory comments, 
participants will be in-patient until at least 
8 days after dosing.

Participants will receive a medical alert 
card, with details of the study, clinical site 
and Investigator, when they are discharged 
from the unit.  They will be instructed to 
contact the unit with any safety concerns 
they might have, and to show the medical 
alert card to any other medical professional 
they might consult. 


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7.1
Time and Events Table
Procedure
Pre-
Screen 1
Screen 
2
In-patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2 Day 3 Day 4
Week
NA
1
NA
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
9
15
29
57
85
127 169 183
225 5
253 5
281 5
Informed consent
X 6
Pre-screening 
Blood eosinophils 
X 7
Inclusion & 
exclusion criteria
X
X
X
Demography
X
Medical history 10
X
Concomitant 
medication
HIV, Hep B and 
Hep C screen 
X
FSH and 
estradiol 8
X
Pregnancy test 9
X
X
X
X
X
X
X
X 5
X 5
X 5
Drug, alcohol and 
cotinine screen
X
X
Asthma 
reversibility test
X 11
Genetic sample
X 12
Administer IP
X
ACT 13
X
X
X
X 5
X 5
X 5
Height, weight 
and BMI
X 14
X 14
X 5,14
X 5,14
X 5,14
Full phys exam
X
X 5
X 5
X 5
Brief phys exam
X
X
X
X
X


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Procedure
Pre-
Screen 1
Screen 
2
In-patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2 Day 3 Day 4
Week
NA
1
NA
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
9
15
29
57
85
127 169 183
225 5
253 5
281 5
Dispense rescue 
SABA
X
Resupply, as required.
Haematology 
(including blood 
eosinophil count), 
Clin. Chem., 
Urinalysis and 
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Serum save (for 
immunological 
analysis, if 
needed)
X
Ad hoc, as required by symptoms – see Appendix 3.
Inflammatory 
markers
X
Ad hoc, as required by symptoms – see Appendix 3.
Complement (C3 
& C4)
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Total IgE
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
PK Blood 
Samples
See Table 4.
Immunogenicity
X
X
X
X
X
X
X
X
X 5
X 5
X 5
CICs
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
12-lead ECG 15
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Vital signs 16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
AE/SAE review 
(inc local ISR up 
to 72 h after 
dosing)
X 17
IL-5 sample
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5


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Procedure
Pre-
Screen 1
Screen 
2
In-patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2 Day 3 Day 4
Week
NA
1
NA
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
9
15
29
57
85
127 169 183
225 5
253 5
281 5
Exploratory 
biomarkers of 
asthma in blood 
X
X
X
Spirometry
X
X
X
X
X
X
X
X 5
X 5
X 5
PEF Training 18
X
PEF 18
X 18
Diary review 18
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Abbreviations:  ACT = Asthma Control Test; AE = adverse event; BMI = body mass index; CICs = circulating immune complexes; CRP = C-reactive protein; ECG = 
electrocardiogram; FSH = follicle stimulating hormone; h = hour(s); Hep B = Hepatitis B; Hep C = Hepatitis C; HIV = human immunodeficiency virus; IgE = 
immunoglobulin E; IL-5 = interleukin-5; IP = Investigational Product; ISR = injection site reactions; PEF = peak expiratory flow; PK = pharmacokinetic; SABA = 
short acting -agonist; SAE = serious adverse event.
Notes:
1.
Pre-screen up to 12 weeks before dosing.  Blood eosinophils must be ≥200 cells/µL for participants to proceed to screening.  Blood eosinophil count may be 
existing data or obtained at a pre-screen visit.
2.
Screening up to 4 weeks before randomisation.  Screening procedures may be done at one or more visits, within the screening window.
3.
In the UK, all participants will be in-patient for at least 72 h after dosing.  In Germany, all participants will be in-patient for at least 8 days after dosing (see 
Appendix 8 for the German-specific time and events table).
4.
Allowed time deviations will be documented in the Study Reference Manual.
5.
All participants will have all out-patient visits up to Week 26 after dosing.  Each cohort will also have out-patient visits after week 26, depending on the dose, as 
follows:  

2 and 10 mg:  Week 32 only

30 mg and 100 mg:  Week 36 only 

300 mg:  Weeks 32 and 40
(For unplanned dose levels, the timing of out-patient visits will be documented in a Note to File.) 
6.
Informed consent will be taken either at the pre-screen visit, for participants who don’t have an existing eosinophil count, or at screening, for those who do.
7.
Blood eosinophils will be included in the haematology panel at all time points other than the pre-screen visit.  
8.
If required to confirm postmenopausal status.
9.
Women on hormone replacement therapy, whose post-menopausal status cannot be confirmed, only.
10. Including cardiovascular (CV) disease, asthma exacerbation, and drug, alcohol and smoking history.
11. At pre-screening or screening, only if historical data (as described in inclusion criterion 4) is unavailable.


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12. If the participant consents, an optional, genetic sample will be collected once during the study.  
13. At each applicable visit, ACT should be done before any other assessment.
14. Height at pre-screening or screening only.
15. ECGs triplicate at all time points.  ECGs should be time-matched to baseline (i.e. pre-dose on Day 1) from Day 2 onwards.
16. Blood pressure and heart rate in triplicate before dosing; single measurements after dosing.  Single temperature and respiratory rate measurements at all time 
points.
17. Only SAEs are collected before dosing (see Section 7.3.1).
18. PEF will be recorded in the evening before bedtime on the day of the screening visit, then twice each day (once in the morning upon waking and once in the 
evening before bedtime) from the day after screening until the end of the study.  Training of the participant in how to take measurements will occur at screening.  
PEF measurements will be taken and results will be recorded by the site while the participant is in-patient at the clinical site (ie from the evening of Day –1 until 
the morning of discharge).  At all other time points, the participant will record their PEF as instructed, on their diary card, along with any rescue medication use 
and adverse events.  Site staff will review the diary cards at each out-patient Visit.


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Change 14: Section 7.4.1, Blood sample collection and Appendix 2 (footnote 4), 
Liver Safety Requirements; reference to appropriate lab manual for instructions 
regarding PK samples
Change from:
Section 7.4.1, Blood sample collection
Processing, storage and shipping procedures are provided in the SRM. 
Appendix 2, Liver Safety Requirements (footnote 4)
PK sample may not be required for participants known to be receiving placebo. Record the 
date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior 
to blood sample draw on the CRF. If a PK sample cannot be collected in the time period indicated 
above, do not obtain a PK sample. Instructions for sample handling and shipping are in the SRM.
Change to:
Section 7.4.1, Blood sample collection
Processing, storage and shipping procedures are provided in the appropriate lab manual. 
Appendix 2, Liver Safety Requirements (footnote 4)
4)
PK sample may not be required for participants known to be receiving placebo. Record the date/time of 
the PK blood sample draw and the date/time of the last dose of study treatment prior to blood sample 
draw on the CRF. If a PK sample cannot be collected in the time period indicated above, do not obtain 
a PK sample. Instructions for sample handling and shipping are in the appropriate lab manual.
Rationale: To clarify that information regarding the handling of PK samples will be 
located in the appropriate lab manual and not the SRM.
Change 15: Section 7.3.6, Clinical Safety Laboratory Assessments, addition of 
footnote 1
Change from:
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Haematocrit
Monocytes
Eosinophils (post-dose results 
to be blinded to investigators)
Basophils
Abbreviations:  ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST 
(SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); BUN = blood urea 
nitrogen; FSH = follicle stimulating hormone; HBsAg = hepatitis B surface antigen; hsCRP = highly 
sensitive C-reactive protein; MCH = mean corpuscular haemoglobin; MCV = mean corpuscular volume; 
RBC = red blood cell; UACR = urinary albumin-creatinine ratio; WBC = white blood cell, pH= hydrogen 
ion concentration.


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Change to:
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential
(post-dose results blinded as 
described in footnote 1):
RBC Count
MCV
WBC
Neutrophils 
Hemoglobin
MCH
Lymphocytes 
Haematocrit
Monocytes 
Eosinophils 
Basophils 
Abbreviations:  ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST 
(SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); BUN = blood urea 
nitrogen; FSH = follicle stimulating hormone; HBsAg = hepatitis B surface antigen; anti-HBc = hepatitis B 
core antibody; hsCRP = highly sensitive C-reactive protein; MCH = mean corpuscular haemoglobin; MCV 
= mean corpuscular volume; RBC = red blood cell; UACR = urinary albumin-creatinine ratio; WBC = 
white blood cell, pH= hydrogen ion concentration.
1.
The following post-dose results will be blinded to Investigators and blinded Sponsor 
representatives:  total WBCs; absolute and percentage eosinophils; and percentage 
neutrophils, lymphocytes, monocytes and basophils.
Rationale: To ensure there is no un-blinding that can occur for Eosinophil counts due to 
availability of other components and their contributions to WBC count.


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12.10.5.
Protocol Amendment 5 – Protocol changes for Amendment 05 
(18-Jun-2018), from amendment 04 (02-Feb-2018)
Change 1: Section 4.3, Dose Escalation; Section 5.4.3.2, Criteria for increased 
monitoring of individual participants, QTc 
Change from:
Section 4.3, Dose Escalation

The dose will not be escalated, nor will a dose level be repeated, if, at that dose level:

one or more of the study halting criteria are met (see Section 5.5)

one or more participants has experienced at least one of the criteria for potential 
type III hypersensitivity/immune complex disease, and there is ongoing clinical 
concern about the participant’s condition (see Section 5.4.2)

one or more participants has a QTc > 500 msec or uncorrected QT > 600 msec, or
an increase in QT/QTc ≥ 60 msec
Section 5.2, Exclusion Criteria
12. QTc > 450 msec.
NOTES: 

The QTc is the QT interval corrected for heart rate, for the purposes of 
standardisation, QTc corrected by Fridericia’s formula (QTcF) will be used 
across sites with central over-read to limit variability.

For purposes of data analysis, QTcF or a composite of available values of QTc 
will be used as specified in the Reporting and Analysis Plan (RAP).
Section 5.4.3.2, Criteria for increased monitoring, QTc
Direct observation for 24 hours before discharge with 48 hour ambulatory Holter monitor 
and subsequent repeat assessment at 48 hours *.

QT or QTc change from baseline ≥ 60 msec and no clinical impact.  (Baseline is 
the average of triplicate readings at pre-dose on Day 1.)

QTc > 500 msec or uncorrected QT > 600 msec and no clinical impact.
* To remain under observation if QT/QTc remains the same/increases on assessment at 
24 (end of direct observation) and 72 hours periods (after 48 hour Holter monitor) and for 
consideration of cardiology consult.
Notes:  the QTc should be based on averaged QTc values of triplicate electrocardiograms 
obtained over a brief (up to 10 minutes) recording period.
Section 7.3.5, Electrocardiogram (ECG)

12-lead ECGs will be obtained using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals.  Refer to Section 


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5.4.3.2 for QTc increased monitoring criteria and additional QTc readings that may 
be necessary.
The 12-lead ECG will be performed in the supine position.  At all time points, after a 
5 minutes rest, triplicate ECGs will be obtained over a brief recording period (up to 
10 minutes).  The ECGs will be time-matched to baseline assessment (ie pre-dose on 
Day 1) from Day 2 onwards.  
Change to:
Section 4.3, Dose Escalation

The dose will not be escalated, nor will a dose level be repeated, if, at that dose level:

one or more of the study halting criteria are met (see Section 5.5)

one or more participants has experienced at least one of the criteria for potential 
type III hypersensitivity/immune complex disease, and there is ongoing clinical 
concern about the participant’s condition (see Section 5.4.2)

one or more participants has a QTcF > 500 msec or uncorrected QT > 600 msec, 
or an increase in QTcF > 60 msec, in the absence of any other identifiable reason 
(e.g. concomitant medication). In such a scenario, if after review of all clinical 
safety data for the participant(s), the increased QT is considered to be isolated and 
not clinically significant in the opinion of the medical monitor and investigators, 
dose escalation and/or dosing of further patients at the dose level at which the 
event was observed can occur only after ethics and regulatory approval of a 
substantial amendment.
Section 5.2, Exclusion Criteria
12. QTcF > 450 msec.
NOTES: 

The QTc is the QT interval corrected for heart rate, for the purposes of 
standardisation, QTc corrected by Fridericia’s formula (QTcF) will be used 
across sites with central over-read to limit variability.

For purposes of data analysis, QTcF or a composite of available values of QTc 
will be used as specified in the Reporting and Analysis Plan (RAP).
Section 5.4.3.2 Criteria for increased monitoring, QTc
Direct observation for 24 hours before discharge with 48 hour ambulatory Holter monitor 
and subsequent repeat assessment at 48 hours *.

QTcF change from baseline > 60 msec and no clinical impact.  (Baseline is the 
average of triplicate readings at pre-dose on Day 1).

QTcF > 500 msec or uncorrected QT > 600 msec and no clinical impact.
* To remain under observation if QTcF (or QT if > 600 msec) remains the same/increases 
on assessment at 24 (end of direct observation) and 72 hours periods (after 48 hour Holter 
monitor) and for consideration of cardiology consult.


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Notes:  the QTcF should be based on averaged QTcF values of triplicate 
electrocardiograms obtained over a brief (up to 10 minutes) recording period.
Section 7.3.5, Electrocardiogram (ECG)

12-lead ECGs will be obtained using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals.  Refer to Section 
5.4.3.2 for QTc increased monitoring criteria and additional QTc readings that may 
be necessary.
The 12-lead ECG will be performed in the supine position.  At all time points, after a 
5 minutes rest, triplicate ECGs will be obtained over a brief recording period (up to 
10 minutes).  The ECGs will be time-matched to baseline assessment (ie pre-dose on 
Day 1) from Day 2 onwards.  For QT interval corrected for heart rate (QTc), for the 
purposes of standardisation, Fridericia’s correction formula (QTcF) was selected and will 
be used across sites with central over-read to limit variability.
Rationale: A raw QT interval change from baseline as one of the criteria for limiting 
dose escalation and for increased monitoring of individual participants has been included 
in error.  QTcF has been chosen as the most appropriate corrective measure of QT for this 
study and this is now reflected throughout.  Accordingly, one of the required criteria for 
limiting further dose escalation and increased monitoring of individuals is now a change 
in QTcF from baseline of > 60 msec.
Change 2: Section 5.3, Pre-screening/Screening/Baseline/Run-in Failures
Addition of:
Participants who would not have been a screen failure on the basis of the entry criteria in 
the current version of the protocol may be rescreened for entry into the study.  
Participants who could not be dosed for logistical reasons within the permissible 
screening window after passing screening for a cohort, may be rescreened for entry into a 
subsequent cohort.  Rescreened participants should be assigned a new participant 
number.
Rationale: To allow rescreening of a participant if they were not a screen failure, or 
would not have been one under the current version of the protocol.
Change 3: Section 6.10.1, Permitted Medications and Non-Drug Therapies; Section 
7.1, Time and Events Table, Section 7.2, Screening and Critical Baseline 
assessments; Section 12.8, Appendix 8, Country Specific Requirements 
Change from:
Section 6.10.1, Permitted Medications and Non-Drug Therapies
Asthma medication will be temporarily withheld before the reversibility test at pre-
screening or screening, and spirometry assessments at screening and on Day –1:  SABAs 
will be withheld for 6 hours; LABAs will be withheld for 12 hours; and LABAs with 
ultra-long activity will be withheld for 24 hours.  


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7.1, Time and Events Table
Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 5
253 5
281 5
Drug, alcohol and 
cotinine screen
X
X
Asthma 
reversibility test
X 11
Genetic sample
X 12
11. At pre-screening or screening, only if historical data (as described in inclusion criterion 4) is unavailable.
Section 7.2, Screening and Critical Baseline assessments
The Asthma Control Test (Appendix 7) should be completed by participants before any other assessment at a clinic visit, in the order 
specified.
A reversibility test will be done at screening, as described in the SRM.  See Section 6.10.1 for medication restrictions before the test.
Section 12.8.2, Appendix 8, Country Specific Requirements
Procedure
Pre-
Screen 
1
Screen 2
In-patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2 Day 3 Day 4
Week
NA
1
NA
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
9
15
29
57
85
127 169 183
225 5
253 5
281 5
Drug, alcohol and 
cotinine screen
X
X
Asthma 
reversibility test
X 11
Genetic sample
X 12
11. At pre-screening or screening, only if historical data (as described in inclusion criterion 4) is unavailable.


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Change to:
Section 6.10.1, Permitted Medications and Non-Drug Therapies
Asthma medication will be temporarily withheld before spirometry assessments at screening and on Day –1:  SABAs will be withheld for 
6 hours; LABAs will be withheld for 12 hours; and LABAs with ultra-long activity will be withheld for 24 hours.  
7.1, Time and Events Table
Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 5
253 5
281 5
Drug, alcohol and 
cotinine screen
X
X
Genetic sample
X 11
Section 7.2, Screening and Critical Baseline assessments
The Asthma Control Test (Appendix 7) should be completed by participants before any other assessment at a clinic visit, in the order 
specified.
Section 12.8, Appendix 8, Country Specific Requirements
Procedure
Pre-
Screen 
1
Screen 2
In-patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2 Day 3 Day 4
Week
NA
1
NA
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
9
15
29
57
85
127 169 183
225 5
253 5
281 5
Drug, alcohol and 
cotinine screen
X
X
Genetic sample
X 11


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Rationale: To clarify that, because reversibility is no longer an inclusion criterion in the most recent version of the protocol, there is no 
need for it to be performed at pre-screening or screening.
Change 4: Section 7.1, Time and Events table, Table 4
Change from:
Table 4
Pharmacokinetic sampling time points
Dose level
Pre-dose
Post-dose
Hours
Days
2
8
24
48
5
8
15
29
57
85
127
169
183
225
253
281
2 mg and 10 mg 
X
X
X
X
X
X
X
X
X
X
X
30 mg and 100 mg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
300 mg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Notes:  For unplanned dose levels, PK sampling time points will be documented in a Note to File.


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Pharmacokinetic sampling time points
Dose level
Pre-dose
Post-dose
Hours
Days
2
8
24
48
5
8
15
29
57
85
127
169
183
225
253
281
2 mg and 10 mg 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
30 mg and 100 mg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
300 mg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Notes:  For unplanned dose levels, PK sampling time points will be documented in a Note to File.
Rationale: Extension of the PK sampling period is required for participants in cohorts 1 and 2, in order to better characterise the PK 
profile of GSK3511294. 
Change 5: Section 7.3.6, Clinical Safety Laboratory Assessments
Change from:
NOTE:  Local laboratory results are only required in the event that the central laboratory results are not available in time for either a 
treatment and/or response evaluation to be performed – for example:  on Day –1, when results should be available before dosing on 
Day 1; at 48 h post-dose, when results should be available before the participant is discharged from the clinical unit; or at any other time 
when a participant is unwell and results are required urgently. If a local sample is required it is important that the sample for central 
analysis is obtained at the same time. Additionally if the local laboratory results are used to make either a treatment or response 
evaluation, the results must be entered into the CRF.


