An Observer-blind, Dose Ranging Safety and Immunogenicity Study of GSK Biologicals' GSK1557484A Vaccine in Children 6 to Less Than 36 Months of Age
Phase: PHASE2
Conditions: Influenza
Sponsor: GlaxoSmithKline

CONFIDENTIAL
27-MAR-2017
1
Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals S.A.
Rue de l’Institut 89,
1330, Rixensart, Belgium
Primary Study 
vaccine(s)/product(s) and 
number(s)
GlaxoSmithKline (GSK) Biologicals’ Influenza 
A/Indonesia/05/2005 (H5N1) vaccine adjuvanted
with AS03 (GSK1557484A)
Other Study vaccines
GSK Biologicals’ Influenza A/Indonesia/05/2005 
(H5N1) vaccine, unadjuvanted
Title
An observer-blind, dose ranging safety and 
immunogenicity study of GSK Biologicals’ 
GSK1557484A vaccine in children 6 to less than 36 
months of age
Detailed Title
A phase II observer-blind, multicentre, dose-ranging 
study of children 6 to less than 36 months of age who 
are to be primed with a 2-dose series of GSK 
Biologicals’ AS03-adjuvanted A/Indonesia/05/2005 
(H5N1) vaccine 
Study identifier
116938 (FLU Q-PAN H5N1=AS03-023)
EudraCT Number
2015-003458-42
Date of protocol
Final Version 1: 17 October 2015
Date of protocol amendment
Amendment 1 Final: 20 January 2016
Amendment 2 Final: 27 March 2017
Co-ordinating author
(Amended: 27-MAR-2017)
, Science Writer
Contributing authors
(Amended: 27-MAR-2017)
Clinical Research and Development Lead
Project Statistician
Lead Statistician
Study Delivery Lead
Clinical Read-outs Team Lead
Clinical Safety representative
Project Data Manager
Clinical Trial Supply Manager
Global Regulatory Leader
GSK Biologicals’ Protocol DS v 14.1.1
Copyright 2015-2017 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
1
27-MAR-2017
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
2
Protocol Amendment 2 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
116938 (FLU Q-PAN H5N1=AS03-023)
EudraCT Number
2015-003458-42
Date of protocol amendment
Amendment 2 Final: 27 March 2017
Detailed Title
A phase II observer-blind, multicentre, dose-ranging 
study of children 6 to less than 36 months of age who 
are to be primed with a 2-dose series of GSK 
Biologicals’ AS03-adjuvanted A/Indonesia/05/2005 
(H5N1) vaccine 
Sponsor signatory
Anne Schuind, MD
Signature
Date
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
2
27-MAR-2017
- ----------------Checksum----------------!Ver.!Created On -   -
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff 2.0 4/25/2017 3:46:51 PM -   -
---------------------------------------------------------------------------- -
For internal use only

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
3
Protocol Amendment 2 Rationale
Amendment number:
Amendment 2
Rationale/background for changes:
The heterologous immunogenicity testing described as secondary study 
objective will be assessed by microneutralization (MN) assay in addition to HI 
assay. MN provides additional relevant information to evaluate cross reactivity 
being a more sensitive and less HA antigen-specific assay than the HI assay. In 
addition, updated EMA guidance [EMA/CHMP/VWP/457259/2014 Guideline 
on Influenza Vaccines. Non-clinical and Clinical Module] requires both HI and 
neutralization data for cross-reactivity assessment. 
Minor edits in other sections were made for clarification.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
3
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
4
Protocol Amendment 2 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational vaccine(s)/product(s) and other study-related 
duties and functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative. 

To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s). 

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine(s)/product(s), and more generally about 
his/her financial ties with the sponsor. GSK Biologicals will use and disclose the 
information solely for the purpose of complying with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study. 