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Change to:
NOTE:  Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed – for example:  on Day –1, when results should be available before dosing on 
Day 1; at 48 h post-dose for all sentinel participants; at 48 h post-dose when results 
should be available before the participant is discharged from the clinical unit in the UK; 
on Day 8, when results should be available before the participant is discharged from the 
clinical unit in Germany; or at any other time when a participant is unwell and results are 
required urgently. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
CRF.
Rationale: To clarify that local labs are required for all sentinel participants at the 
48 hour time point to enable dosing of the rest of the cohort.  As the German in-patient 
stay is longer than the UK, local labs prior to discharge from the clinical site are required 
on Day 8 and not at 48 hours post dosing (Day 3).
12.10.6.
Protocol Amendment 6 – Protocol changes for Amendment 06 
(07-JAN-2019), from Amendment 05 (18-JUN-2018)
A description of changes and rationale are provided below.  The opportunity to make 
corrections to very minor typographical errors has been taken.
Change 1: Section 1.2., Study Rationale
Change from:
In stream data review will occur during the study to support dose escalation decisions, 
and a formal interim analysis is planned once the accumulated safety, PK and PD data is 
deemed sufficient to determine the doses, and dosing interval, to take forward to the next 
phase of development.
Change to:
In stream data review will occur during the study to support dose escalation decisions, 
and formal interim analyses are planned to ensure accumulated safety, PK and PD data is 
deemed sufficient to determine the doses, and dosing interval, to take forward to the next 
phase of development.
Change 3: Section 6.3., Blinding
Change from:
A formal unblinded interim analysis will be performed by GSK (see Section 9.3.2)
Change from:


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Formal unblinded interim analyses will be performed by GSK (see Section 9.3.2)
Change 2: Section 9.3.2., Interim Analyses
Change from:
In stream data review will occur during the study to support dose escalation decisions, 
with a formal interim analysis planned once the accumulated safety, PK and PD data is 
deemed sufficient to determine the doses and a dose interval to move forward into the 
next phase of development, but is not expected to affect the progression of this FTIH 
study.
Currently, the interim analysis is projected to occur once data is available at the 12-week 
time point after dosing in Cohort 4 (planned 100 mg dose).  The primary focus of the 
interim analysis will be reduction in blood eosinophil counts.  The ratio to baseline will 
be derived for each dose and time point and will be compared to corresponding data from 
the placebo arm.  Posterior means and corresponding 95% credible intervals will be 
constructed for each of the available doses and time points. Furthermore, posterior 
probabilities that the placebo adjusted ratio is less than various thresholds of interest will 
be constructed. 
The interim analysis will be performed by GSK Clinical Statistics and only the 
responsible statistician (and Quality control [QC] statistician) and the CPMS 
representative will have access to individual participant data.  However, the findings of 
the interim analysis will be shared with the entire GSK study team.
Change to:
In stream data review will occur during the study to support dose escalation decisions, 
and formal interim analyses are planned to ensure accumulated safety, PK and PD data is 
deemed sufficient to determine the doses and dosing interval to move forward into the 
next phase of development but is not expected to affect the progression of this FTIH 
study.
Currently, the first interim analysis is projected to occur once data is available at the 
12-week time point after dosing in Cohort 4 (planned 100 mg dose).  The primary focus 
of this interim analysis will be reduction in blood eosinophil counts.  The ratio to baseline 
will be derived for each dose and time point and will be compared to corresponding data 
from the placebo arm.  Posterior means and corresponding 95% credible intervals will be 
constructed for each of the available doses and time points. Furthermore, posterior 
probabilities that the placebo adjusted ratio is less than various thresholds of interest will 
be constructed. 
The earliest next interim analysis is planned no earlier than once data is available at the 
26-week time point after dosing Cohort 4 (planned 100 mg dose).  The primary focus of 
this and potential subsequent interim analyses will be the same as the first interim 
analysis (described above).
The interim analyses will be performed by GSK Clinical Statistics and only the 
responsible statistician (and Quality control [QC] statistician) and the CPMS 


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representative will have access to individual participant data.  However, the findings of 
the interim analyses will be shared with the entire GSK study team. 
Rationale: Inclusion of additional interim analyses to better assess blood eosinophil 
count return towards baseline profiles at the highest dose levels investigated and better 
inform dose and dosing regimen to move forward into the next phase of development.  
The earliest additional interim analysis is planned no earlier than once data is available at 
the 26-week time point after dosing Cohort 4 (planned 100 mg dose).

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205722
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a randomised double-blind 
(sponsor open), placebo-controlled, single ascending dose, 
First Time in Human study in participants with mild to 
moderate asthma to assess safety, tolerability, 
immunogenicity, pharmacokinetics and pharmacodynamics 
of GSK3511294 administered subcutaneously.
Compound Number 
:
GSK3511294
Effective Date 
:
23-MAY-2019
Description:

The purpose of this RAP amendment is to describe the planned analyses and output 
to be included in the Clinical Study Report for Protocol GSK Document Number 
2016N270529_06

This RAP is intended to describe the safety, tolerability, immunogenicity, 
pharmacokinetic (PK) and pharmacodynamic (PD) analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Dose Escalation, Interim Analyses and Statistical Analysis Complete (SAC) 
deliverables.

All displays (Tables, Figures & Listings) will use the term 'Subjects'. However, RAP 
text will refer to "Participants" in-line with the master RAP template and protocol.

At the time of this RAP amendment, the Dose Escalations and Interim Analysis 1 
have taken already place. Following Interim Analysis 1, the protocol was amended 
to allow additional interim analyses to examine PD and PK data over a longer 
duration. 
RAP Author(s):
Author
Date
Lead
NA
Principal Statistician (Clinical Statistics)
Co-Authors
, Director Clinical Pharmacology (CPMS)
20 May 2019
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
205722
2
RAP Team Review Confirmations
(Method: E-mail)
Reviewer
Date
22 MAY 2019
Discovery Medicine Physician Director
(RD Respiratory Clinical Dev)
22 May 2019
Programmer/Analyst (Respiratory, Clinical Programming)
Clinical Statistics and Clinical Programming Line Approvals
(Method: Pharma TMF eSignature)
Approver
Date
23 May 2019
Director, Clinical Statistics
23 May 2019
Director, Programming
PPD
PPD
PPD
PPD


CONFIDENTIAL
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
1.1.
RAP Amendments ........................................................................................7
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................10
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.2.
Final Analyses ............................................................................................16
4.
ANALYSIS POPULATIONS ...................................................................................18
4.1.
Protocol Deviations.....................................................................................18
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................20
5.1.
Study Treatment & Sub-group Display Descriptors.....................................20
5.2.
Baseline Definitions ....................................................................................20
5.3.
Multicentre Studies .....................................................................................21
5.4.
Examination of Covariates, Other Strata and Subgroups............................21
5.4.1.
Covariates and Other Strata ........................................................21
5.4.2.
Examination of Subgroups...........................................................21
5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................21
6.
STUDY POPULATION ANALYSES .......................................................................23
6.1.
Overview of Planned Study Population Analyses........................................23
7.
SAFETY ANALYSES .............................................................................................24
7.1.
Overview of Planned Analyses ...................................................................24
7.2.
Adverse Events Analyses ...........................................................................25
7.3.
Adverse Events of Special Interest Analyses..............................................25
7.4.
Clinical Laboratory Analyses.......................................................................25
7.5.
Other Safety Analyses ................................................................................25
8.
LUNG FUNCTION TESTS .....................................................................................25
9.
PHARMACOKINETIC ANALYSES.........................................................................26
9.1.
Primary Pharmacokinetic Analyses.............................................................26
9.1.1.
Endpoint / Variables.....................................................................26
9.1.1.1.
Drug Concentration Measures....................................26
9.1.1.2.
Derived Pharmacokinetic Parameters.........................26
9.1.2.
Summary Measures.....................................................................27
9.1.3.
Population of Interest...................................................................27
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................27
9.1.5.
Statistical Analyses / Methods .....................................................27
9.1.5.1.
Statistical Methodology Specification..........................27


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9.2.
Secondary Pharmacokinetic Analyses........................................................28
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES..................................30
10.1.
Statistical Analyses / Methods ....................................................................30
11. IMMUNOGENICITY ANALYSES............................................................................30
12. CIRCULATING IMMUNE COMPLEXES.................................................................31
13. COMPLEMENT, IgE AND INFLAMMATORY MARKERS.......................................31
14. PHARMACODYNAMIC AND BIOMARKER ANALYSES........................................32
14.1.
Primary Pharmacodynamic and Biomarker Analyses..................................32
14.1.1.
Endpoint / Variables.....................................................................32
14.1.2.
Population of Interest...................................................................32
14.1.3.
Strategy for Intercurrent (Post-Randomization) Events ................32
14.1.4.
Statistical Analyses / Methods .....................................................32
14.1.4.1.
Statistical Methodology Specification..........................32
14.2.
Secondary Pharmacodynamic (and / or Biomarker) Analyses.....................34
14.2.1.
Endpoint / Variables.....................................................................34
14.2.2.
Summary Measure ......................................................................34
14.2.3.
Population of Interest...................................................................35
14.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................35
14.2.5.
Statistical Analyses / Methods .....................................................35
15. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................36
15.1.
Statistical Analyses / Methods ....................................................................36
16. REFERENCES.......................................................................................................37
17. APPENDICES........................................................................................................38
17.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................38
17.1.1.
Exclusions from Per Protocol Population .....................................38
17.2.
Appendix 2: Schedule of Activities ..............................................................39
17.2.1.
Protocol Defined Schedule of Events...........................................39
17.3.
Appendix 3: Assessment Windows .............................................................43
17.3.1.
Definitions of Assessment Windows for Analyses........................44
17.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................46
17.4.1.
Study Phases ..............................................................................46
17.4.2.
Treatment States .........................................................................46
17.4.2.1.
Treatment States for Safety and 
Pharmacodynamic Data .............................................46
17.4.2.2.
Study Phases for Concomitant Medication .................46
17.4.3.
Study Phases for Adverse Events................................................47
17.4.4.
Treatment Emergent Flags for Adverse Events ...........................47
17.5.
Appendix 5: Data Display Standards & Handling Conventions....................48
17.5.1.
Reporting Process .......................................................................48
17.5.2.
Reporting Standards....................................................................48
17.5.3.
Reporting Standards for Pharmacokinetic Data ...........................50
17.6.
Appendix 6: Derived and Transformed Data ...............................................51
17.6.1.
General........................................................................................51


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17.6.2.
Safety ..........................................................................................51
17.6.3.
Pharmacokinetic ..........................................................................51
17.6.4.
Population Pharmacokinetic, Pharmacokinetic/ 
Pharmacodynamic (PopPK, PKPD) .............................................52
17.6.5.
Pharmacodynamic and Biomarker ...............................................52
17.6.6.
Other ...........................................................................................52
17.7.
Appendix 7: Reporting Standards for Missing Data.....................................53
17.7.1.
Premature Withdrawals................................................................53
17.7.2.
Handling of Missing Data.............................................................53
17.7.2.1.
Handling of Missing and Partial Dates ........................54
17.8.
Appendix 8: Values of Potential Clinical Importance ...................................55
17.8.1.
Laboratory Values........................................................................55
17.8.2.
ECG.............................................................................................56
17.8.3.
Vital Signs....................................................................................56
17.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ......................57
17.9.1.
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................57
17.9.2.
Population Pharmacokinetic (PopPK) Methodology.....................57
17.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses ....................59
17.10.1. Pharmacokinetic / Pharmacodynamic Dataset 
Specification ................................................................................59
17.10.2. Pharmacokinetic / Pharmacodynamic Methodology.....................59
17.11. Appendix 11: Abbreviations & Trade Marks ................................................60
17.11.1. Abbreviations...............................................................................60
17.11.2. Trademarks .................................................................................62
17.12. Appendix 12: List of Data Displays..............................................................63
17.12.1. Data Display Numbering..............................................................63
17.12.2. Mock Example Shell Referencing ................................................63
17.12.3. Deliverables.................................................................................63
17.12.4. Study Population Tables..............................................................64
17.12.5. Safety Tables...............................................................................66
17.12.6. Safety Figures .............................................................................71
17.12.7. Pharmacokinetic Tables...............................................................72
17.12.8. Pharmacokinetic Figures .............................................................73
17.12.9. Pharmacokinetic Population (PopPK) Tables...............................75
17.12.10.Pharmacokinetic Population (PopPK) Figures .............................76
17.12.11.Pharmacodynamic and Exploratory Markers................................77
17.12.12.Pharmacodynamic and Exploratory Markers Figures...................79
17.12.13.Pharmacokinetic / PharmacodynamicTables ...............................80
17.12.14.Pharmacokinetic / Pharmacodynamic Figures .............................81
17.12.15.Other Tables................................................................................82
17.12.16.Other Figures...............................................................................85
17.12.17.ICH and Other Listings.................................................................86
17.13. Appendix 13: Example Mock Shells for Data Displays ................................94


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the dose escalation 
outputs, the interim analyses and the analyses to be included in the Clinical Study Report 
for Protocol:
Revision Chronology:
2016N270529_00
13-JUN-2013
Original
2016N270529_01
21-JUN-2013
To correct errors in the Secondary Medical Monitor’s email 
address and in the inflammatory marker tests to be performed 
at screening.
2016N270529_02
04-AUG-2017
To amend the pharmacokinetic stopping criterion and clarify 
that saline for placebo will be an EU licensed product sourced 
locally by trial sites, in response to comments from the 
Medicines and Healthcare Products Regulatory Agency.
2016N270529_03
04-SEP-2017
To correct errors and make minor clarifications.
2016N270529_04
02-FEB-2018
To amend the timeframe for collection of PEF measurements. 
To clarify that demography, height, weight and BMI will be 
collected at the pre-screening visit if this
visit is required. Alignment of ECG collection timeframe. 
Clarify timeframe for review of safety data from sentinel 
participants. Clarify that sentinel participants will be used at
each escalating dose level. To remove the necessity for 
evidence of airway hyperresponsiveness, airflow variation 
(peak flow rate or FEV1) or reversible airflow obstruction at 
inclusion. Added live vaccines to prohibited concomitant 
medications list. Added Right Bundle Branch Block as an 
exclusion criteria. Clarification of the study halting criteria. 
Clarification that each participants consent must be available, 
as well as obtained, before they are entered into the study. 
Added an exclusion criteria regarding vulnerable participants. 
Clarify the definition of a pre-screening failure. Added in 
country specific requirements for Germany, concerning the 
addition of Hepatitis B core antibody test screening and to 
increase the in-patient period to 8-days post dosing. Clarified 
that the PK sample information is located in the appropriate 
lab manual and not the study reference manual. To ensure 
there is no un-blinding that can occur for Eosinophil counts 
due to availability of other components and their contributions 
to WBC count.
2016N270529_05
18-JUN-2018
A raw QT interval change from baseline as one of the criteria 
for limiting dose escalation and for increased monitoring of 
individual participants has been included in error. QTcF
has been chosen as the most appropriate corrective measure 
of QT for this study and this is now reflected throughout. 
Accordingly, one of the required criteria for limiting further
dose escalation and increased monitoring of individuals is now 
a change in QTcF from baseline of > 60 msec. To remove the 
requirement for reversibility testing at prescreening/screening, 


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Revision Chronology:
as evidence of reversibility is no longer a requirement for
inclusion as per the previous amendment. Consequently, 
participants who would not be a screen failure under the entry 
criteria in the current version of the protocol may be 
rescreened. Furthermore, participants that were not a screen 
failure but could not be dosed during the screening window 
due to logistical reasons may also be rescreened. To extend 
the PK sampling period in the 2 mg and 10 mg cohorts, to 
better characterise the PK profile of
GSK3511294. To clarify that local labs are required for all 
sentinel participants at the 48 hour time point to enable dosing 
of the rest of the cohort. As the German in-patient
stay is longer than the UK, local labs prior to discharge from 
the clinical site are required on Day 8 and not at 48 hours post 
dosing (Day 3). Minor corrections of typos throughout.
2016N270529_06
07-Jan-2019
Inclusion of additional interim analyses to better assess blood 
eosinophil count return towards baseline profiles at the 
highest dose levels investigated and better inform dose
and dosing regimen to move forward into the next phase of 
development. The earliest additional interim analysis is 
planned no earlier than once data is available at the 26-week
time point after dosing Cohort 4 (planned 100 mg dose).
1.1.
RAP Amendments 
The original RAP was finalised prior to the first interim analysis. This RAP amendment 
was written after the first interim analysis and prior to any subsequent interim analyses, 
and prior to final DBF.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 6 (Dated: 07/JAN/2019).
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To assess the safety and 
tolerability of ascending single 
subcutaneous (SC) doses of 
GSK3511294 in participants 
with mild to moderate asthma

Adverse events (AE), serious adverse events
(SAE), including systemic reactions and local 
injection site reactions

Vital signs, electrocardiograms (ECGs), 
laboratory safety data – including liver and renal 
chemistry, high sensitivity C-reactive protein 


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Objectives
Endpoints
(hsCRP), and complement (C3 and C4)
Secondary Objectives
Secondary Endpoints

To evaluate the plasma 
pharmacokinetics (PK) of 
ascending single SC doses of 
GSK3511294 in participants 
with mild to moderate asthma

To evaluate the dose response of 
blood eosinophil counts after 
ascending single SC doses of 
GSK3511294 in participants 
with mild to moderate asthma

To assess the immunogenicity of 
GSK3511294

Plasma PK parameters of GSK3511294 after 
single SC doses: AUC(0-∞), AUC(0-t), AUC(0-
Week4), AUC(0-Week12), AUC(0-Week26), 
%AUCex, Cmax, tmax, tlast, CL/F, Vd/F, λz and 
t½ when assessable*

Ratio to baseline in absolute blood eosinophil 
count

Frequency and titers of binding anti-drug 
antibodies (ADAs) to GSK3511294, before and 
after GSK3511294 administration
Exploratory Objectives
Exploratory Endpoints

To assess the effect of single SC 
doses of GSK3511294 on lung 
function

Serum total IL-5 following 
single SC doses of GSK3511294

To explore drug specific 
circulating immune complexes 
(CIC) after single SC doses of 
GSK3511294

To determine the effect of single 
SC doses of GSK3511294 on 
serum markers of asthma

To explore the PK/PD (blood 
eosinophil count) relationship 
after single SC doses of 
GSK3511294, if deemed 
appropriate

Change from baseline: forced expiratory volume 
in 1 second (FEV1), forced vital capacity (FVC), 
peak expiratory flow (PEF)

Serum total IL-5 levels

Levels of CICs

Change from baseline in asthma biomarkers

GSK3511294 plasma concentration and blood 
eosinophil count for determination of Half 
maximal effective concentration (EC50) and 
maximum effect, if deemed appropriate
* PK parameter abbreviations: AUC(0-∞) = area under the concentration-time curve from time zero
(pre-dose) extrapolated to infinite time; AUC(0-t) = area under the concentration-time curve from time zero
(pre-dose) to last time of quantifiable concentration within a participant across all treatments;
AUC(0-WeekX) = area under the concentration-time curve from time zero to Week X; %AUCex =
percentage of AUC(0-∞) obtained by extrapolation; Cmax = maximum observed concentration;
tmax = time of occurrence of Cmax; tlast = time of last quantifiable concentration; CL/F = apparent
clearance following subcutaneous dosing; Vd/F = apparent volume of distribution after subcutaneous
administration; λz = terminal phase elimination rate constant; t½ = terminal phase half-life.


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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

Single ascending dose FTIH study to evaluate the safety, tolerability, 
immunogenicity, PK and pharmacodynamics of subcutaneously administered 
GSK3511294 in participants with mild to moderate asthma and blood 
eosinophils ≥ 200 cells/μL at screening.

Multi-centre, randomised, double-blind (sponsor clinical pharmacology 
modelling and simulation [CPMS] and statistician representatives open), 
placebo-controlled, parallel-group study.
Dosing

Each participant will receive a single SC dose of GSK3511294 or placebo

Sentinel participants: In each cohort, one placebo and one GSK3511294 
participant will be dosed before the remaining participants. Providing no 
safety issues are identified in the sentinel participants over an observation 
period of at least 72 hours, the remaining participants in the cohort may be 
dosed. 
The Investigator will discuss any safety concerns with the GlaxoSmithKline 
(GSK) medical monitor before dosing the remaining participants in a cohort. 
Sentinel dosing is not required in cohorts investigating a dose lower than or 
equal to the highest dose tested to date.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

Planned single ascending SC doses of GSK3511294 were 2, 10, 30, 100 and 
300 mg. 

Actual dose levels matched the planned doses.

Planned cohort sizes are shown in the Overview of Study Design and Key 
Features figure; additional participants may be added to cohorts, if necessary
to characterise the PK or pharmacodynamics of GSK3511294. 

In each cohort, participants will be randomised 3:1 to receive GSK3511294 or 
placebo. 

Additional cohorts of up to 12 participants may be added to test additional 
dose levels or to repeat a dose level already tested, if deemed necessary; 
however, the dose will not exceed 300 mg. The planned sample size is n=48 
participants; the maximum sample size is n=72 participants (excluding 


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Overview of Study Design and Key Features
replacements for prematurely withdrawn participants).
Interim 
Analyses

In stream data review occurred during the study to support dose escalation 
decisions. A formal interim analysis (IA1) took place once data were 
available at the 12-week time point after dosing in Cohort 4 (100 mg dose). 
The aim of the first interim analysis was to determine the doses and a dosing 
interval to move forward into the next phase of development.

The primary focus of the first interim analysis was the reduction in blood 
eosinophil counts. The ratio to baseline was derived for each dose and time
point and compared to corresponding data from the placebo arm. Posterior 
means and corresponding 95% credible intervals were constructed for each of 
the available doses and time points. Furthermore, posterior probabilities that 
the placebo adjusted ratio is less than various thresholds of interest were
constructed.

Following the review of the data from the first interim analysis, the protocol 
was amended to allow additional interim analyses to further assist the clinical 
development plan of the asset. None of the interim analyses are expected to 
affect the progression of this FTIH study.

Subsequent interim analyses will also mainly focus on the reduction in blood 
eosinophil counts and if deemed appropriate may also review CIC, IL-5, PK
and immunogenicity data, as data permit.

In addition, blinded summary tables by cohort may be produced to facilitate 
review of safety data for Global Safety Board (GSB).
2.4.
Statistical Hypotheses / Statistical Analyses
Given this study is the FTIH for GSK3511294, there are no formal statistical hypotheses
to be tested. The assessment of safety and tolerability of single SC doses of
GSK3511294 in this study will not include any formal comparisons. 
For the PK and PD data, where appropriate, an estimation approach will be adopted and 
point estimates with corresponding confidence intervals will be provided. In addition, for 
the analysis of blood eosinophils, posterior means and corresponding 95% credible 
intervals will be constructed for each dose and time point. Furthermore, posterior 
probabilities that the placebo adjusted ratio is less than various thresholds of interest will 
be constructed.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
In Stream Data Review

In stream data review occurred during the study to support dose escalation decisions. 

Clinical Statistics were responsible for producing summary statistics of blood 
eosinophil data by dose and timepoint. Participants assigned to placebo were pooled 
across cohorts. Care was taken to ensure that no outputs were shared with the study 
team that would have inadvertently disclosed the treatment allocation of individual 
participants either that had started dosing or who had yet to be dosed. For example, 
n’s were not displayed in the summary statistics of incomplete cohorts where 1 
participant had yet to be dosed.

Blood eosinophil count data were natural log-transformed prior to summarising and 
back-transformed as appropriate. The following summary statistics were presented: 
number of participants with available data (n) (if blind could be maintained), 
geometric mean, 95% CI of geometric mean and Standard Deviation (SD) logs.
Blood eosinophil count data and blood eosinophil count ratio to baseline were
presented. Outputs were produced using SAS software and independently Quality 
Controlled (QCed). Cut-off dates for each dose escalation meeting were agreed in 
advance and all available data for the cohort were included unless the inclusion of 
partial data for a specific timepoint and individual would have unblinded any 
participants. Summaries for earlier cohorts were updated if additional data were
available for those cohorts. 

Dose escalation was only allowed after review of the following data at the highest 
dose level tested to date: at least 4 weeks’ post-dose safety data and at least 2 weeks’ 
post-dose PK data from at least 4 participants on active treatment; and at least 72 
hours’ post-dose safety data from the remaining participants in the cohort. In the 
unlikely event that one or more of the remaining participants discontinued the study 
within 72 hours after dosing, all available safety data from that/those participants 
were to have been reviewed. There were no minimum data requirements for blood 
eosinophil data – all available data were summarised.

Clinical Pharmacology Modelling & Simulation (CPMS) were responsible for 
producing summary statistics of available derived PK parameters by cohort. CPMS 
are unblinded to study treatment. Care was taken to maintain the study blind. 
Summaries for earlier cohorts were updated if deemed appropriate. The following 
summary statistics were presented: geometric mean, 95% CI of geometric mean, SD 
logs, geometric coefficient of variation (CV) (%), median, minimum and maximum. 
Estimates for Cmax and AUC(0-∞) with 95% prediction interval at the next dose level 
were provided.

The outputs are for study team guidance and will not form part of the Clinical Study 
Report though formal summaries and plots of the final, complete and cleaned data 
will form part of the Clinical Study Report. 


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
In addition, blinded summary tables by cohort may be produced to facilitate review 
of safety data for GSB. If produced, these will be identical to the SAC outputs except 
will be presented by cohort rather than by actual treatment. Any AE summaries will 
have a total column. Possible candidates for blinded safety outputs for GSB are 
indicated in Appendix 12. 
Planned Interim Analyses

A first formal interim analysis took place once the accumulated safety, PK and 
PD data were deemed sufficient to determine the doses and a dosing interval to 
move forward into the next phase of development. This did not affect the 
progression of this FTIH study.

The first interim analysis (IA1) occurred once data were available at the 12-week 
time point after dosing in Cohort 4 (100 mg or placebo). 

A second interim analysis (IA2) will take place after blood eosinophil data are 
available up to Week 26 for all subjects in Cohorts 1 – 4 and in at least 7 out of 
the 8 participants in Cohort 5 (300mg or placebo). 

A third interim analysis (IA3) is planned to occur once blood eosinophil data are 
available at the 32-week timepoint for 7 out of the 8 participants in Cohort 5 
(300mg or placebo).

Currently there are no plans for a fourth interim analysis (IA4), but this might be 
re-assessed after the results for the third interim analysis have been discussed. If 
performed, IA4 would be a repeat of a sub-set of the outputs included in IA3 but
would include available data at the latest timepoints. 

The aim of the interim analyses is to assist in the clinical development plan of the 
asset by informing dose and dosing interval recommendations for future 
GSK3511294 studies.

IA1 focussed on the reduction in blood eosinophil count data, but also included a 
review of the PK data. IA2 will only include a review of blood eosinophil data. 
IA3 in addition to blood eosinophil data will also include CIC, IL-5, Complement, 
Total IgE, immunogenicity and PK data, as data permit. IA4 (if performed) will 
be a subset of the outputs produced for IA3.

The blood eosinophil count, CIC, IL-5 and immunogenicity data included in any
interim analyses (where applicable) will not have been fully cleaned by Data 
Management as they will remain blinded to the results. Nevertheless, 
haematology and biomarker sample dates and times data will have been cleaned. 
A list of data required for the interim analyses is provided in the table below:


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Form
Source
Reason
Notes
Interim 
Analysis
LAB
DM dataset
Require clean 
dataset to 
merge sample 
dates and times 
to enable 
windowing 
rules to be 
applied
Only dates/times 
corresponding to 
LBTESTCD=EOS_BL
C were required for 
IA1. In addition, 
dates/times 
corresponding to 
LBTESTCD=
IGE_PLC, C3_PLC and
C4_PLC are required
for IA3 and may also be 
required for IA4 (if 
performed). For blood 
eosinophil counts, this 
dataset will only contain 
results for screening 
values. Post dose results 
are treated as missing 
with an original text 
result of ‘BLINDED’
for EOS_BLC. Must be 
a record for each subject 
for each visit. There 
shouldn’t be any 
missing records for 
intermediate visits.
Blood 
eosinophil 
count data 
required 
for all 
interim 
analyses,
IgE, C3 
and C4 
required 
for IA3 
and may 
be 
included 
in IA4 if 
performed
.
Lab test results
Q2
Contain actual 
blood 
eosinophil 
counts as well 
as IgE, and 
Complement 
(C3 and C4) 
data
Must not be 
disseminated outside of 
CS or CPMS. CS will 
directly query any odd-
looking results.
Blood 
eosinophil 
count data 
required 
for all 
interim 
analyses, 
IgE, C3 
and C4 
required 
for IA3
and may
be 
required 
for IA4 if 
performed
.


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Form
Source
Reason
Notes
Interim 
Analysis
EXPOSURE
DM dataset
Needed so that 
actual date and 
time of dosing 
can be merged 
in order to 
apply the 
windowing 
rules.
All
RAND
DM dataset
Required to 
merge on 
randomisation 
numbers and 
subsequently 
the actual 
treatment 
codes.
All
Randomisation
CSV file 
from 
RandAll NG 
Coordinator
Actual 
treatment 
allocations are 
required, 
though study 
team members 
will only 
review 
summary 
information.
This information is 
already available to CS 
up to the latest cohort to 
be reviewed at the dose 
escalation meetings. 
Must not be 
disseminated outside of 
CS or CPMS.
All
CONMEDS
DM dataset
CS don’t 
require this 
dataset, but all 
concomitant 
medications 
must be clean 
and up to date 
to make 
decisions on 
protocol 
deviations.
Will need to discuss 
protocol deviations 
prior to the interim 
analysis and identify if 
any subjects need to be 
excluded or partially 
excluded from the 
interim analysis. 
All
PK 
SMS2000
Required for 
population PK 
analysis
Treatment details and 
body weight need to be 
merged on to the PK 
concentration dataset
Required 
for IA1
and IA3, 
may be 
required 
for IA4 if 


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Form
Source
Reason
Notes
Interim 
Analysis
performed
VITALS
DM dataset
Body weight 
(latest available 
Predose) 
required for 
population PK 
analysis
Required 
for IA1
and IA3, 
may be 
required 
for IA4 if 
performed
BIOMARK
DM dataset
IL-5 and CIC 
sample dates 
and times
DM to reconcile dates 
and times of collections 
but will remain blinded 
to test results.
Required 
for IA3, 
may be 
required 
for IA4 if 
performed
IL-5 results
Alliance 
Pharma
IL-5 data
DM will remain blinded 
to test results. Test 
result must not be 
disseminated outside of 
CS or CPMS.
Required 
for IA3, 
may be 
required 
for IA4 if 
performed
CIC results
BIB
CIC data
DM will remain blinded 
to test results. Test 
result must not be 
disseminated outside of 
CS or CPMS
Required 
for IA3, 
may be 
required 
for IA4 if 
performed
IMGEN
DM dataset
Immunogenicit
y sample dates 
and times
DM to reconcile dates 
and times of collections 
but will remain blinded 
to test results. 
Required 
for IA3, 
may be 
required 
for IA4 if 
performed
Immunogenicit
y results
GSK 
Clinical 
Immunolog
y Lab (US)
Binding 
antibody and 
neutralising 
antibody 
detection
DM will remain blinded 
to test results. Test 
result must not be 
disseminated outside of 
CS or CPMS
Required 
for IA3, 
may be 
required 
for IA4 if 
performed

The primary focus of the interim analyses will be reduction in blood eosinophil 
counts. The ratio to baseline will be derived for each dose and time point and will be 


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compared to corresponding data from the placebo arm. Posterior means and 
corresponding 95% credible intervals will be constructed for each of the available 
doses and time points. 

For each available dose group, the posterior probability that the placebo adjusted 
ratio to baseline in blood eosinophils is 0.16 at the 12-week timepoint will be 
calculated. This corresponds to the posterior probability that the reduction from 
baseline in blood eosinophil count is at least 84% compared to placebo at Week 12.
If this probability exceeds 80%, the dose will be deemed to have met the pre-defined 
success criterion.

The same statistical methods will be applied for the interim analyses as for the SAC 
analysis.

For the interim analyses, the posterior probability that the placebo adjusted ratio 
from baseline in blood eosinophils is less than various thresholds (e.g. 0.50, 0.30
and 0.15) at appropriate timepoints including at least 12, 18, 26 and 32 weeks (if 
available) will also be calculated, dependent on the previous results. For example, if 
there is insufficient evidence of a 50% improvement over placebo (corresponding to 
a ratio of 0.50), then lower ratio thresholds will not be investigated. Later timepoints 
may also be included if it is considered there are sufficient data.

The PD interim analysis will be performed by GSK Clinical Statistics and only the 
responsible statistician (and Quality control [QC] statistician) will have access to 
individual participant data. However, the findings of the interim analysis will be 
shared with the entire GSK study team and relevant decision-makers within GSK.

In support of the blood eosinophil data analysis, an interim population PK analysis 
will be conducted. The population PK parameters will be estimated using planned 
sampling times. This analysis will be performed by GSK CPMS who will be 
unblinded to study treatment.

Interim analysis outputs may be shared with relevant regulatory authorities to discuss 
the clinical development plan strategy.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final SDL has 
been declared by Data Management.
3.
All criteria for unblinding the randomisation codes have been met. 
4.
Randomisation codes have been distributed according to RandAll NG procedures.
5.
PK data have been uploaded 


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6.
Data Quality Lead (DQL) has declared database freeze (DBF)


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

Comprised of all participants who were screened.

Listings (unless 
specified 
otherwise)
Safety

Comprised of all randomised participants who receive 
at least one dose of study treatment.

This population will be based on the treatment the 
participant actually received rather than their 
randomised treatment.

Note that any non-randomised participant that 
received at least one dose of study treatment should 
be listed.

Study Population

Safety
Pharmacokinetic
(PK)

Participants in the ‘Safety’ population for whom a 
pharmacokinetic sample was obtained and analysed.

PK
Pharmacodynamic
(PD)

Participants in the ‘Safety’ population for whom a post-
dose pharmacodynamic (ie blood eosinophil) sample 
was obtained and analysed.

Blood eosinophils
Enrolled

All participants who were randomised. Note screening 
failures (who never passed screening even if 
rescreened and even if they did pass pre-screening) 
and participants screened but never enrolled into the 
study (Reserve, Not Used) are excluded from the 
Enrolled population if they were not randomised. 
Participants that were randomised, but not dosed (e.g. 
because of failing pre-dosing checks) are included in 
the Enrolled population.

Study Population
1.
Refer to Appendix 12: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan (V1.0/05Oct2017).
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised on the protocol deviations 
dataset. 
o Protocol deviations will be assessed prior to unblinding at the interim analyses as 
well as prior to the final unblinding and freezing of the data. It is likely that 
participants who were included in the interim analysis will have the same analysis 
population flag at final analysis that they had at interim analysis. However, it is 
possible that information may come to light after the interim analyses that hadn’t 


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been considered at the interim analyses, leading to a change in analysis population 
flag at final analysis for individual subjects.
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided at the final analysis. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description[2]
Description
Order [1]
A
GSK3511294 2 mg SC
GSK 2 mg
2
B
GSK3511294 Dose level 2
GSK 10 mg
3
C
GSK3511294 Dose level 3
GSK 30 mg
4
D
GSK3511294 Dose level 4
GSK 100 mg
5
E
GSK3511294 Dose level 5
GSK 300 mg
6
F
GSK3511294 Dose level 6
GSK XX mg
7
G
GSK3511294 Dose level 7
GSK XX mg
8
N/A
GSK3511294 All Active Doses
GSK All Doses
9
N/A
All doses including placebo
Total
10
P
Placebo
Placebo
1
NOTES:
1.
Order represents treatments being presented in Tables, Figures and Listings (TFL), as appropriate.
2.
Actual dose levels will be confirmed during the study. Dose levels 6 and 7: no current plans but included in case 
additional doses are to be investigated or doses are to be repeated. Replace X’s with actual dose used in the 
cohort.
Treatment comparisons for each dose group versus placebo will be displayed using the 
following format, with XX replaced with the actual dose
GSK XX mg vs Placebo
A column denoting all active doses will be displayed for all safety tables. Some
population summaries will include an overall total for all subjects in the population. 
These will be indicated in the programming notes for the relevant table specifications.
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to dose 
and used as baseline.
Unless otherwise stated, if baseline data are missing no derivation will be performed and 
baseline will be set to missing.


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5.3.
Multicentre Studies
In this multicentre global study, enrolment will be presented by country and investigative 
site.
Centre 
Number
Name
Country
Status
-Hannover
Germany
Active
Berlin
Germany
Active
-Manchester
United Kingdom
Active
-London
United Kingdom
Active
-London
United Kingdom
Active
-Cambridge
United Kingdom
Active
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered.
Category
Details
Strata
None
Covariates
Baseline blood eosinophil counts
5.4.2.
Examination of Subgroups

There will be an optional sensitivity analysis to assess the impact of participants in 
the following subgroups for the primary PD analysis. Although not expected in this 
patient population, exacerbations and changes in medication could affect the PD 
results. Other subgroups of interest may be defined prior to unblinding.
Subgroup
Categories 
ICS Asthma Medication 
Changed 
Exacerbations or other events 
leading to the use of 
corticosteroids
>=1 
5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Section
Component
17.3
Appendix 3: Assessment Windows
17.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
17.5
Appendix 5: Data Display Standards & Handling Conventions
17.6
Appendix 6: Derived and Transformed Data
17.7
Appendix 7: Reporting Standards for Missing Data
17.8
Appendix 8: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “Safety” population, unless otherwise 
specified.
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics and prior and concomitant 
medications will be based on GSK Core Data Standards.  Details of the planned displays
are presented in Appendix 12: List of Data Displays.