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
4
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
5
eTrack study number and 
Abbreviated Title
116938 (FLU Q-PAN H5N1=AS03-023)
EudraCT Number
2015-003458-42
Date of protocol amendment
Amendment 2 Final: 27-March-2017
Detailed Title
A phase II observer-blind, multicentre, dose-ranging 
study of children 6 to less than 36 months of age who 
are to be primed with a 2-dose series of GSK 
Biologicals’ AS03-adjuvanted A/Indonesia/05/2005 
(H5N1) vaccine 
Investigator name
Signature
Date
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
5
27-MAR-2017
- ----------------Checksum----------------!Ver.!Created On -   -
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff 2.0 4/25/2017 3:46:51 PM -   -
---------------------------------------------------------------------------- -
For internal use only

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
6
Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals S.A.
Rue de l’Institut 89, 1330, Rixensart, Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to
protocol Section 8.3.1.
Study Contact for Reporting SAEs: refer to the local study contact information 
document.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
6
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
7
SYNOPSIS
Detailed Title
A phase II observer-blind, multicentre, dose-ranging study of 
children 6 to less than 36 months of age who are to be primed 
with a 2-dose series of GSK Biologicals’ AS03-adjuvanted 
A/Indonesia/05/2005 (H5N1) vaccine 
Indication
Active immunization against influenza A virus H5N1 subtype 
Rationale for the 
study and study 
design

Rationale for the study: GSK’s AS03-adjuvanted 
monovalent pandemic H5N1 influenza vaccine
manufactured in Dresden (Germany) and tested in clinical 
studies in children (6 to 35 months or 3 to 5 years old) 
had an increase in reactogenicity (especially fever) with 
increasing number of doses (after a second or third dose). 
GSK aims to reduce reactogenicity if feasible while 
maintaining adequate immunogenicity. This dose-ranging 
study will either confirm that the current pediatric 
formulation represents an acceptable balance between 
immunogenicity and reactogenicity, or will suggest that 
the adjuvant or antigen dose, or both, could be modified. 

Rationale for the study design: This study will assess 
the balance between immune responses and adverse 
effects associated with different amounts of AS03 
adjuvant and Q-Pan H5N1 antigen in combination in 
children 6-35 months of age. 
The quality of the 2-dose priming will be assessed 
through the anamnestic response elicited by an antigen 
challenge administered 12 months later. All subjects will 
receive an unadjuvanted booster dose of 3.75 µg HA 
which was selected to this effect in an effort to (a) 
minimize reactogenicity in these young children, and (b) 
facilitate an assessment of the anamnestic response to 
each priming regimen by increasing the potential of 
detecting differences between groups, which may be 
masked by a vigorous response to an AS03 adjuvanted 
booster dose rather than plain antigen. The persistence of 
the immune response approximately 12 months (Day
385) after dose 2 will also be evaluated. 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
7
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
8
Objective(s)
(Co-)Primary

To assess the performance of alternative dosing regimens 
for primary immunization with Q-Pan H5N1 vaccine 
using an immunogenicity-fever index that considers:

immunogenicity by HI assay 21 days after the 
second priming dose, and 

fever scores after the first and second priming doses. 

To assess the performance of alternative dosing regimens 
for primary immunization with Q-Pan H5N1 vaccine 
using an immunogenicity-fever index that considers:

immunogenicity by MN assay 21 days after the 
second priming dose and 

fever scores after the first and second priming doses. 
The reference dose for each of these assessments will be 
1.9 µg HA with AS03B (half the approved adult dose).
Booster dose 

To assess the performance of dosing regimens for booster 
immunization with Q-Pan H5N1 vaccine considering:

immune response by HI assay 7 days after a 12-
month booster dose of 3.75 µg HA Q-Pan H5N1 
plain antigen

To assess the performance of dosing regimens for booster 
immunization with Q-Pan H5N1 vaccine considering:

immune response by MN assay 7 days after a 12-
month booster dose of 3.75 µg HA Q-Pan H5N1 
plain antigen
Secondary:

To describe the HI immune response to the vaccine-
homologous virus 21 days after the second dose for each 
dosing regimen