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7.
SAFETY ANALYSES
The safety analyses will be based on the “Safety” population, unless otherwise specified.
7.1.
Overview of Planned Analyses
Table 1 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 12: List of Data Displays.
Table 1
Overview of Planned Safety Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Adverse Events
All AEs 
Y
Y
Drug-related AEs
Y
Serious AEs
Y
Y
AEs leading to withdrawal
Y
Y
Relationship between SOC and verbatim  
text
Y
AEs by Preferred Term 
with Occurrences >=5%
Y
AEs of Special Interest
Y
Y
AEs by ADA Assay Result Category
Y
Laboratory Data
Liver and renal Chemistry
Y
Y1
Y
Haematology
Y1
Y
Urinalysis Data
Y1
Y
High sensitivity C-reactive protein 
(hsCRP)
Y
Y
ECG
ECG Values
Y
Y2
Y
ECG Findings
Y
Y
Frequency of Maximum ECG Values
by Pre-Specified Categories
Y
Vital Signs
Vital Signs Values
Y3
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual participant observed raw data.     
[1] Two Listings of chemistry and haematology data will be produced. One will list all abnormalities of PCI and the other 
will list all chemistry/haematology data for all participants with any chemistry/haematology abnormalities.
[2] Two  listings of ECG data will be produced. One will list all ECG abnormalities of PCI and the other will list all ECG 
data for all participants with any ECG PCI values.
[3]Two listings of vital signs data will be produced. One will list all vital signs abnormalities of PCI and the other will list 
all vital signs data for all participants with any vital signs PCI values. 


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7.2.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 12: List of Data Displays.
7.3.
Adverse Events of Special Interest Analyses
A summary table showing the number and percent of subjects, broken down by preferred 
term will be created using Hypersensitivity SMQ (narrow), Anaphylactic Reaction SMQ
(narrow) and Vasculitis SMQ (narrow) as well as the number and percent of subjects with 
events of injection site reaction broken down by preferred term using MedDRA high 
level term (HLT) “Injection site reactions” under General disorders and administration 
site conditions SOC. 
In addition, a profile summary table will be produced containing information including, 
but not be limited to, the number of occurrences of the event, event characteristics, time 
to onset, intensity, outcome and whether it led to withdrawal from the study.
A listing will be produced for subjects reporting events under the specified above SMQs 
and MedDRA HLT.
7.4.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. The details of the planned displays are in Appendix 12: List of Data 
Displays.
7.5.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. Test results for hsCRP 
and Complement (C3 and C4) will be included within the laboratory data transfer and 
summarised in the same format as the standard haematology and chemistry data. For the purposes 
of summary statistics, any values <LLQ for hsCRP will be imputed to half the LLQ value (i.e. 
imputed to 0.075). The details of the planned displays are presented in Appendix 12: List 
of Data Displays.
8.
LUNG FUNCTION TESTS
FEV1, % predicted normal FEV1 and FVC will be summarised at each scheduled timepoint. The 
details of the planned displays are presented in Appendix 12: List of Data Displays.


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9.
PHARMACOKINETIC ANALYSES

The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” 
population, unless otherwise specified.
9.1.
Primary Pharmacokinetic Analyses
9.1.1.
Endpoint / Variables
9.1.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 17.5.3
Reporting Standards for Pharmacokinetic)
Blood sampling time will be related to the start of dosing. Linear and semi-logarithmic
individual plasma concentration-time profiles (by dose and participant) and mean (±SD) 
and median profiles by GSK3511294 dose will be plotted. Plasma concentrations of 
GSK3511294 will be listed and summarised by dose and nominal time.
9.1.1.2.
Derived Pharmacokinetic Parameters
GSK3511294 Pharmacokinetic parameters will be calculated by standard non-
compartmental analysis according to current working practices and using Phoenix.
All calculations of non-compartmental PK parameters will be based on actual sampling 
times. For each participant and for each dose, pharmacokinetic parameters described in 
Table 2 will be determined from the GSK3511294 plasma concentration-time data, as 
data permit.

All pharmacokinetic parameters will be listed and summarised descriptively by dose.
Table 2
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-t)
Area under the plasma concentration-time curve from time zero to the time of the last 
quantifiable concentration (C(t)) will be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.
AUC(0-∞)
Area under the plasma concentration-time curve from time zero extrapolated to infinity will 
be calculated as: 
AUC(0-inf) = AUC(0-t) + C(t) / lambda_z
AUC(0-
WeekX)
Area under the plasma concentration-time curve from time zero to Week X will be 
calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid. Planned parameters are AUC(0-Week4), 
AUC(0-Week12) and AUC(0-Week26).
%AUCex
The percentage of AUC (0-∞) obtained by extrapolation (%AUCex) will be calculated as:
[AUC(0-inf) – AUC(0-t)] / AUC(0-inf) x 100
Cmax
Maximum observed plasma concentration, determined directly from the plasma 
concentration-time data.
z
Terminal phase elimination rate constant.
The number of points used to determine λz will also be reported.


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Parameter
Parameter Description
tmax
Time to reach Cmax, determined directly from the plasma concentration-time data.
t½
Apparent terminal phase half-life will be calculated as: 
t½ = ln2 / lambda_z
tlast
Last time point where the concentration is above the limit of quantification
CL/F
Apparent clearance
CL/F=dose / AUC(0-inf)
Vd/F
Apparent volume of distribution 
Vd/F=dose/ (z x AUC(0-inf))
NOTES:

Additional parameters may be included as required.
9.1.2.
Summary Measures

Area under plasma concentration-time curve (AUC (0-∞)) and Cmax following a 
single dose
9.1.3.
Population of Interest 
The primary pharmacokinetic analyses will be based on the “Pharmacokinetic” 
population, unless otherwise specified.
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Missing concentrations and concentrations below the limit of quantification of the assay 
will be handled as described in Guidance Document GUI_51487.
9.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
9.1.5.1.
Statistical Methodology Specification
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data are available (i.e. if participants have well defined plasma profiles). Analyses may 
not be performed on Cmax or AUC if the team considers there are a large amount of data 
either below the limit of quantification or non-calculable; alternatively, if the dose with 
limited data is at the lower end of the dose range, the data of this dose will be excluded,
and the appropriate analysis conducted on the rest of the data. However, if there are non-
calculable PK parameter data at intermittent doses no statistical analyses will be 
performed. A minimum of 3 doses will be required to assess dose proportionality.


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Pharmacokinetic Statistical Analyses for Dose Proportionality: Power Method
Endpoint / Variables

AUC(0-∞) and Cmax to be separately analysed after loge-transformation.
Model Specification

Dose proportionality (Power Model)

Fixed effect model with log dose as a covariate 
Model Checking & Diagnostics

Model assumptions will be applied, but appropriate adjustments may be made based on the 
data.

Normality assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. 
checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable.

If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data
Model Results Presentation

The coefficient of the slope with 90% confidence intervals, on the log scale, will be calculated, 
using the pooled estimate of variance, and used to assess dose proportionality. Point 
estimates and confidence intervals for the slope will be reported to 2 decimal places.

Scatter plots of log PK parameter vs Log (dose) will be produced for AUC(0-inf) and Cmax.
9.2.
Secondary Pharmacokinetic Analyses
Dose proportionality will also be assessed using the ANOVA method 
Pharmacokinetic Statistical Analyses for Dose Proportionality: ANOVA Method
Endpoint(s)

AUC(0-), Cmax

Each endpoint to be assessed separately.
Model Specification

The PK parameter will be dose-normalised prior to loge-transformation by multiplying by the 
reference dose / dose

Dose will be fitted as a fixed effect

To calculate the dose normalised parameters, the derived parameter for each dose will be 
divided by the relevant dose and multiplied by the chosen nominal dose (10mg). 
Model Checking & Diagnostics

Refer to dose proportionality power method analyses.
Model Results Presentation

Point estimates for the adjusted means on the loge scale, the mean difference between each 
dose (test) and the reference dose and associated 90% confidence interval will be constructed 
using the residual variance. These will not be presented.

The point estimate and confidence interval will then be exponentially back-transformed to allow 
the presentation of the adjusted (least square) geometric means for each treatment (dose) and 
associated 90% confidence intervals for the ratio test/reference.


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Pharmacokinetic Statistical Analyses for Dose Proportionality: ANOVA Method

Plots will also be provided showing the adjusted geometric mean ratio of test to reference 
treatment (dose) for AUC(0-∞) and Cmax together with 90% confidence interval.

Boxplots of dose-normalised AUC(0-) and Cmax versus dose will also be produced, a 
separate plot for each PK parameter.


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10.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
The primary goal of this analysis is to characterize the population pharmacokinetics of 
GSK3511294 administered subcutaneously in participants with mild to moderate asthma 
enrolled in this single dose escalation FTIH study. The influence of participant
demographics (e.g. weight, Body Mass Index (BMI)), and if deemed appropriate, 
baseline characteristics on the pharmacokinetics of GSK3511294 in this population will 
be investigated, as data permit. The individual participant PK parameters and predicted 
concentrations (post-hoc estimates) will be estimated and may be used to conduct any
subsequent exposure and/or concentration-response (PK/PD) analyses (PD=blood 
eosinophil count), if deemed appropriate.
10.1.
Statistical Analyses / Methods
A summary of the planned population pharmacokinetic analyses are outlined below:
o
GSK3511294 plasma concentration-time data will be analysed by population methods
(non-linear mixed effects modelling) using appropriate software (e.g. NONMEM, 
SAS).
o
A description of the key models tested during the model development will be 
provided and tabulated.
o
The population PK parameter estimates with 95% CI from the final model will be 
tabulated. Goodness of fit plots for the final model will be presented.
o
Individual predicted GSK3511294 plasma concentrations will be listed.
o
Individual post-hoc PK parameter estimates will be listed.
In support of the described analysis, a specific dataset will be generated. Further details 
of the population PK analysis methodology are provided in Appendix 9: Population 
Pharmacokinetic (PopPK) Analyses.
11.
IMMUNOGENICITY ANALYSES
For the immunogenicity assessment, two types of anti-drug antibody (ADA) assays will 
be performed, a binding antibody assay and a neutralizing antibody assay.
For the binding assay, there will be a three-tiered analysis: screening, confirmation and 
titration. The screening assay produces a result of positive or negative relative to a 
screening cut point. Positive samples continue with the confirmation assay, which also 
produces a result of positive or negative relative to a confirmation cut point.  For positive 
confirmation samples, a titre value will also be obtained to quantify the degree of binding 
in a titration assay and the sample will be tested with the neutralizing assay, which also 
reports results as positive or negative.


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The binding ADA results at each available timepoint, including Predose as well as at any 
time post-baseline, will be summarised. Summary statistics for the titre result will also be 
presented by visit. 
The binding ADA results at each visit will be categorised as negative, transient positive 
(defined as a single confirmatory positive immunogenic response that does not occur at 
the final study assessment) or persistent positive (defined as a confirmatory positive 
immunogenic response for at least 2 consecutive assessments or a single result at the final 
study assessment). In addition, the highest post-baseline binding ADA confirmatory 
result obtained for a subject will be summarised. Subjects with both positive and negative 
results will be identified in the positive category. Summary statistics for the highest titre 
result will also be presented.
A summary of adverse events by highest post-baseline binding ADA result will be 
produced.
A summary of positive confirmation binding ADA assay results in the subset of subjects 
who did not have a positive confirmation binding ADA assay result prior to the dosing of 
study treatment will also be presented. Neutralizing antibody assay results will be 
summarised by visit and will also be summarised by category (positive or negative).
Immunogenicity data will be listed for participants with at least one positive screening 
binding assay result.
12.
CIRCULATING IMMUNE COMPLEXES
The presence of CICs will be determined in serum samples using a validated 
bioanalytical assay, using immunoglobulin detection. Further characterization with drug 
specific detection may be performed as needed. Summary statistics will be presented of 
CIC concentration by visit. A summary figure will also be presented.
13.
COMPLEMENT, IgE AND INFLAMMATORY MARKERS
Complement (C3 and C4) and Total IgE will be summarised by parameter and visit and 
presented as a table and as a figure. The summary table will include baseline 
concentration, concentrations at each visit and ratio to baseline at each visit. Summary 
statistics to be presented are n, geometric mean, standard deviation (on log scale), 
median, minimum and maximum.
Inflammatory markers at screening will comprise Tumour necrosis factor-alpha (TNF-α),
IL-2, IL-6, IL-10, Interferon-gamma (IFN-γ) and C3a. A screening serum sample will
also be stored for assay of Antinuclear antibodies (ANA), Anti-neutrophil cytoplasmic
antibody (ANCA) and anti-DNA antibodies, if required at a later date based on
symptoms. After dosing, additional inflammatory markers and tests will be considered
on an ad hoc basis should there be clinical concerns regarding an immune mediated AE. 
Inflammatory marker data will be presented as a listing.


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14.
PHARMACODYNAMIC AND BIOMARKER ANALYSES
14.1.
Primary Pharmacodynamic and Biomarker Analyses
14.1.1.
Endpoint / Variables

Blood eosinophil ratio to baseline (following log-transformation)
14.1.2.
Population of Interest
The primary pharmacodynamics and biomarker analyses will be based on the
“Pharmacodynamic” population, unless otherwise specified.
14.1.3.
Strategy for Intercurrent (Post-Randomization) Events
Missing data will not be imputed. Important events, such as the use of disallowed 
medication, that could affect the blood eosinophil counts will be considered during the 
review of protocol deviations prior to unblinding. A decision will be made prior to 
unblinding as to whether participants are full or partial protocol violators. Full protocol 
violators will be excluded from the PD population and partial violators will have only 
assessments included that occurred prior to the violation.
14.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 14.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
14.1.4.1.
Statistical Methodology Specification
Endpoint / Variables

Blood eosinophil ratio to baseline (following log-transformation)
Model Specification

Data will be analysed by fitting a Bayesian dose response model. The 4-parameter Emax 
model will be fitted by first intent:

Log Blood Ratio =E0 - Emax * (Dosen  / (ED50n+Dosen) + Eb
where E0 is the basal effect corresponding to the response when the dose is zero, Emax is the 
maximum eosinophil reduction. ED50 is the dose achieving half the maximum eosinophil 
reduction, n is the slope parameter and Eb is the baseline eosinophil count. 

However, should the data not allow for a suitable model fit, then other models, such as the 3-
parameter Emax model, may be attempted. Alternatively, other endpoints may be investigated 
if they allow a more suitable model fit. For example, weighted means may be analysed, derived 
as Area Under Effect Curve up to Week 26 (AUEC(0-Week 26)) divided by the duration. AUEC 
would be calculated using the linear trapezoidal rule for blood eosinophil counts or ratio to 


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baseline and will be based on actual sample times.

This endpoint will be analysed using Bayesian inference assuming non-informative 
priors of the form;
PRIOR e0˜Normal (0,1, sd=1000);
PRIOR Emax˜Normal(0.1, sd=1000, lower=0);
PRIOR ed50˜Beta(0.5, 5);
PRIOR n~Uniform(0.5, 5);
Model Checking & Diagnostics

Refer to the relevant documentation (Bayesian Statistics Best Practice at GSK –
Clinical Trials using Bayesian Inference).
Model Results Presentation

For each dose and timepoint, blood eosinophil ratios will be summarised with 
descriptive statistics

Posterior means and corresponding 95% credible intervals will be constructed for 
each dose and time point.

At the interim analysis, for each available dose group, the posterior probability 
that the placebo adjusted ratio from baseline in blood eosinophils is 0.16 at the
12 week timepoint will be calculated. If this probability exceeds 80%, the dose 
will be deemed to have met the pre-defined success criterion.

At the final analysis, for each dose group, the posterior probability that the 
placebo adjusted ratio from baseline in blood eosinophils is 0.25 at the 26 week 
timepoint will be calculated. If this probability exceeds 80%, the dose will be 
deemed to have met the pre-defined success criterion.

For both the interim analyses and the final analysis, the posterior probability that 
the placebo adjusted ratio from baseline in blood eosinophils is less than various 
thresholds (e.g. 0.50,0.30 and 0.15) at appropriate timepoints including at 
least 12, 18, 26 and 32 week timepoints (data permitting for the interim analysis)
will also be calculated, dependent on the previous results. For example, if there is 
insufficient evidence of a 50% improvement over placebo (corresponding to a 
ratio of 0.50), then lower ratio thresholds will not be investigated.  
Subgroup Analyses

N/A
Sensitivity and Supportive Analyses

If the PD and Safety populations differ, the same statistical analysis using the Safety 
population may also be conducted.

If any participants experience an exacerbation during the treatment phase and are given 
systemic steroids, or if they change their ICS asthma medication or if they are prescribed 
corticosteroids during the treatment phase, then the same statistical analysis may be 
conducted excluding those participants. 

The primary analysis will be repeated using windowed observations (See Section 17.3.1).

Ratio to Baseline Blood eosinophils will be loge transformed and compared between 


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treatments using a mixed model repeated measures analysis, adjusting for baseline blood 
eosinophil count (loge scale) as a fixed effect. Visit and Treatment will be fitted as categorical 
fixed effects variables. Treatment by Visit and baseline blood eosinophil count by visit 
interaction effects will be included in the model as fixed effects. Each dose will be compared to 
Placebo at each Visit. The following SAS options will be applied:
o
REPEATED statement with TYPE=UN to specify an unstructured covariance structure 
for the R matrix.
o
The OBSMARGIN option on the LSMEANS statement in order to compute the 
adjusted geometric means with weights proportional to the input data set.
o
The Kenward and Roger method (DDFM = KR) for approximating the 
denominator degrees of freedom to correct for bias in the estimated variance-
covariance matrix.
14.2.
Secondary Pharmacodynamic (and / or Biomarker) Analyses
Absolute blood eosinophil count data will be summarised descriptively by visit.
Serum samples will be collected during this study to measure total IL-5 levels as a
marker of target engagement. Serum total IL-5 levels will be summarised descriptively.
Serum samples will also be collected during this study to allow the potential to measure 
biomarkers to identify factors that may influence the development of asthma and/or 
medically related conditions or the development of asthma treatments, as well as the 
biological and clinical responses to GSK3511294. If these samples are analysed for 
potential biomarkers, then they will be reported as a separate report. They will not form 
part of the SAC outputs.
14.2.1.
Endpoint / Variables

Blood eosinophil counts

Serum IL-5, Total
14.2.2.
Summary Measure
Both blood eosinophil counts data and Total serum IL-5 data are expected to be log-
normally distributed and so will be log-transformed (natural logs) prior to summarisation 
by endpoint, treatment group and visit. Summary statistics to be presented are: n, 
geometric mean, SD Log, Median, Min, Max. For Total Serum IL-5 data the number of 
BLQ results will also be presented. Any values below the Lower Limit of Quantification 
(LLQ) will be imputed using LLQ/2.
Geometric means (95% CIs) will be plotted for both endpoints based on absolute values.


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14.2.3.
Population of Interest 
The secondary pharmacodynamics (and / or biomarker) analyses will be based on the 
‘Pharmacodynamic’ population, unless otherwise specified.
14.2.4.
Strategy for Intercurrent (Post-Randomization) Events
Missing data will not be imputed. 
14.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 14.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.


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15.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES
The primary goal of this analysis is to investigate the relationship between plasma 
concentration and blood eosinophil count after single subcutaneous doses of 
GSK3511294 in participants with mild to moderate asthma enrolled in this FTIH study, if 
data permits, by population methods using for example an indirect response model. The 
influence of covariates such as participant baseline characteristics or if appropriate 
participant demographics on the PK/PD relationship will be investigated, as data permits.
These PK/PD outputs will be produced by CPMS.
15.1.
Statistical Analyses / Methods
A summary of the planned population pharmacokinetic / pharmacodynamic analyses are 
outlined below:
o
GSK3511294 plasma concentration (or pharmacokinetic parameter) and blood 
eosinophil count data will be analysed by population methods (non-linear mixed-
effects modelling) using appropriate software (e.g., NONMEM, SAS).  
o
A description of the key models tested during the model development will be 
provided and tabulated.
o
The population PD parameter estimates with 95% CI from the final model will be 
tabulated. Goodness of fit plots for the final model will be presented.
In support of the described analysis, a specific dataset will be generated. Further details 
of the population PK/PD analysis methodology are provided in Appendix 10: 
Pharmacokinetic / Pharmacodynamic Analyses.


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16.
REFERENCES
GlaxoSmithKline Document No.: 2016N270529_06: A randomised double-blind 
(sponsor open), placebo-controlled, single ascending dose, First Time in Human study in 
participants with mild to moderate asthma to assess safety, tolerability, immunogenicity, 
pharmacokinetics and pharmacodynamics of GSK3511294 administered subcutaneously. 
Effective date: 07-JAN-2019.


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17.
APPENDICES
17.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
17.1.1.
Exclusions from Per Protocol Population
A participant meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01
Inclusion #2 – Did not have >=200 cells/L blood eosinophil count at screening
02
Prohibited Medication was taken


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17.2.
Appendix 2: Schedule of Activities
17.2.1.
Protocol Defined Schedule of Events
Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 5
253 5
281 5
Informed consent
X 6
Pre-screening 
Blood eosinophils 
X7
Inclusion & 
exclusion criteria
X
X
X
Demography
X
Medical history 10
X
Concomitant 
medication
HIV, Hep B and 
Hep C screen 
X
FSH and estradiol 
8
X
Pregnancy test 9
X
X
X
X
X
X
X
X 5
X 5
X 5
Drug, alcohol and 
cotinine screen
X
X
Genetic sample
X 11
Administer IP
X
ACT 12
X
X
X
X 5
X 5
X 5
Height, weight and 
BMI
X 13
X 13
X 5,13
X 5,13
X 5,13
Full phys exam
X
X 5
X 5
X 5
Brief phys exam
X
X
X
X
X


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Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 5
253 5
281 5
Dispense rescue 
SABA
X
Resupply, as required.
Haematology 
(including blood 
eosinophil count), 
Clin. Chem., 
Urinalysis and 
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Serum save (for 
immunological 
analysis, if 
needed)
X
Ad hoc, as required by symptoms – see Appendix 3.
Inflammatory 
markers
X
Ad hoc, as required by symptoms – see Appendix 3.
Complement (C3 
& C4)
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Total IgE
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
PK Blood Samples
See Table 4.
Immunogenicity
X
X
X
X
X
X
X
X
X 5
X 5
X 5
CICs
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
12-lead ECG 14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Vital signs 15
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
AE/SAE review 
(inc local ISR up to 
72 h after dosing)
X 16
IL-5 sample
X
X
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Exploratory 
biomarkers of 
asthma in blood 
X
X
X
Spirometry
X
X
X
X
X
X
X
X 5
X 5
X 5
PEF Training 17
X


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Procedure
Pre-
Screen 
1
Screen 
2
In-Patient Period 3,4
Out-patient Visits 4,5
Day
–1
Day 1
Day 2
Day 3
Day 4
Week
NA
1
2
4
8
12
18
24
26
32 5
36 5
40 5
Pre-
dose
0
2 h
8 h
24 h
48 h
72 h
Day
5
8
15
29
57
85
127
169
183
225 5
253 5
281 5
PEF 17
X 17
Diary review 17
X
X
X
X
X
X
X
X
X
X 5
X 5
X 5
Abbreviations:  ACT = Asthma Control Test; AE = adverse event; BMI = body mass index; CICs = circulating immune complexes; CRP = C-reactive protein; ECG = 
electrocardiogram; FSH = follicle stimulating hormone; h = hour(s); Hep B = Hepatitis B; Hep C = Hepatitis C; HIV = human immunodeficiency virus; IgE = 
immunoglobulin E; IL-5 = interleukin-5; IP = Investigational Product; ISR = injection site reactions; PEF = peak expiratory flow; PK = pharmacokinetic; SABA = 
short acting -agonist; SAE = serious adverse event.
Notes:
1.
Pre-screen up to 12 weeks before dosing.  Blood eosinophils must be ≥200 cells/µL for participants to proceed to screening.  Blood eosinophil count may be 
existing data or obtained at a pre-screen visit.
2.
Screening up to 4 weeks before randomisation.  Screening procedures may be done at one or more visits, within the screening window.
3.
In the UK, all participants will be in-patient for at least 72 h after dosing.  In Germany, all participants will be in-patient for at least 8 days after dosing (see 
Appendix 8 of the protocol for the German-specific time and events table).
4.
Allowed time deviations will be documented in the Study Reference Manual.
5.
All participants will have all out-patient visits up to Week 26 after dosing.  Each cohort will also have out-patient visits after week 26, depending on the dose, as 
follows:  

2 and 10 mg:  Week 32 only

30 mg and 100 mg:  Week 36 only 

300 mg:  Weeks 32 and 40
(For unplanned dose levels, the timing of out-patient visits will be documented in a Note to File.) 
6.
Informed consent will be taken either at the pre-screen visit, for participants who don’t have an existing eosinophil count, or at screening, for those who do.
7.
Blood eosinophils will be included in the haematology panel at all time points other than the pre-screen visit.  
8.
If required to confirm postmenopausal status.
9.
Women on hormone replacement therapy, whose post-menopausal status cannot be confirmed, only.
10. Including cardiovascular (CV) disease, asthma exacerbation, and drug, alcohol and smoking history.
11. If the participant consents, an optional, genetic sample will be collected once during the study.  
12. At each applicable visit, ACT should be done before any other assessment.
13. Height at pre-screening or screening only.
14. ECGs triplicate at all time points.  ECGs should be time-matched to baseline (i.e. pre-dose on Day 1) from Day 2 onwards.
15. Blood pressure and heart rate in triplicate before dosing; single measurements after dosing.  Single temperature and respiratory rate measurements at all time 
points.


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16. Only SAEs are collected before dosing (see Section 7.3.1).
17. PEF will be recorded in the evening before bedtime on the day of the screening visit, then twice each day (once in the morning upon waking and once in the 
evening before bedtime) from the day after screening until the end of the study.  Training of the participant in how to take measurements will occur at screening.  
PEF measurements will be taken and results will be recorded by the site while the participant is in-patient at the clinical site (ie from the evening of Day –1 until 
the morning of discharge).  At all other time points, the participant will record their PEF as instructed, on their diary card, along with any rescue medication use 
and adverse events.  Site staff will review the diary cards at each out-patient visit.
Note: References to Sections, Appendices and Tables in this Schedule of Activities refer to parts of Protocol amendment 6 (Dated: 07/JAN/2019).


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17.3.
Appendix 3: Assessment Windows

All scheduled and unscheduled data will be considered for each assessment 
window.

In summary tables, only scheduled timepoints for that cohort and assessment will 
be displayed. For example, spirometry data are not expected to be collected at all 
timepoints; if any spirometry data were taken e.g. at Week 4 then they will not be 
summarised. Similarly, Week 36 is not an expected visit for Cohorts 1 or 2 and so 
any data for the 2 lowest dose groups should not be displayed for Week 36.  

Only 1 value per participant, assessment and assessment window will be used in 
the calculation of summary statistics for that assessment; if a participant has more 
than 1 valid observation within an assessment window then the observation 
closest to the planned time will be used. If 2 observations are equidistant from the 
planned timepoint then the mean of the values will be taken.

The assigned assessment windows will be shown in the listings, together with the 
planned assessment times.

For the blood eosinophil data, windows based both on the study day and the 
dosing time have been agreed for the later timepoints. For example, to be included 
in the Day 85 (Week 12) window, the blood eosinophil sample must have been 
taken on Day 83, Day 84, Day 85, Day 86, Day 87 or Day 88 AND the time of the 
sample must have been within 3h relative to the Day 1 dosing time. If more than 1 
sample with valid and non-missing results falls within this window, then only the 
results for the sample that was taken closest to the target timepoint will be 
included in the summary table. Both results will be included in the listing.

All PD and safety summary outputs will be displayed by scheduled timepoint (not 
applying windowing rules). In addition, the statistical analysis for blood 
eosinophil data will also be displayed by windowed timepoint. Unwindowed 
outputs will be considered as the primary outputs, with the windowed output
produced as a sensitivity analysis. 


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17.3.1.
Definitions of Assessment Windows for Analyses
Analysis Set 
/ Domain
Parameter (if applicable)
Target 
Analysis Window
Analysis 
Timepoint
Label
Beginning 
Timepoint
Ending 
Timepoint
PD 
Blood eosinophil data 
sensitivity analysis
Day -1
< Day 1 0h
(Latest Predose)
Day -1
Day 2 
(24h)
Day 2 (22h)
Day 2 (26h)
Day 2 (24h)
Day 3 
(48h)
Day 3 (46h)
Day 3 (50h)
Day 3 (48h)
Day 4 
(72h)
Day 4 (70h)
Day 4 (74h)
Day 4 (72h)
Day 5 
(96h)
Day 5 (93h)
Day 5 (99h)
Day 5
Day 8 
(Week 1)
1 Day and 3h of dosing time
Day 8 (Week 1)
Day 15 
(Week 2)
2 days and 3h of dosing 
time
Day 15 (Week 2)
Day 29 
(Week 4)
2 days and 3h of dosing time
Day 29 (Week 4)
Day 57 
(Week 8)
2 days and 3h of dosing time
Day 57 (Week 8)
Day 85 
(Week 12)
2 days and 3h of dosing time
Day 85 (Week 12)
Day 127 
(Week 18)
4 days and 3h of dosing time
Day 127 (Week 
18)
Day 169 
(Week 24)
4 days and 3h of dosing time
Day 169 (Week 
24)
Day 183 
(Week 26)
4 days and 3h of dosing time
Day 183 (Week 
26)
Day 225 
(Week 32)
4 days and 3h of dosing time
Day 225 (Week 
32)
Day 253 
(Week 36)
4 days and 3h of dosing time
Day 253 (Week 
36)
Day 281 
(Week 40)
4 days and 3h of dosing time
Day 281 (Week 
40)
Safety, 
Spirometry, 
Complement, 
IgE and Il-5 
data 
presented by 
visit. 
ECG, Vital signs, laboratory, 
Spirometry,
C3 and C4, IgE, IL-5
Day -1
Any time on Day -1. Note that if 
there is no scheduled Predose 
assessment for the parameter 
then latest valid result prior to 
Day 1 dosing should be used.
Day -1
Immunogenicity, CICs, ECG, 
Vital signs 
Day 1 
(Predose)
75 m prior to dosing time
Day 1 (Predose)
ECG, Vital signs
Day 1 (2h)
Day 1 (1.75h)
Day 1 (2.25h)
Day 1 (2h)
Spirometry
Day 1 (2h)
Day 1 (1.5h)
Day 1 (2.5h)
Day 1 (2h)
ECG, Vital signs
Day 1 (8h)
Day 1 (7.75h)
Day 1 (8.25h)
Day 1 (8h)


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Analysis Set 
/ Domain
Parameter (if applicable)
Target 
Analysis Window
Analysis 
Timepoint
Label
Beginning 
Timepoint
Ending 
Timepoint
Laboratory, Complement, IgE, 
CICs, ECG, Vital signs,
Spirometry, IL-5
Day 2 
(24h)
Day 2 (23.75h)
Day 2 (24.25h)
Day 2 (24h)
Laboratory, Complement, IgE, 
ECG, Vital signs, IL-5
Day 3 
(48h)
Day 3 (47h)
Day 3 (49h)
Day 3 (48h)
Laboratory, Complement, IgE, 
ECG, Vital signs, Spirometry, 
IL-5
Day 4 
(72h)
Day 4 (71h)
Day 4 (73h)
Day 4 (72h)
Laboratory, Complement, IgE, 
ECG, Vital signs, IL-5
Day 5
Assessment must have been 
done on Day 5
Day 5
Laboratory, ECG, Vital signs, 
Spirometry, IL-5
Day 8 
(Week 1)
1 day
Day 8 (Week 1)
Laboratory, Complement, 
Immunogenicity, CICs, ECG, 
Vital signs, IL-5
Day 15 
(Week 2)
1 day
Day 15 (Week 2)
Laboratory, Complement, IgE, 
Immunogenicity, CICs, ECG, 
Vital signs, IL-5
Day 29 
(Week 4)
3 days
Day 29 (Week 4)
Laboratory, Complement, IgE, 
Immunogenicity, CICs, ECG, 
Vital signs, Spirometry, IL-5
Day 57 
(Week 8)
3 days 
Day 57 (Week 8)
Laboratory, Complement, IgE, 
Immunogenicity, CICs, ECG, 
Vital signs, IL-5
Day 85 
(Week 12)
3 days 
Day 85 (Week 12)
Laboratory, Complement, IgE, 
Immunogenicity, CICs, ECG, 
Vital signs, IL-5
Day 127 
(Week 18)
3 days
Day 127 (Week 
18)
Laboratory, Complement, IgE, 
Immunogenicity, CICs, ECG, 
Vital signs, IL-5
Day 169 
(Week 24)
3 days
Day 169 (Week 
24)
Laboratory, Complement, 
Immunogenicity, CICs, ECG, 
Vital signs, IL-5
Day 183 
(Week 26)
3 days
Day 183 (Week 
26)
Laboratory, Complement, IgE, 
Immunogenicity, CICs, ECG, 
Vital signs, Spirometry, IL-5
Day 225 
(Week 32)
3 days
Day 225 (Week 
32)
Laboratory, Complement, IgE, 
Immunogenicity, CICs, ECG, 
Vital signs, Spirometry, IL-5
Day 253 
(Week 36)
3 days
Day 253 (Week 
36)
Laboratory, Complement, IgE, 
Immunogenicity, CICs, ECG, 
Vital signs, Spirometry, IL-5
Day 281 
(Week 40)
3 days
Day 281 (Week 
40)


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17.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
17.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
dosing.
17.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to 
dosing.
17.4.2.1.
Treatment States for Safety and Pharmacodynamic Data
Treatment State
Definition
Pre-Treatment
Date and Time ≤ Dosing Date and Time
On-Treatment
Date and Time > Dosing Date and Time
17.4.2.2.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If concomitant medication end date is not missing and is before 28 days prior to 
screening visit
Concomitant
Any medication that is not considered as prior. These will be further split into those that 
were started prior to dosing and those started after dosing as follows:

Pre-Treatment: Start Date and Time ≤ Dosing Date and Time

On-Treatment: Start Date and Time > Dosing Date and Time
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.


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17.4.3.
Study Phases for Adverse Events
Treatment State
Definition
Pre-Treatment
AE Start Date and time < Study Treatment Start Date and time
On-Treatment
If AE Start date and time Study treatment start date and time
Onset Time  
Since Dose 
(Days)
If Dose Date ˃ AE Start Date = AE Start Date - Treatment Start Date
If Dose Date ≤ AE Start Date = AE Start Date - Treatment Start Date +1
Missing otherwise.
Duration (Days) 
AE End Date – AE Start Date + 1
Drug-related
If relationship is marked ‘YES’ on Inform/CRF OR value is missing.
17.4.4.
Treatment Emergent Flags for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE start date is on or after treatment start date 
NOTES: 

Time of study treatment dosing and start/stop time of AEs should be considered


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17.5.
Appendix 5: Data Display Standards & Handling 
Conventions
All displays (Tables, Figures & Listings) will use the term 'Subjects'. However, RAP text 
will refer to "Participants" in-line with the master RAP template and protocol.
17.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: UK1SALX00175.corpnet2.com
HARP Area
SAC: GSK3511294/MID205722/Final_01 
Interim 1 (restricted access): GSK3511294/MID205722/Internal_01
Unblinded data review for dose escalations (restricted access): 
GSK3511294/MID205722/Internal_03
Interim 2 (restricted access): GSK3511294/MID205722/Internal_02
Interim 3 (restricted access): GSK3511294/MID205722/Internal_04
Dry-run: GSK3511294/MID205722/Internal_05
Interim 4 (restricted access): GSK3511294/MID205722/Internal_06 (if performed)
GSB: GSK3511294/MID205722/Safety_02 (if performed)
QC Spreadsheet
SAC: ARWORK\GSK3511294\MID205722\Final_01\Documents
Interim1: ARWORK\GSK3511294\MID205722\Internal_01\Documents
Interim2: ARWORK\GSK3511294\MID205722\Internal_02\Documents
Interim3: ARWORK\GSK3511294\MID205722\Internal_04\Documents
Interim4: ARWORK\GSK3511294\MID205722\Internal_06\Documents (if performed)
Dry-run: ARWORK\GSK3511294\MID205722\Internal_05\Documents
Unblinded data review for dose escalations: 
ARWORK\GSK3511294\MID205722\Internal_03\Documents
GSB: ARWORK\GSK3511294\MID205722\Safetyl_02\Documents (if performed)
Analysis Datasets 

Analysis datasets will be created according to Integrated Data Standards Library (IDSL)
dataset standards.
Generation of RTF Files

RTF files will be generated for all SAC and GSB (if performed) tables.
17.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings


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Formats

All data will be reported according to the actual treatment the participant received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted 
for reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Actual time relative to dosing will be used for individual participant plasma concentration-
time figures and for derivation of PK parameters.

Windowed time relative to dosing will be used in all other summary figures, summary 
tables, statistical analyses and calculation of any derived parameters, unless otherwise 
stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the participant’s listings.

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from summary figures and summary tables. The 
statistical analysis of blood eosinophil data will be performed using planned times and 
repeated using windowed times.
Unscheduled Visits

Only planned timepoints will be included in summary tables and/or figures. Results from unscheduled 
assessments will be included in summaries if they are within the scheduled time window and are closer 
to the target timepoint than the scheduled assessment. 

All scheduled and unscheduled visits will be included in listings and individual participant figures.

If there is an ‘any time post baseline’ category or a ‘Worst case’ category, then both scheduled 
and unscheduled results will be considered.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principles 7.01 to 7.13.