To assess the performance of alternative dosing regimens 
for primary immunization with Q-Pan H5N1 vaccine 
considering persistence of immune response by HI and 
MN assay at Day 385 in terms of persistence index

To assess the performance of the H5N1 vaccine regimens 
in terms of vaccine-homologous HI and MN antibody 
titers on Days 0, 42, 385 and Day 392.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
8
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
9

To assess the immunogenicity of the H5N1 vaccine 
regimens in terms of vaccine-heterologous HI and MN 
antibody titers on Days 0, 42, 385 and Day 392.
(Amended: 27-MAR-2017)

To assess vaccine induced cell-mediated immune 
responses (frequency of CD3+/CD4+/CD8+ T-cells) on 
Days 0, 42, 385 and Day 392.

To describe reactogenicity and safety of the different 
priming regimens in terms of solicited (7-days after each 
vaccination) and unsolicited (21 days after each 
vaccination) adverse events (AEs).

To describe safety of the unadjuvanted booster dose in 
terms of solicited (7 days post boost) and unsolicited (30 
days post boost) AEs.

To describe safety in terms of medically attended events
(MAEs), AEs of special interest (AESIs), potential 
immune-mediated diseases (pIMDs), and serious adverse 
events (SAEs) during the entire study period. (Amended: 
27-MAR-2017)
Study design

Experimental design: phase II, observer blind, 
randomized, multi-center, multi-country study, parallel 
groups. 

Duration of the study: approximately 415 days after 
vaccination on Day 0. 

Epoch 001: Primary Epoch starting at Visit 1 (Day 0) 
through Visit 5-TC2 (Day 240) and ending at the 
start of Visit 6 (Day 385).

Epoch 002: Booster Epoch starting at Visit 6 (Day 
385) through Visit 8-TC 3 (Day 415).

Study groups: Approximately 37 subjects will be enrolled 
in each of the 5 following study groups:

190_B: 
1.9 g H5N1 HA antigen adjuvanted 
with AS03B 

090_C: 
0.9 g H5N1 HA antigen adjuvanted 
with AS03C 

190_C: 
1.9 g H5N1 HA antigen adjuvanted 
with AS03C 

375_C: 
3.75 g H5N1 HA antigen adjuvanted 
with AS03C 

375_D: 
3.75 g H5N1 HA antigen adjuvanted 
with AS03D 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
9
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
10
Synopsis Table 1
Study groups and epochs foreseen in the study
Study groups
Number of 
subjects
Epochs
Epoch 001 (Primary Series)
Epoch 002 (Booster)
190_B
37 
● 
● 
090_C
37 
● 
● 
190_C 
37 
● 
● 
375_C 
37 
● 
● 
375_D
37 
● 
● 
Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment 
name
Vaccine/Product name
(Formulation)
Study Groups
190_B
090_C 
190_C 
375_C
375_D
1.9 mcg 
H5N1 HA + 
AS03B
FLU-Q-PAN
(A/Indonesia/05/2005 H5N1 HA, 15 
µg/mL) 
● 
AS03A 
(AS03 47.44 mg/mL , final vaccine 
dose contains 5.93 mg tocopherol)
● 
0.9 mcg 
H5N1 HA + 
AS03C 
FLU-Q-PAN
(A/Indonesia/05/2005 H5N1 HA, 15 
µg/mL) 
● 
AS03A 
(AS03 47.44 mg/mL, final vaccine 
dose contains 2.97 mg tocopherol)
● 
1.9 mcg 
H5N1 HA + 
AS03C 
FLU-Q-PAN  
(A/Indonesia/05/2005 H5N1 HA, 15 
µg/mL)
● 
AS03B 
(AS03 23.72 mg/mL; final vaccine 
dose contains 2.97 mg tocopherol
● 
3.75 mcg 
H5N1 HA + 
AS03C 
FLU-Q-PAN
(A/Indonesia/05/2005 H5N1 HA, 30 
µg/mL)
● 
AS03B 
(AS03 23.72 mg/mL; final vaccine 
dose contains 2.97 mg tocopherol
● 
3.75 mcg
H5N1 HA + 
AS03D 
FLU-Q-PAN
(A/Indonesia/05/2005 H5N1 HA, 30 
µg/mL)
● 
AS03C 
(AS03 11.86 mg/mL; final vaccine 
dose contains 1.48 mg tocopherol)
● 
3.75 mcg 
H5N1 HA 
FLU-Q-PAN
(A/Indonesia/05/2005 H5N1 HA, 15 
µg/mL)
● 
● 
● 
● 
● 