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17.5.3.
Reporting Standards for Pharmacokinetic Data
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created 
according to the ‘Standards for the Transfer and Reporting of PK Data 
using HARP’ guideline.
Note: BLQ concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards. Note: BLQ concentration values will be 
imputed as per GUI_51487 for descriptive summary statistics/analysis and 
summarized graphical displays only. 
NONMEM/Pop PKPD
File
Pop-PKPD file (CSV and SAS) for the Pop-PK and Pop PKPD analyses by Clinical 
Pharmacology Modelling and Simulation function will be created according to the 
Pop PKPD Dataset Specification document (separate document).
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to Standards for Handling NQ Impacted PK Parameters.
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Descriptive Summary 
Statistics (Log 
Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) of 
logged data and between geometric coefficient of variation (CVb (%)) will be 
reported.
CVb (%) = √ (exp(SD2) - 1) * 100
      (SD = SD of log transformed data) 
Parameters Not 
Being Log 
Transformed
Tmax and tlast
Parameters to be 
listed only
First point, last point and number of points used to determine z.


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17.6.
Appendix 6: Derived and Transformed Data
17.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two values within a time window (as per Section 17.3.1) the value closest to the target day 
for that window will be used. If values are the same distance from the target, then the mean will be 
taken.

Participants having both High and Low values for Normal Ranges at any post-baseline visit (including 
post-baseline unscheduled assessments) for safety parameters will be counted in both the High and 
Low categories of “Any visit post-baseline” row of related summary tables. This will also be applicable 
to relevant Potential Clinical Importance summary tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Date ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
Baseline

If the baseline value is missing, then all subsequent derived baseline variables will also be missing. The
baseline definition will be footnoted on all change from baseline displays.

Unless otherwise specified, baseline measurements will be derived as follows:
Change from Baseline= Post-Dose Visit Value – Baseline
% Change from Baseline=100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Change from Baseline= Calculate the change from baseline at each given 
timepoint and determine the maximum change
Ratio to Baseline= Post-Dose Visit Value/Baseline
17.6.2.
Safety
Adverse Events
AE’S of Special Interest

Please refer to Section 7.3.
17.6.3.
Pharmacokinetic
PK parameters

PK concentrations will be handled as described in document GUI_51487.

PK parameters will be derived as described in document GUI_51487.


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17.6.4.
Population Pharmacokinetic, Pharmacokinetic/ 
Pharmacodynamic (PopPK, PKPD)
PK concentrations
Blood eosinophil counts

PK concentrations below the limit of quantification of the assay will be treated as missing.

Zero value blood eosinophil count will be imputed with a value of 0.005.
17.6.5.
Pharmacodynamic and Biomarker
Blood eosinophils
Ratio to Baseline

Blood eosinophil counts will be natural log-transformed prior to analysis. Any zero values will be 
imputed with a value of 0.005 prior to log transformation.

Missing values e.g. due to missed assessments will not be imputed. This will include values missing at 
baseline.

Baseline is defined as the latest Predose non-missing blood eosinophil count.

Change from Baseline at time T=log (blood eosinophil count at Time T) – log(Baseline blood eosinophil 
count).

Ratio to Baseline at time T=exp(Change from Baseline at time T) 

If the weighted mean (0-Week 26) is derived, it will be calculated as AUEC(0-Week 26)/duration up to 
Week 26 visit. If the Week 26 result is missing then AUEC(0-Week 26) will be set to missing. If derived, 
AUEC will be calculated using the linear trapezoidal rule for blood eosinophil counts or ratio to 
baseline and will be based on actual sample times.
17.6.6.
Other
Asthma Control Test (ACT)

Total ACT score will be derived for each subject at each ACT assessment visit.

The 5 subscores will be added to create the total ACT score.

Each subscale may have the value 1- 5; Total ACT score may range from 5 – 25.

If any of the subscores are missing then the total score will be set to missing for that subject at that visit. 


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17.7.
Appendix 7: Reporting Standards for Missing Data
17.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e. as specified in the protocol) was defined as the 
completion of all phases of the study including the follow-up visit. 

Withdrawn participants may be replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will be slotted as per Appendix 3: Assessment Windows
17.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection tool/eCRF:
o
These data will be indicated by the use of a “blank” in participant listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 

Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers
o
Any participants excluded from the summaries and/or statistical analyses 
will be documented along with the reason for exclusion in the clinical study 
report.
Biomarkers

Any values below the Lower Limit of Quantification (LLQ) will be assigned a 
value of ½ LLQ for display purposes in Figures and for computation of summary 
statistics. Any values above the Upper Limit of Quantification (ULQ) will be 
assigned to the ULQ for display purposes in Figures and for computation of 
summary statistics. If multiple LLQ and /or ULQ values are available per assay 
(for example if multiple runs with different standard curves are utilised) then the 
LLQ and/or ULQ value used for the above imputation shall be the minimum of 
the available LLQs and/or the maximum of the ULQs. Where biomarker 
concentrations are from an assay of an increased dilution factor the LLQ and 
ULQ will be multiplied by this factor.

If the number of LLQ (and/or ULQ) values is large for an Individual biomarker 
then alternative analysis methods such as TOBIT analysis may be required. 
“Large” is hard to define prospectively and may depend upon the dataset in 
question.  Any such methodology will be documented in the statistical 
contributions to the study report.

Imputed values will be used in tables and figures, unless the proportion of 
imputed values at a given time point is large, in which case the summary 
statistics may not be presented for that time point and/or alternative actions will 
be taken and documented in the study report.

Where values are imputed, the number of such imputations will be included as a 
summary statistic in the relevant summary tables.


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17.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.


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17.8.
Appendix 8: Values of Potential Clinical Importance
17.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
130
550
While Blood Cell Count (WBC)
x109/ L
3
15
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
mmol/L
30
Calcium
mmol/L
2
2.75
Creatinine
mmol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Magnesium
mmol/L
0.5
1.23
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18
32
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT


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Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
hsCRP
10
17.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTcF Interval
msec
> 450 1
Absolute PR Interval
msec
< 110 1
> 220 1
Absolute QRS Interval
msec
< 75 1
> 110 1
Absolute QT
msec
>600
Change from Baseline
Increase from Baseline QTcF
msec
> 60 1
NOTES:  1 Represent standard ECG values of PCI for HV studies
17.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110


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17.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses
17.9.1.
Population Pharmacokinetic (PopPK) Dataset Specification
Specifications for the generation of the dataset will be provided in a separate document.
17.9.2.
Population Pharmacokinetic (PopPK) Methodology
GSK3511294 plasma concentration-time data collected in this single ascending dose 
FTIH study will be analysed by population methods (non-linear mixed-effects 
modelling), using appropriate software (e.g., NONMEM or SAS), and based on the PK 
population. GSK3511294 plasma concentrations below the limit of quantification of the 
assay will be treated as missing. Outlier data will be assessed for plausibility; however,
the aim is to use all available data whenever possible. Any decision to exclude data will 
be fully documented and specified in the clinical study report.
Data will be analysed by fitting a one-compartment pharmacokinetic model with first-
order absorption and elimination. Since bodyweight is a known determinant of 
monoclonal antibodies exposure, the inclusion of bodyweight into the model using 
allometry with fixed physiological allometric exponents of 0.75 and unity for clearance 
and volume, respectively, will be tested. If deemed appropriate and if data permits, the 
effect of other covariates may be investigated.
Covariate selection will be based on physiological plausibility, supported by graphical 
evaluation (PK parameters vs. covariates), and formally by automated linear model fitting 
using for example proc glmselect in SAS 9.2 (or higher). Individual PK parameters and 
covariates will be log-transformed and standardized before analysis. For forward and 
backward selections, significance levels of 0.1 and 0.05 will be applied, respectively. Co-
linearity between covariates will be carefully considered.
Identified covariates will then be subjected to traditional covariate analysis (with 
estimation step) and will follow the procedures described below. If deemed appropriate 
box plots of apparent systemic clearance versus covariates of interest (e.g. 
immunogenicity status) will be provided.
A description of the key models tested during the model development and the population 
PK parameter estimates with 95% CI from the final model will be provided and 
tabulated. Individual predicted GSK3511294 plasma concentrations and individual post-
hoc PK parameter estimates will be listed.
Covariate Model Selection Procedures
The covariate model building will follow a step-wise process consisting of a forward and 
backward selection procedure. The likelihood ratio test will be used to evaluate the 
significance of incorporating or removing covariates into the population model based on 
alpha levels set a priori. For forward and backward selections, a significance level of 


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0.05 and 0.01 for first order conditional estimation with interaction (FOCE-I) will be 
used, respectively.

Step-wise forward addition procedure
Each covariate will be included individually in the ‘base model’ to identify covariates 
resulting in a decrease in the objective function value (OFV) of > 3.84, χ2 < 0.05 for 1 
degree of freedom (df) using FOCE-I. The retained covariates will then be added to the 
base model one by one, starting with the most significant ones until all covariates have 
been tested. Note, if a covariate exponent estimate is numerically small, the covariate will 
not be retained; irrespective of objective function. This will constitute the full model.

Backward elimination procedure
From the full model, the significance of each covariate will be tested individually by 
removing covariate one by one until all non-significant covariates have been excluded. A 
covariate will be retained if upon removal, the OFV increase by more than 6.64 points 
(χ2< 0.01 for 1 df) using FOCE-I. Note, a covariate may be retained in the model despite 
being found non-statistically significant, if there is a strong rationale for its inclusion. 
This will constitute the final model. Centering of continuous covariates may be 
considered, as appropriate. The mean or median value of the participants included in the 
study may be used for example.
Model Evaluation
The uncertainty in the parameter estimates will be assessed. Furthermore, the model 
performance will be investigated using a set of goodness of fit plots and if deemed 
necessary, by Visual Predictive Check (VPC) method. Other evaluation methods may be 
used (e.g., bootstrapping) if deemed appropriate.


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17.10.
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses
17.10.1.
Pharmacokinetic / Pharmacodynamic Dataset Specification
Specifications for the generation of the dataset will be provided in a separate document.
17.10.2.
Pharmacokinetic / Pharmacodynamic Methodology
GSK3511294 plasma concentration (or pharmacokinetic parameter) and blood 
eosinophil count data collected in this single ascending dose FTIH study will be analysed 
by population methods (non-linear mixed-effects modelling), using appropriate software
(e.g., NONMEM, SAS). Zero values for the baseline blood eosinophil count as well as 
for blood eosinophil count post-dosing will be imputed a value of 0.005. Outlier data will 
be assessed for plausibility; however, the aim is to use all available data whenever 
possible. Any decision to exclude data will be fully documented and specified in the 
clinical study report.
A two-stage approach will be employed whereby post-hoc individual predicted 
GSK3511294 plasma concentrations will be merged with blood eosinophil data before 
model fitting. Data will be analysed by fitting an indirect response model parameterised 
in term of baseline blood eosinophil count (KRO), rate of elimination of eosinophils in 
the blood (Kout), concentration resulting in 50% of maximum drug effect (IC50) and 
maximum effect (Imax). 
If deemed appropriate and if data permits, the effect of covariates (e.g., baseline blood 
eosinophil count) may be investigated.
Covariate selection will be based on physiological plausibility, supported by graphical 
evaluation (PD parameters vs. covariates), and formally by automated linear model fitting 
using for example proc glmselect in SAS 9.2 (or higher). Individual PD parameters and 
covariates will be log-transformed and standardized before analysis. For forward and 
backward selections, significance levels of 0.1 and 0.05 will be applied, respectively. Co-
linearity between covariates will be carefully considered. Identified covariates will then 
be subjected to traditional covariate analysis (with estimation step) and will follow the 
same procedures as described in Appendix 9.
A description of the key models tested during the model development and the population 
PD parameter estimates with 95% CI from the final model will be provided and 
tabulated.
Model evaluation will be as described in Appendix 9.


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17.11.
Appendix 11: Abbreviations & Trade Marks
17.11.1.
Abbreviations
Abbreviation
Description
ACT
Asthma Control Test
ADA
Anti-drug antibody
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIC
Akaike's Information Criteria
ANOVA
Analysis of Variance
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve from time zero
(pre-dose) extrapolated to infinite time
%AUCex
Percentage of AUC(0-) obtained by extrapolation
AUC(0-t)
Area under the concentration-time curve from time zero
(pre-dose) to last time of quantifiable concentration within a participant across 
all treatments
AUC(0-Week x)
Area under the concentration-time curve from time zero to Week x
AUEC(0-Week 
x)
Area under the PD effect-time curve from time zero to Week x
BLQ
Below limit of Quantification
BMI
Body Mass Index
C
Complement
CI
Confidence Interval
CIC
Circulating immune complex
CL
Clearance
CL/F
Apparent clearance following subcutaneous dosing
Cmax
Maximum observed concentration
CPMS
Clinical Pharmacology Modelling & Simulation
CPSSO
Clinical Pharmacology Science & Study Operations
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
Df
Degrees of Freedom
DOB
Date of Birth
DP
Decimal Places
DQL
Data Quality Lead
EC50
Half maximal effective concentration
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration


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Abbreviation
Description
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
FEV1
Forced expiratory volume in 1 second
FOCE-I
First order conditional estimation with interaction
FTIH
First Time in Humans
FVC
Forced vital capacity
GSB
Global Safety Board
GSK
GlaxoSmithKline
hsCRP
High Sensitivity C-reactive Protein
IA
Interim Analysis
IC50
Concentration resulting in 50% of maximum drug effect
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IgE
Immunoglobulin E
IL
Interleukin
Imax
Maximum effect
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
KOUT
Rate of elimination of eosinophils in the blood
KRO
Baseline blood eosinophil count
z
Terminal phase elimination rate constant
LLQ
Lower Limit of Quantification
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model Repeated Measures
n
Number of participants with available data
NONMEM
Non-linear mixed-effects modelling
OFV
Objective function value
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PEF
Peak expiratory flow
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
PSAP
Program Safety Analysis Plan
QC
Quality Control
QTcF
Fridericia’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SC
Subcutaneous
SD
Standard Deviation


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Abbreviation
Description
SDL
Source Data Lock
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
t½
Terminal phase half-life
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
tlast
Time of last quantifiable concentration
tmax
Time of occurrence of Cmax
Vd/F
Apparent volume of distribution after subcutaneous
Administration
VPC
Visual Predictive Check
17.11.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
HARP
NONMEM
RANDALL NG
Phoenix
SAS
WinNonlin


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17.12.
Appendix 12: List of Data Displays
17.12.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Safety
2.1 to 2.n
2.1 to 2.n
Pharmacokinetic
3.1 to 3.n
3.1 to 3.n
Population Pharmacokinetic (PopPK)
4.1 to 4.n
4.1 to 4.n
Pharmacodynamic and Exploratory Markers
5.1 to 5.n
5.1 to 5.n
Pharmacokinetic / Pharmacodynamic
6.1 to 6.n
6.1 to 6.n
Other
7.1 to 7.n
7.1 to 7.n
Section
Listings
Listings
1 to x
17.12.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Population Pharmacokinetic (PopPK)
POPPK_Fn
POPPK_Tn
POPPK_Ln
Pharmacodynamic and Exploratory Markers
PD_Fn
PD_Tn
PD_Ln
Pharmacokinetic / Pharmacodynamic
PKPD_Fn
PKPD_Tn
PK/PD_Ln
Other
OTH_Fn
OTH_Tn
OTH_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
17.12.3.
Deliverables
Delivery 
Description
IAn
Interim Analysis n
GSB
Global Safety Board
SAC
Final Statistical Analysis Complete


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17.12.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Participant Disposition
1.1.
Safety
ES1
Summary of Participant Disposition for the Participant
Conclusion Record
ICH E3, FDAAA, EudraCT
SAC
1.2.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC
1.3.
Enrolled
NS1
Summary of Number of Participant by Country and Site ID
EudraCT/Clinical Operations
SAC
Protocol Deviation
1.4.
Safety
DV1
Summary of Important Protocol Deviations
ICH E3
Include total column
SAC
Population Analysed
1.5.
All subjects
SP1
Summary of Study Populations 
IDSL
SAC
Demographic and Baseline Characteristics
1.6.
Safety
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
Include BMI
Include an overall total group.
SAC
1.7.
Enrolled
DM11
Summary of Age Ranges
EudraCT
SAC
1.8.
Safety
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC
1.9.
Safety
FH1
Summary of Family History of Cardiovascular Risk Factors
SAC


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
1.10.
Safety
MH1 
Summary of Current Medical Conditions
ICH E3 
SAC
1.11.
Safety
MH1 
Summary of Past Medical Conditions
ICH E3
Separate summaries for Current & 
Past conditions, if collected.
SAC
1.12.
Safety
CM1
Summary of Prior Medications by Asthma Medication Status
ICH E3
Split by Asthma medication and 
non-asthma medication.
SAC
1.13.
Safety
CM1
Summary of Concomitant Medications by Asthma Medication 
Status – Pre-Treatment
ICH E3
Split by Asthma medication and 
non-asthma medication.
Only present if at least 5 
medications were started within 28 
days before screening visit and if 
the start date of medication is prior 
to dosing.
SAC
1.14.
Safety
CM1
Summary of Concomitant Medications by Asthma Medication 
Status – On Treatment
ICH E3
Split by Asthma medication and 
non-asthma medication.
SAC


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17.12.5.
Safety Tables
Note that a column denoting all active doses will be displayed for all safety summary tables. 
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
2.1.
Safety
CP_AE1p
Summary of All Adverse Events by System Organ Class and 
Preferred Term
ICH E3
Include a total column
Post dose AEs only
GSB (if 
required) / SAC
2.2.
Safety
AE5A
Summary of Adverse Events by System Organ Class and 
Preferred Term and Maximum Intensity
ICH E3
SAC
2.3.
Safety
CP_AE1p
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term
ICH E3
.
SAC
2.4.
Safety
CP_AE1p
Summary of All Adverse events leading to study withdrawal by 
System Organ Class and Preferred Term
Only produce if at least 5 
participants have an AE that leads 
to study withdrawal.
SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.5.
Safety
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences)
FDAAA, EudraCT
Note that due to the low numbers in 
each treatment group, all AEs will 
be included. If 1 subject has a 
particular AE then this will 
automatically result in more than 
5% of that treatment group having 
that AE.
SAC
Serious and Other Significant Adverse Events
2.6.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
If required
SAC
2.7.
Safety
SAF_T2
Summary of AEs of Special Interest (On-treatment)
GSB (if 
required) / SAC
2.8.
Safety
SAF_T3
Summary Profile of On-Treatment Adverse Events of Special 
Interest
Present by event of special interest. 
If no subjects experience a 
particular AE of special interest, 
then no need to summarise for that 
special interest AE.
SAC
2.9.
Safety
Similar to Table 
3.43 in 
sb240563/mid2
00862/final/
Summary of Adverse Events, by ADA Assay Result Category
(On-Treatment)
AE table should be based on the 
highest post-baseline binding 
antibody result
Present postdose AEs only
SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10.
Safety
AE3
Summary of Non-Serious Drug-Related Adverse Events by 
Overall Frequency
This is a required input to the  Plain 
Language Summary (PLS) 
requirements.
SAC
2.11.
Safety
SAF_T1
Adverse Event Overview
Include rows for:
Any AEs
   On-treatment AEs
    AEs related to study treatment
    AEs leading to study withdrawal
Any SAEs
    On-treatment SAEs
    SAEs relating to study treatment
Fatal SAEs
Fatal SAEs related to study 
treatment
Retain rows even if zero counts in 
all treatment columns.
GSB (if 
required) / SAC
Laboratory: Chemistry 
2.12.
Safety
LB1
Summary of Chemistry Changes from Baseline 
ICH E3
Include hsCRP
SAC
2.13.
Safety
LB17
Summary of Worst Case Chemistry Relative to Potential Clinical 
Importance (PCI Criteria) Post-Baseline Relative to Baseline
ICH E3
GSB (if 
required) / SAC


CONFIDENTIAL
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.14.
Safety
LB15
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline
SAC
Laboratory: Haematology
2.15.
Safety
LB1
Summary of Haematology Changes from Baseline
ICH E3
SAC
2.16.
Safety
LB17
Summary of Worst Case Haematology Results Relative to 
Potential Clinical Importance (PCI) Criteria Post-Baseline 
Relative to Baseline
ICH E3
GSB (if 
required) / SAC
2.17.
Safety
LB15
Summary of Worst Case Haematology Results Relative to 
Normal Range Post-Baseline Relative to Baseline
SAC
Laboratory: Urinalysis
2.18.
Safety
UR1
Summary of Urinalysis Results 
ICH E3
SAC
Laboratory: Hepatobiliary (Liver)
2.19.
Safety
SAF_T4
Summary of Hepatobiliary Laboratory Abnormalities
Based on Liver10 standard shell.
SAC
ECG
2.20.
Safety
EG1
Summary of ECG Findings 
IDSL
SAC
2.21.
Safety
EG10
Summary of Maximum QTcF Values Post-Baseline Relative to 
Baseline by Category
IDSL
GSB (if 
required) / SAC
2.22.
Safety
LAB17
Summary of Worst Case ECG Results Relative to Potential 
Clinical Importance (PCI) Criteria Post-Baseline Relative to 
Baseline
Include each of the ECG PCI 
criteria
SAC
2.23.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
SAC


CONFIDENTIAL
205722
70
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.24.
Safety
EG11
Summary of Maximum Increase in QTcF Values Post-Baseline 
Relative to Baseline by Category
IDSL
SAC
Vital Signs
2.25.
Safety
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
GSB (if 
required) / SAC
2.26.
Safety
VS7
Summary of Worst Case Vital Signs Results Relative to 
Potential Clinical Importance (PCI Criteria) Post-Baseline 
Relative to Baseline
IDSL
SAC


CONFIDENTIAL
205722
71
17.12.6.
Safety Figures
Safety: Figures
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Hepatobiliary (Liver)
2.1.
Safety
sb240563/mid205050/final_02
Scatter Plot of Maximum vs Baseline for ALT
Use a different colour and 
symbol for each dose group.
SAC
2.2.
Safety
sb240563/mid205050/final_02 
Figure 3.2
Scatter Plot of Maximum ALT vs Maximum Total Bilirubin
Use a different colour and 
symbol for each dose group.
SAC


CONFIDENTIAL
205722
72
17.12.7.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverabl
e [Priority]
Pharmacokinetic Concentrations and Parameters
3.1.
PK
PKCT1
Summary of Plasma GSK3511294
Pharmacokinetic Concentration-Time Data
SAC
3.2.
PK
PKPT1
Summary of Derived Plasma GSK3511294
Pharmacokinetic Parameters
Cmax, AUC(0-), AUC(0-t), 
AUC(0-WeekX), CL/F, Vd/F, 
z, t½, %AUCextrapolated, 
tmax, tlast.
SAC
3.3.
PK
PKPT3
Summary of Derived Plasma GSK3511294
Pharmacokinetic Parameters (log transformed) 
Cmax, AUC(0-), AUC(0-t), 
AUC(0-WeekX), CL/F, Vd/F, 
z, t½, %AUCextrapolated.
SAC
Dose Proportionality
3.4.
PK
See Table 3.8 in 
/arenv/arprod/gsk226955
7/pii116617/parts_cb/driv
ers/t_pkpower_partcb.sa
s
Summary of Results of Statistical Analysis of 
Plasma GSK3511294 Cmax and AUC(0-) to 
Assess Dose Proportionality, Power Model
SAC
3.5.
PK
Table 3.10 in 
/arenv/arprod/gsk226955
7/pii116617/parts_cb/driv
ers/t_pkaccum_stat_part
cb.sas
Summary of Results of Statistical Analysis of 
Plasma GSK3511294 Cmax and AUC(0-) to 
Assess Dose Proportionality, ANOVA Model
SAC


CONFIDENTIAL
205722
73
17.12.8.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / Example Shell
Title
Programming 
Notes
Deliverabl
e [Priority]
Pharmacokinetic Concentrations 
3.1.
PK
PKCF1x
Individual Participant Plasma GSK3511294 Concentration-Time Plots 
(Linear and Semi-log) by Treatment
One treatment per 
page (all participants 
within a treatment 
group on one plot). 
Add a horizontal line 
at y-axis = 20 pg/mL 
and footnote: LLQ = 
20 pg/mL,Set pre-
dose NQs to missing.
SAC
3.2.
PK
PKCF1x
Individual Participant Plasma GSK3511294 Concentration-Time Plots 
(Linear and Semi-log) by Participant
SAC
3.3.
PK
PKCF2
Mean (SD) Plasma GSK3511294 Concentration-Time Plot (Linear 
and Semi-Log)
SAC
3.4.
PK
PKCF3
Median Plasma GSK3511294 Concentration-Time Plot (Linear and 
Semi-Log)
SAC
Dose Proportionality
3.5.
PK
PK28
Plot of Individual (+ Geometric Mean and 90% CIs) for Plasma 
GSK3511294 PK Parameters versus Dose 
AUC(0-) and Cmax
SAC
3.6.
PK
Fig 3.9 in 
/arenv/arprod/gsk2269
557/pii116617/parts_c
b/drivers/f_pkcmax_do
senorm_partcb.sas
Box Plot of Dose Normalised Plasma GSK3511294 PK Parameters 
against Dose
Separate plots for 
AUC(0-) and Cmax
SAC


CONFIDENTIAL
205722
74
Pharmacokinetic: Figures
No.
Population
IDSL / Example Shell
Title
Programming 
Notes
Deliverabl
e [Priority]
3.7.
PK
PK28
Plot of Individual (+ Geometric Mean and 95% CIs) Log 
GSK3511294 PK parameter vs Log (dose) 
Separate plots for 
AUC(0-) and Cmax
SAC


CONFIDENTIAL
205722
75
17.12.9.
Pharmacokinetic Population (PopPK) Tables
Pharmacokinetic Population (POPPK): Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Insert Endpoint Category
4.1.
PK
Description and Evaluation of Key PK Models Tested
Provided by CPMS
SAC
4.2.
PK
Population PK Parameter Estimates with 95% CI of Final PK Model
Provided by CPMS
IA1, IA3, IA4 (if 
performed and 
required), SAC
4.3.
PK
Demographics Summary
Provided by CPMS
SAC
4.4.
PK
Samples Summary
Provided by CPMS
SAC


CONFIDENTIAL
205722
76
17.12.10. Pharmacokinetic Population (PopPK) Figures
Pharmacokinetic Population (POPPK): Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Insert Endpoint Category
4.1.
PK
Plasma GSK3511294 concentration-time profiles (by treatment)
Provided by CPMS
IA1, IA3, IA4 (if 
performed and 
required), SAC
4.2.
PK
Model goodness of fit plots
Provided by CPMS
IA1, IA3, IA4 (if 
performed and 
required), SAC
4.3.
PK
Continuous covariate correlation plot
Provided by CPMS
SAC
4.4.
PK
Categorical covariate correlation plot
Provided by CPMS
SAC
4.5.
PK
Automated covariate selection
Provided by CPMS
SAC
4.6.
PK
Visual predictive check
Provided by CPMS
SAC
4.7.
PK
Observed plasma GSK3511294 concentration-time profiles by 
anti-drug antibody status
Provided by CPMS
SAC
4.8.
PK
Plasma GSK3511294 observed/predicted concentration-time 
profiles (by participant)
Provided by CPMS
IA1, IA3, IA4 (if 
performed and 
required), SAC
4.9.
PK
Box plot of apparent systemic clearance versus covariates of 
interest (if necessary)
Provided by CPMS
SAC


CONFIDENTIAL
205722
77
17.12.11. Pharmacodynamic and Exploratory Markers
Pharmacodynamic and Exploratory Markers: Tables
No.
Population
IDSL / Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
Blood Eosinophils
5.1.
PD
PD_T1: Same format as 
Table 2.73 in 
/arenv/arprod/sb240563
/mid200862/final
Summary of Blood Eosinophil Data
Extract from 
haematology panel 
of lab dataset.
Treat as log-
normal data
SAC output will 
supersede IA 
output, IA output 
will have ‘at 
Interim’ in the title. 
Will need to be 
careful not to 
unblind for interim 
output.
IA1 and 
subsequent 
IAs, SAC
5.2.
PD
PD_T2
Statistical Analysis of Change from Baseline Blood Eosinophil Data 
SAC output will 
supersede IA 
output, IA output 
will have ‘at 
Interim’ in the title. 
Will need to be 
careful not to 
unblind for interim 
output.
IA1 and 
subsequent 
IAs, SAC
5.3.
PD
PD_T2
Statistical Analysis of Change from Baseline Blood Eosinophil Data 
(Windowing Sensitivity Analysis)
Apply time window 
rules
SAC


CONFIDENTIAL
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78
Pharmacodynamic and Exploratory Markers: Tables
No.
Population
IDSL / Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
5.4.
PD
Similar format to 
/sb240563/mid205050/fin
al_02/
Table 5.2
Statistical Analysis of Ratio to Baseline Blood Eosinophil Data (MMRM 
Sensitivity Analysis)
Will need to split 
treatments across 
2 pages.
SAC
5.5.
Safety
PD_T2
Statistical Analysis of Change from Baseline Blood Eosinophil Data 
If Safety population 
and PD population 
are different
SAC
5.6.
PD
PD_T2
Statistical Analysis of Change from Baseline Blood Eosinophil Data Excluding 
Subjects with Use of Corticosteroids or Change in ICS Asthma Medication 
If applicable
SAC
IL-5
5.7.
PD
See Table 6.75 in 
sb240563/mea112997/fin
al
Summary of Serum Total IL-5 [units] Over Time
Add a footnote if 
any BLQ values 
are imputed.
Total only (no free)
IA3 and 
subsequent 
IAs if 
performed 
and 
required,
SAC


CONFIDENTIAL
205722
79
17.12.12. Pharmacodynamic and Exploratory Markers Figures
Pharmacodynamic and Exploratory Markers: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Blood eosinophils
5.1.
PD
PD_F1
Geometric means (and 95% CIs) of Ratio to Baseline Blood 
Eosinophils 
SAC output will supersede IA output, IA 
output will have ‘at Interim’ in the title. 
Will need to be careful not to unblind for 
interim output.
IA1 and 
subsequent IAs, 
SAC
5.2.
PD
PD_F1
Geometric Means (and 95% CIs) of Blood Eosinophil Count 
Data (<units>)
SAC output will supersede IA output, IA 
output will have ‘at Interim’ in the title. 
Will need to be careful not to unblind for 
interim output.
IA1 and 
subsequent IAs, 
SAC
5.3.
PD
PD_F2
Predicted and Observed Blood Eosinophil Ratios to Baseline
By treatment group
IA1 and 
subsequent IAs, 
SAC
Serum IL-5
5.4.
PD
PD_F1
Geometric Means (and 95% CIs) of Total Serum IL-5 Data 
(<units>)
Plot absolute values rather than ratios 
to baseline. Include a reference line for 
the LOQ
IA3 and 
subsequent IAs
if performed 
and required, 
SAC


CONFIDENTIAL
205722
80
17.12.13. Pharmacokinetic / PharmacodynamicTables
Pharmacokinetic / Pharmacodynamic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Insert Endpoint Category
6.1.
PD
Description and Evaluation of Key PKPD Models Tested
Provided by CPMS
SAC
6.2.
PD
Population PD Parameter Estimates with 95% CI of Final PKPD 
Model
Provided by CPMS
SAC
6.3.
PD
Demographics summary (only if different from study population)
Provided by CPMS
SAC
6.4.
PD
Samples summary
Provided by CPMS
SAC


CONFIDENTIAL
205722
81
17.12.14. Pharmacokinetic / Pharmacodynamic Figures
Pharmacokinetic / Pharmacodynamic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Insert Endpoint Category
6.1.
PD
Blood eosinophil count-time profiles
Provided by CPMS
SAC
6.2.
PD
Model goodness of fit plots
Provided by CPMS
SAC
6.3.
PD
Continuous covariate correlation plot
Provided by CPMS
SAC
6.4.
PD
Categorical covariate correlation plot
Provided by CPMS
SAC
6.5.
PD
Automated covariate selection
Provided by CPMS
SAC
6.6.
PD
Visual predictive check
Provided by CPMS
SAC
6.7.
PD
Observed blood eosinophil count -time profiles by anti-drug 
antibody status
Provided by CPMS
SAC
6.8.
PD
Observed/predicted blood eosinophil count-time profiles (by 
participant)
Provided by CPMS
SAC


CONFIDENTIAL
205722
82
17.12.15. Other Tables
Other: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Lung Function Tests 
7.1.
Safety
Similar format 
to Table 3.11 in 
/arenv/arprod/s
b240563/mid20
1312/final/
Summary of Spirometry Data
Summarise FEV1, FVC and 
%Predicted Normal FEV1
SAC
7.2.
Safety
PFT3
Summary of Changes from Baseline Spirometry Data
SAC
Immunogenicity
7.3.
Safety
SAF_T5
Summary of Binding Antibody by Visit
Positive/Negative at each visit as well 
as transient positive and transient 
positive at post dose visits. Separate 
column for each dose. Include the titre 
value (min, median and max) when 
available for participants with a positive 
result
IA3 and 
subsequent IAs
if performed 
and required, 
SAC
7.4.
Safety
sb240563/mid2
04958/final_01 
Table 9.2
Summary of Binding Antibody by Visit – Subjects Without 
Positive Result Prior to Dosing
Positive/Negative at each visit. 
Separate column for each dose. Include 
the titre value (min, median and max) 
when available for participants with a 
positive result
SAC
7.5.
Safety
sb240563/mid2
04958/final_01 
Table 9.3
Summary of Neutralising Antibody by Visit
SAC


CONFIDENTIAL
205722
83
Other: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
CICs
7.6.
Safety
Summary of Circulating Immune Complexes
Data from Biomark dataset
IA3 and 
subsequent IAs
if performed 
and required, 
SAC
Complement, IgE and Inflammatory Markers
7.7.
Safety
See 
sb240563/mea
115588/final 
Table 6.71
Summary of Complement (C3 and C4) and IgE
C3, C4 and IgE from LAB dataset 
Present by parameter and visit
IA3 and 
subsequent IAs
if performed 
and required, 
SAC
Exacerbations
7.8.
Safety
sb240563/mea
112997/final/t_e
ff_6_01.sas
Summary of Frequency of All Exacerbations
Only present If at least 5 exacerbations 
reported.
SAC
7.9.
Safety
Similar to 
sb240563/mea
115575/final/dri
vers/Table 6.19
Overview of Exacerbations
Do not split into different treatment 
phases. All post dose exacerbations to 
be displayed on the same page. Include 
all exacerbation data categories that 
are collected e.g. hospitalisation, 
clinical significance, etc. 
Only summarise exacerbations if 
reported by >= 5 participants. 
SAC


CONFIDENTIAL
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84
Other: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Asthma Control Test (ACT)
7.10.
Safety
Similar to Table 
6.56 in 
sb240563/mea
115588/final
Summary of Asthma Control Test (ACT) Total Scores
Note that the example is for ACQ rather 
than ACT. Total ACT score can range 
from 5 – 25.
SAC


CONFIDENTIAL
205722
85
17.12.16. Other Figures
Other: Figures
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
CICs
7.1.
Safety
PD_F1
Geometric Means (and 95% CIs) of CICs 
(<units>)
Plot absolute values rather 
than ratios to baseline. 
Include a reference line for 
the LOQ
IA3 and 
subsequent 
IAs if 
performed 
and 
required, 
SAC
Complement, IgE and Inflammatory Markers
7.2.
Safety
PD_F1
Geometric Means (and 95% CIs) of 
Complement and IgE Data 
Plot absolute values rather 
than ratios to baseline. 
Include a reference line for 
the LOQ if applicable
IA3 and 
subsequent 
IAs if 
performed 
and 
required, 
SAC


CONFIDENTIAL
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17.12.17. ICH and Other Listings
Listings
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Participant Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
2.
Enrolled
ES2 
Listing of Reasons for Study Withdrawal
ICH E3
SAC
3.
Safety
BL1
Listing of Participants for Whom the Treatment 
Blind was Broken
ICH E3
SAC
4.
Safety
TA1
Listing of Planned and Actual Treatments
IDSL
SAC
Protocol Deviations
5.
Safety
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC
6.
Safety
IE3 
Listing of Participants with Inclusion/Exclusion 
Criteria Deviations
ICH E3
SAC
Populations Analysed
7.
Enrolled
SP3
Listing of Participants Excluded from Any 
Population
ICH E3
SAC
Demographic and Baseline Characteristics
8.
Screened
DM2
Listing of Demographic Characteristics
ICH E3
Include all parameters in 
demography summary table
SAC
9.
Screened
DM9 
Listing of Race
ICH E3
SAC


CONFIDENTIAL
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87
Listings
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
10.
Screened
CP_CM3 
Listing of Concomitant Medications
IDSL
SAC
Exposure and Treatment Compliance
11.
Safety 
EX3
Listing of Exposure Data
ICH E3
SAC
Adverse Events
12.
Screened
CP_AE8
Listing of All Adverse Events
ICH E3
GSB (if 
required) / 
SAC
13.
Screened
AE7
Listing of Participant Numbers for Individual 
Adverse Events
ICH E3
SAC
14.
Screened
AE2
Listing of Relationship Between Adverse Event 
System Organ Classes, Preferred Terms, and 
Verbatim Text
IDSL
SAC
Serious and Other Significant Adverse Events
15.
Screened
CP_AE8a
Listing of Serious Adverse Events
ICH E3
SAC
16.
Screened
CP_AE8
Listing of Adverse Events Leading to Withdrawal 
from Study 
ICH E3
SAC
17.
Safety
CP_AE8a
Listing of Adverse Events of Special Interest
ICH E3
Order by each category of 
AE of SI.
SAC
18.
Safety
Listing of Cardiovascular Events
If applicable
SAC


CONFIDENTIAL
205722
88
Listings
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
19.
Safety
CP_AE8
Listing of Adverse Events for Participants with at 
least One Positive Predose Binding Assay
SAC