Vaccination schedule: 

All subjects are to receive an AS03 adjuvanted H5N1 
vaccine given as a two-dose primary series at a 21 
day interval.

All subjects are to receive a 3.75 g HA, un-
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
10
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
11
adjuvanted H5N1 vaccine as a booster dose at Day 
385.

Control: None

Treatment allocation: Randomization will be 1:1:1:1:1 
with 37 subjects per group.

Blinding: observer-blind
Synopsis Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001 
observer-blind
Epoch 002 
observer-blind

Sampling schedule:

All study groups: Day 0 (before vaccination); Day 42 
(post primary course); Day 385 (persistence) and Day 392 
(booster response) 

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF).

Safety monitoring: 

The study will be under the oversight of an iSRC

Ongoing monitoring of reactogenicity and safety data will 
be performed by an internal safety review committee 
(iSRC). Details of the data review will be further 
explained in a separate iSRC charter.
Number of subjects
approximately 185
Endpoint(s)
Primary:
Immunogenicity-fever indices

Humoral immune response in terms of vaccine-
homologous HI antibody for each group: 

LL (lower limit) of 95%CI of GMT group ratio at Day 
42 using 1.9 µg HA with AS03B as reference 

Humoral immune response in terms of vaccine-
homologous MN antibody for each group: 

LL of 95%CI GMT group ratio at Day 42 using 1.9 µg 
HA with AS03B as reference 

Fever measurement (≥38°C) post dose 1 and dose 2
For each subject, a fever index will be calculated using 
temperature measurements 3-days post Dose 1 (D0-D2) 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
11
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
12
and 3-days post Dose 2 (D21-D23) 
Immune response to a booster dose

For immune response in terms of HI antibodies against 
vaccine-homologous antigen

Mean Geometric Increase (MGI) at Day 392 relative to 
Day 385 

For the immune response in terms of MN antibodies 
against vaccine-homologous antigen

MGI at Day 392 relative to Day 385 
Secondary Endpoints
Immunogenicity

For humoral immune response in terms of HI antibodies 
against vaccine-homologous/heterologous antigens post 
primary immunization, the following aggregate variables 
will be calculated for each group:
Seroconversion rates (SCR) at Day 42 
Seroprotection rates (SPR) at Day 42 
MGI at Days 42 relative to Day 0 

For humoral immune response in terms of vaccine-
homologous MN antibody post the primary immunization, 
following aggregate variables will be calculated for each 
group:
MGI at Day 385 relative to Day 0

For humoral immune response in terms of HI antibodies 
against vaccine-homologous/heterologous antigens (at 
Days 0, 42 and 385 post the primary immunization, at Day 
392 (7 days post booster dose)), the following aggregate 
variables will be calculated for each group:
Seropositivity rates at Days 0, 42, 385 and Day 392 
Seroconversion rates (SCR) at Day 385 (relative to Day 
0) and Day 392 (relative to Days 0 and 385) 
Seroprotection rates (SPR) at Days 0, 385 and 392 
Geometric Mean Titer (GMT) at Days 0, 42, 385, 392 
MGI at Day 385 (relative to Day 0), MGI at Day 392 
(relative to Days 0 and 385) 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
12
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
13

For humoral immune response in terms of vaccine-
homologous/heterologous MN antibodies, the following 
aggregate variables will be calculated for each group
(Amended: 27-MAR-2017):
Seropositivity rates at Days 0, 42,385 and 392 
GMT at Days 0, 42,385 and Day 392 
Vaccine response rate (VRR) at Days 42, 385 (relative 
to Day 0) and Day 392 (relative to Days 0 and 385)