CONFIDENTIAL
205722
89
Listings
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Hepatobiliary (Liver)
20.
Safety
MH2
Listing of Medical Conditions for Participants
with Liver Stopping Events
IDSL
SAC
21.
Safety
SU2
Listing of Substance Use for Participants with 
Liver Stopping Events
IDSL
SAC
All Laboratory
22.
Safety
CP_LB5
Listing of All Clinical Chemistry Laboratory Data 
for Participants with PCI Abnormalities
ICH E3
Will include hsCRP data.
SAC
23.
Safety
CP_LB5
Listing of All Haematology Laboratory Data for 
Participants with PCI Abnormalities
ICH E3
SAC
24.
Safety
CP_LB5
Listing of Clinical Chemistry Abnormalities of 
Potential Clinical Importance
Subset of ‘Listing of All 
Clinical Chemistry 
Laboratory Data for 
Participants with PCI 
Abnormalities’.
SAC
25.
Safety
CP_LB5
Listing of Haematology Abnormalities of 
Potential Clinical Importance
Subset of ‘Listing of All 
Hematology Laboratory 
Data for Participants with 
PCI Abnormalities’
SAC
26.
Safety
UR2A/UR2B
Listing of All Urinalysis Data 
ICH E3
SAC
27.
Safety
CP_LB5
Listing of Liver Chemistry Data for Subjects with 
ALT at Least 3xULN
Include ALT, bilirubin and 
INR only
SAC


CONFIDENTIAL
205722
90
Listings
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
28.
Safety
CP_EG3
Listing of All ECG Values for Participants with 
Any Value of Potential Clinical Importance
IDSL
Based on means of 
triplicate values
SAC
29.
Safety
CP_EG4
Listing of ECG Values of Potential Clinical 
Importance
IDSL
Based on means of 
triplicate values
SAC
30.
Safety
CP_EG5
Listing of All ECG Findings for Participants with 
an Abnormal ECG Finding
IDSL
SAC
31.
Safety
EG5
Listing of Abnormal ECG Findings
IDSL
SAC
Vital Signs
32.
Safety
CP_VS4
Listing of All Vital Signs Data for Participants 
with Any Value of Potential Clinical Importance
IDSL
SAC
33.
Safety
CP_VS4
Listing of Vital Signs of Potential Clinical 
Importance
IDSL
Subset of above listing.
SAC
Lung Function Tests
34.
Screened
PFT8
Listing of Spirometry Data
FEV1, FVC and %predicted 
normal FEV1. Individual 
readings are not 
databased, only max of the 
3 readings.
SAC


CONFIDENTIAL
205722
91
Listings
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic Data
35.
PK
Listing of Plasma GSK3511294 Pharmacokinetic 
Concentration-Time Data (Observed)
SAC
36.
PK
Listing of Plasma GSK3511294 Pharmacokinetic 
Parameters
From noncompartmental 
analysis
SAC
37.
PK
Listing of Plasma GSK3511294 Pharmacokinetic 
Concentration-Time Data (Predicted)
From popPK analysis
Data provided by CPMS to 
CS for listing generation
SAC
38.
PK
Listing of Model Predicted Plasma GSK3511294 
Pharmacokinetic Parameters
From popPK analysis
Data provided by CPMS to 
CS for listing generation
SAC
39.
PK
Listing of Data and Participants Excluded from 
Analysis
From popPK analysis
Provided by CPMS
SAC
40.
PK
Final PK Model Listings
From popPK analysis
Provided by CPMS
SAC
Immunogenicity
41.
Safety
IMM2
Listing of Immunogenicity Data for Participants 
with at Least One Positive Screening Binding 
Assay
Include columns for 
Screening Binding Assay, 
Confirmation Binding 
Assay, Confirmation 
Binding Assay Titre, 
Transient/Persistent, 
Neutralizing Antibody 
Assay
SAC
Exacerbations
42.
Screened
Similar to 
sb240563/mea115575/final/Listing 6.02
Listing of Exacerbations
If applicable
SAC


CONFIDENTIAL
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92
Listings
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Asthma Control Test (ACT)
43.
Screened
Similar format to EQ5
Listing of Asthma Control Test (ACT) Data
Include all subscores and 
total score. Present codes 
and decodes in a similar 
way to EQ5. Replace 
‘Utility/ Thermometer Score’ 
with ‘Total Score’.
SAC
CICs
44.
Screened
Listing of Circulating Immune Complexes Data
SAC
Complement, IgE Data and Inflammatory Markers
45.
Screened
See Listing 6.04 in /arenv/arprod/sb240563
/mea115588/final
Listing of Complement (C3 and C4) and IgE
SAC
46.
Screened
Similar to 
gsk2269557/pii115117/part_c_cohort_4 
Listing 33
Listing of Inflammatory Markers
SAC
Pharmacodynamic and Exploratory Markers
47.
Screened
See Listing 18 in /arenv/arprod/sb240563
/mid200862/final
Listing of Blood Eosinophil Data
Blood eosinophil counts 
and ratios to baseline. 
Include windowed time 
column.
SAC
48.
Screened
Similar to sb240563/mid205050/final_02/
Listing 38
Listing of Serum IL-5 Data
Total IL-5 only
SAC
PK/PD
49.
PD
Listing of Data and Participants Excluded from 
Analysis
From popPKPD analysis
Provided by CPMS
SAC


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Listings
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
50.
PD
Final PKPD Model Listings
From popPKPD analysis
Provided by CPMS
SAC


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17.13.
Appendix 13: Example Mock Shells for Data Displays
Example SAF_T1
Protocol: GSK123456                                                                            Page 1 of n
Population: Safety
Table X
Adverse Event Overview
Treatment A
(N=100)
Treatment B
(N=100)
Any AE
50 (50%)
50 (50%)
  On-treatment AEs
  AEs related to study treatment
20 (10%)
XX (XX%)
20 (10%)
XX (XX%)
  AEs leading to study withdrawal
    
5  (5%)
5  (5%)
Any SAE
10 (10%)
10 (10%)
  On-treatment SAEs
  SAEs related to study treatment
20 (10%)
XX (XX%)
20 (10%)
XX (XX%)
  Fatal SAEs
2  (2%)
2  (2%)
  Fatal SAEs related to study treatment
1  (1%)
1  (1%)
Note to programmer: List placebo, each individual dose group on order of ascending dose and then all active doses column.
Based on Standard Shell AE13. Note that some categories have been deleted/ modified.


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Example SAF_T2
Protocol: 205722                                                                              Page 1 of 1
Population: Safety
                                                 Table X.XX
Summary of AEs of Special Interest (On-treatment)
                                                      GSK    GSK      GSK      GSK      GSK
      GSK
                                           Placebo    2mg    10mg     30mg     100mg    300mg   All Active
                                           (N=12)    (N=6)   (N=6)    (N=9)    (N=9)    (N=6)    (N=36)
------------------------------------------------------------------------------------------------------------
Special Interest Adverse Events
  Hypersensitivity SMQ (narrow)
          X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%) 
    
<Preferred Term 1> 
          X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)
        <Preferred Term 2>                  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)
<Preferred Term 3>        
                       X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)
  Anaphylactic Reaction SMQ (narrow)        X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%) 
    
<Preferred Term 1> 
          X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)
        <Preferred Term 2>                  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)
<Preferred Term 3>        
                        X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)
  Vasculitis SMQ (narrow)                   X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%) 
    
<Preferred Term 1> 
          X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)
        <Preferred Term 2>                  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)
<Preferred Term 3>                                        X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)
  Injection Site Reactions [1]
  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%) 
    
<Preferred Term 1>                  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)
        <Preferred Term 2>                   X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)
<Preferred Term 3>        
                          X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)  X (XX%)
[1] Injection site reactions obtained via the General disorders and administration site conditions SOC under the    
Injection site reactions MedDRA high level term. 
Note to programmer: Table based on simplification of Table 7.32 from sb240563/MEA115588/Final. If there are no qualifying 
events for a particular AE of special interest, then present 0’s for the event row.


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Example: SAF_T3
Protocol: MEA115921                                                                             Page 1 of 3
Population: Safety
                                                 Table 3.37
Summary Profile of On-Treatment Adverse Events of Special Interest
AE of special interest: <Anaphylactic Reaction SMQ>
                                                       Placebo            Mepolizumab 300 mg SC
                                                       (N=68)             (N=68)
           -------------------------------------------------------------------------------------
           All Events
             >=1 event [1]                             3/2 (3%)           5/5 (7%)
             1 event                                   1   (1%)           5   (7%)
             2 events                                  1   (1%)           0
             3 events                                  0                  0
             >=4 events                                0                  0
           Serious Events
             >=1 event [1]                             1/1 (1%)           0
           Events considered related to
           investigational product
             >=1 event [1]                             1/1 (1%)           1/1 (1%)
           Intensity [1]
             Mild                                      0                  4/4 (6%)
             Moderate                                  2/2 (3%)           1/1 (1%)
             Severe                                    1/1 (1%)           0
           Outcome [1]
             Recovered/Resolved                        3/2 (3%)           5/5 (7%)
             Recovering/Resolving                      0                  0
             Not Recovered/Not Resolved                0                  0
             Recovered/Resolved With Sequelae          0                  0
             Fatal  
    0                  0
           Action Taken [1]
             Withdrawn from study                      0                  0
[1] Information presented as number of events / number (%) subjects with at least one event.
Note to programmer: Replace the currently displayed treatment headings with Placebo, each individual dose group in order of ascending 
dose and then all active doses column.


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Example: SAF_T4
Protocol: XYZ100001                                                                             Page 1 of 2
Population: Safety/Other study specific
Table X
Summary of Hepatobiliary Laboratory Abnormalities
Laboratory Criteria [1][2]
Treatment A
(N=123)
Treatment B
(N=240)
n
   122
237
ALT >3xULN and BIL >2xULN [3]
     1 (<1%)
  2 (<1%)
n
    81
182
ALT >3xULN and INR >1.5 [4]
     1  (1%)
  1 (<1%)
n
    80
180
ALT >3xULN and BIL >2xULN [3] and (ALP <2xULN)
     1  (1%)
  1 (<1%)
n
   123
237
ALT >3xULN
     6  (5%)
42 (18%)
ALT >5xULN
     4  (3%)
23 (10%)
ALT >8xULN
     2  (2%)
13  (5%)
ALT >10xULN
     2  (2%)
13  (5%)
ALT >20xULN
     1 (<1%)
  5  (2%)
[1] Subjects may be counted in more than one category.
[2] ALT: alanine aminotransferase; ALP: alkaline phosphatase; BIL: total bilirubin; INR: International 
Normalized Ratio; ULN=upper limit of normal.
[3] If direct bilirubin is available, then direct bilirubin as a portion of total bilirubin must be >35% when 
total bilirubin is >2xULN, in order to satisfy the criteria.  Bilirubin value is on or up to 28 days after ALT 
value.
[4] INR value is on or up to 28 days after ALT value.


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Example: SAF_T4 (continued)
Protocol: XYZ100001                                                                             Page 2 of 2
Population: Safety/Other study specific
Table X
Summary of Hepatobiliary Laboratory Abnormalities
Laboratory Criteria [1][2]
Treatment A
(N=123)
Treatment B
(N=240)
n
    122
    237
BIL >2xULN [3]
      3  (2%)
     12  (5%)
n
    123
    237
ALP >2xULN and Baseline ALP <2xULN or Baseline ALP missing
      2  (2%)
     10  (4%)
Time from Dose to First ALT Elevation >3xULN (days)
    n 
     6  (5%)
     42 (18%)
    Mean
    33.7
     30.1
    SD
    21.13
     15.61
    Median 
    31.0
     21.2
    Min.
    14
      9
    Max.
    56
     48
[1] Subjects may be counted in more than one category.
[2] ALT: alanine aminotransferase; ALP: alkaline phosphatase; BIL: total bilirubin; INR: International 
Normalized Ratio; ULN=upper limit of normal.
[3] If direct bilirubin is available, then direct bilirubin as a portion of total bilirubin must be >35% when 
total bilirubin is >2xULN, in order to satisfy the criteria.  Bilirubin value is on or up to 28 days after ALT 
value.
[4] INR value is on or up to 28 days after ALT value.
[5] Hepatocellular injury is defined as ((ALT/ALT ULN)/(ALP/ALP ULN)) > 5 and ALT >3xULN. ALT and ALP values 
must occur on the same day.


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Example: SAF_T5
Protocol: 204958                                                                                 Page 1 of 2
Population: All Treated Subjects (Safety)
                                                 Table 9.1
                                    Summary of Binding Antibody by Visit
                                              Lyophilised Liquid       Liquid Safety  Total
                                              Vial        Autoinjector Syringe        Liquid     Total
Visit         Assay Result                   (N=85)      (N=79)       (N=80)         (N=159)    (N=244)
----------------------------------------------------------------------------------------------------------
SCREENING     n                              85          79            80            159        244
               NEGATIVE                       83 (98%)    79 (100%)     79  (99%)     158 (>99%) 241  (99%)
               POSITIVE                        2  (2%)     0             1   (1%)       1  (<1%)   3   (1%)
DAY 1         n                              85          79            80            159        244
               NEGATIVE                       83 (98%)    79 (100%)     80 (100%)     159 (100%) 242 (>99%)
               POSITIVE                        2  (2%)     0             0              0          2  (<1%)
DAY 43        n                              84          79            80            159        243
               NEGATIVE                       82 (98%)    77  (97%)     77  (96%)     154  (97%) 236  (97%)
               POSITIVE                        2  (2%)     2   (3%)      3   (4%)       5   (3%)   7   (3%)
                   TRANSIENT POSITIVE          1  (1%)     0             0              0          1  (<1%)
                   PERSISTENT POSITIVE         1  (1%)     2   (3%)      3   (4%)       5   (3%)   6   (2%)
FOLLOW UP     n                              84          79            80            159        243
               NEGATIVE                       82 (98%)    75  (95%)     77  (96%)     152  (96%) 234  (96%)
               POSITIVE                        2  (2%)     4   (5%)      3   (4%)       7   (4%)   9   (4%)
                   PERSISTENT POSITIVE         2  (2%)     4   (5%)      3   (4%)       7   (4%)   9   (4%)
[1] A subject is considered positive if they have at least one positive post-baseline anti-drug
antibody (ADA) result.
[2] Highest post-baseline titre.
PPD


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Example: SAF_T5 (continued)
Protocol: 204958                                                                                 Page 2 of 2
Population: All Treated Subjects (Safety)
                                                 Table 9.1
                                    Summary of Binding Antibody by Visit
                                              Lyophilised Liquid       Liquid Safety  Total
                                              Vial        Autoinjector Syringe        Liquid     Total
Visit         Assay Result                   (N=85)      (N=79)       (N=80)         (N=159)    (N=244)
----------------------------------------------------------------------------------------------------------
ANY           n                              84          79            80            159        243
POST-BASELINE
               NEGATIVE                       81 (96%)    74  (94%)     77  (96%)     151  (95%) 232  (95%)
               POSITIVE [1]                    3  (4%)     5   (6%)      3   (4%)       8   (5%)  11   (5%)
                   TRANSIENT POSITIVE          1  (1%)     1   (1%)      0              1  (<1%)   2  (<1%)
                   PERSISTENT POSITIVE         2  (2%)     4   (5%)      3   (4%)       7   (4%)   9   (4%)
               Titre value [2]         Min.   16           8            32              8          8
                                       Median 16.0        32.0         256.0           32.0       32.0
                                       Max.   32          32           320            320        320
[1] A subject is considered positive if they have at least one positive post-baseline anti-drug
antibody (ADA) result.
[2] Highest post-baseline titre.
PPD


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Example:    PD_T1 (sb240563/mid200862/final/drivers/t_bleos.sas (Table 2.73))
            Page 1 of n
Protocol:     205722
Population: PD
Table Insert Table Number
Summary of Blood Eosinophils (10^9/L)
                                                                   
                                                                Placebo    GSK 2mg    GSK 10mg
           Time Point                                           (N=XX)     (N=8)      (N=8)
           -------------------------------------------------------------------------------------
           Baseline    Blood Eosinophils (10^9/L)    n          XX          X         X 
                                                     Geo. Mean    0.35      0.30
   X.XX
                                                     Std Logs     0.922    1.107     X.XXX
                                                     Median       0.35       0.34      X.XX
                                                     Min.         0.0        0.0       X.X
                                                     Max.         3.7       14.0      XX.X
           Day 2 (24h) Blood Eosinophils (10^9/L)    n          XX         X        X
                                                     Geo. Mean    0.30      0.06      X.XX
                                                    Std Logs     1.129     0.855     X.XXX
                                                     Median       0.35      0.06      X.XX
                                                     Min.         0.0       0.0       X.X
                                                     Max.         2.4        0.9      XX.X
                       Blood Eosinophils Ratio to    n          XX         X         X
                       Baseline
                                                     Geo. Mean    0.86       0.20      X.XX
                                                     Std Logs     1.000      1.099     X.XXX
                                                     Median       0.94       0.17      X.XX
                                                     Min.         0.0        0.0       X.X
                                                     Max.        23.3       20.0      XX.X
Note: Where a result of zero was recorded, a small value (0.005) was added prior to log transformation.
[Note to programmer: Will need to add columns for other dose groups on another page, repeat Day 2 (24h) format 
for all scheduled visits]


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Example: PD_T2
Protocol: 200862                                                                                 
Page 1 of 2
Population: PD
                                                 Table X.XX
                       Statistical Analysis of Change from Baseline Blood Eosinophil Data
                                                                      
Treatment
N
Visit
Ratio to
   95% CI of
  
Prob (Ratio < X.X)
Baseline
Ratio to Baseline    
0.3
0.5
0.75
1.0               
                       --------------------------------------------------------------
GSK 2mg
X
Day 2 (24h)
X.XX
X.XX
X.XX
0.XX
0.XX
0.XX
0.XX
Day 3 (48h)
X.XX
X.XX
X.XX
0.XX
0.XX
0.XX
0.XX
Day 4 (72h)
X.XX
X.XX
X.XX
0.XX
0.XX
0.XX
0.XX
………
Week 32 (Day 225)
X.XX
X.XX
X.XX
0.XX
0.XX
0.XX
0.XX
GSK 10mg 
X
Day 2 (24h)
X.XX
X.XX
X.XX
0.XX
0.XX
0.XX
0.XX
Day 3 (48h)
X.XX
X.XX
X.XX
0.XX
0.XX
0.XX
0.XX
Day 4 (72h)
X.XX
X.XX
X.XX
0.XX
0.XX
0.XX
0.XX
………
Week 32 (Day 225)
X.XX
X.XX
X.XX
0.XX
0.XX
0.XX
0.XX
etc.
Note: Prob ratios displayed will be dependent on the data and the time of analysis. For the interim, prob (ratio < 0.84) will be displayed and for the 
final analysis, prob (ratio <0.75) will be displayed.


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Example: PD_F1
Protocol: 205722                                                                         Page 1 of 1
Population: PD
                                                 Figure X.XX
                       Geometric means (and 95% CIs) of Ratio to Baseline Blood Eosinophils 
Include all available groups, will need to be careful about unblinding at later timepoints for the 
Interim analysis.


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Example PD_F2
Protocol: 205722                                                                         Page 1 of 1
Population: PD