For CMI in terms of frequencies of antigen-specific 
(CD3+/CD4+/CD8+) cells at Days 0, 42, 385 and 392;
Frequencies of cytokine CD4+/CD8+ T-cells per million 
CD4+/CD8+ cells producing two or more markers 
within CD40L, IL-2, TNF-, IFN-upon in vitro
stimulation using A/Indonesia/05/2005 (H5N1) split 
virus as determined by intracellular cytokine staining
(ICS) in a sub-cohort of approximately 20 subjects per 
group at Days 0, 42, 385 and Day 392. (Amended: 27-
MAR-2017)
Reactogenicity /Safety:

Solicited local and general AEs
Occurrence of each solicited local AEs during a 7-day 
follow-up period (i.e., day of vaccination and 6 
subsequent days) after any vaccination.
o
Percentage, intensity and duration of solicited local 
AEs during a 7-day follow-up period (Day 0-Day 6) 
after any vaccination.
Occurrence of each solicited general AEs during a 7-day 
follow-up period (i.e., day of vaccination and 6 
subsequent days) after any vaccination.
o
Percentage, intensity, duration and relationship to 
vaccination of solicited general AEs during a 7-day 
follow-up period (Day 0-Day 6) after any 
vaccination.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
13
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
14

Unsolicited adverse events
For the primary series: occurrence and relationship to 
vaccination of unsolicited adverse events within 21 
days after each vaccine dose.
o
Percentage, intensity and relationship to vaccination 
of unsolicited AEs during a 21-day follow-up 
period (Day 0-Day 20) after each vaccine dose.
For the booster dose [unadjuvanted]: occurrence and 
relationship to vaccination of unsolicited AEs within 30 
days after vaccination
o
Percentage, intensity and relationship to vaccination 
of unsolicited AEs during a 30-day follow-up 
period.
Occurrence and relationship to vaccination of MAEs 
during the entire study period.
o
Percentage and relationship to vaccination of MAEs 
during the entire study period.
Occurrence and relationship to vaccination of pIMDs, 
AESIs and SAEs during the entire study period. 
o
Percentage and relationship to vaccination of 
pIMDs, SAEs, AESIs during the entire study 
period. 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
14
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
15
TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................6
SYNOPSIS......................................................................................................................7
LIST OF ABBREVIATIONS (AMENDED 27-MAR-2017) ...............................................23
GLOSSARY OF TERMS ...............................................................................................25
1.
INTRODUCTION....................................................................................................29
1.1.
Background ................................................................................................29
1.2.
Rationale for the study................................................................................29
1.3.
Rationale for the study design.....................................................................30
1.4.
Benefit : Risk Assessment ..........................................................................31
1.4.1.
Risk Assessment .........................................................................31
1.4.2.
Benefit Assessment .....................................................................32
1.4.3.
Overall Benefit - Risk Conclusion.................................................32
2.
OBJECTIVES.........................................................................................................32
2.1.
Co-Primary Objectives................................................................................32
2.1.1.
Primary Doses .............................................................................32
2.1.2.
Booster Dose...............................................................................33
2.2.
Secondary objectives..................................................................................33
3.
STUDY DESIGN OVERVIEW ................................................................................34
4.
STUDY COHORT...................................................................................................36
4.1.
Number of subjects/centres ........................................................................36
4.2.
Inclusion criteria for enrolment....................................................................37
4.3.
Exclusion criteria for enrolment...................................................................37
5.
CONDUCT OF THE STUDY ..................................................................................39
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................39
5.2.
Subject identification and randomisation of treatment .................................40
5.2.1.
Subject identification....................................................................40
5.2.2.
Randomisation of treatment.........................................................40
5.2.2.1.
Randomisation of supplies..........................................40
5.2.2.2.
Treatment allocation to the subject.............................40
5.2.2.2.1.
Study group and 
randomization/treatment number 
allocation ................................................40
5.2.2.2.2.
Treatment number allocation for 
subsequent doses ..................................41
5.3.
Method of blinding ......................................................................................41
5.4.
General study aspects ................................................................................42
5.5.
Outline of study procedures ........................................................................42
5.6.
Detailed description of study procedures ....................................................44
5.6.1.
Informed consent.........................................................................44
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
15
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
16
5.6.2.
Check inclusion and exclusion criteria .........................................44
5.6.3.
Collect demographic data ............................................................44
5.6.4.
Medical history.............................................................................44
5.6.5.
Physical examination ...................................................................44
5.6.6.
Pre-vaccination vital signs ...........................................................44
5.6.7.
Check contraindications, warnings and precautions to 
vaccination...................................................................................45
5.6.8.
Study group and randomization/treatment number 
allocation .....................................................................................45
5.6.9.
Blood sampling for immune response assessment ......................45
5.6.10.
Study Vaccine administration.......................................................45
5.6.11.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................45
5.6.12.
Recording of AEs.........................................................................46
5.6.13.
Study conclusion..........................................................................46
5.7.
Biological sample handling and analysis.....................................................46
5.7.1.
Use of specified study materials ..................................................47
5.7.2.
Biological samples.......................................................................48
5.7.3.
Laboratory assays .......................................................................48
5.7.4.
Biological samples evaluation......................................................50
5.7.5.
Immunological correlates of protection.........................................50
6.
STUDY VACCINE ADMINISTRATION...................................................................51
6.1.
Description of study vaccine(s)/product(s) ..................................................51
6.2.
Storage and handling of study vaccine .......................................................54
6.3.
Dosage and administration of study vaccine(s)/product(s)..........................55
6.4.
Replacement of unusable vaccine/product doses .......................................55
6.5.
Contraindications to subsequent vaccination ..............................................55
6.6.
Warnings and precautions ..........................................................................56
6.7.
Concomitant medications/products and concomitant vaccinations..............56
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................56
6.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses........................57
6.8.
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses .........................................................................57
7.
HEALTH ECONOMICS ..........................................................................................57
8.
SAFETY.................................................................................................................58
8.1.
Safety definitions ........................................................................................58
8.1.1.
Definition of an adverse event......................................................58
8.1.2.
Definition of a serious adverse event ...........................................59
8.1.3.
Solicited adverse events..............................................................60
8.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................60
8.1.5.
Other adverse events...................................................................60
8.1.5.1.
Potential immune-mediated diseases .........................60
8.1.5.2.
CHMP-defined adverse events of special 
interest (AESIs) ..........................................................63
8.2.
Detecting and recording adverse events/SAEs ...........................................63
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
16
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
17
8.2.1.
Time periods for detecting and recording adverse 
events/SAEs ................................................................................64
8.2.2.
Post-Study adverse events/SAEs ................................................66
8.2.3.
Evaluation of adverse events/SAEs .............................................66
8.2.3.1.
Active questioning to detect adverse 
events/SAEs...............................................................66
8.2.3.2.
Assessment of intensity..............................................67
8.2.3.2.1.
Solicited AEs ..........................................67
8.2.3.2.2.
Unsolicited AEs ......................................68
8.2.3.3.
Assessment of causality .............................................68
8.2.3.4.
Assessment of outcomes............................................69
8.2.3.5.
Medically attended visits.............................................70
8.3.
Prompt reporting of serious adverse events and other events to 
GSK Biologicals..........................................................................................70
8.3.1.
Contact information for reporting serious adverse events 
and pIMDs ...................................................................................70
8.3.2.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................71
8.3.2.1.
Back-up system in case the electronic reporting 
system does not work.................................................71
8.3.3.
Reporting of pIMDs to GSK Biologicals........................................71
8.3.4.
Updating of SAE and pIMD information after removal of 
write access to the subject’s eCRF ..............................................72
8.3.5.
Regulatory reporting requirements for serious adverse 
events..........................................................................................72
8.4.
Follow-up of adverse events/SAEs .............................................................72
8.4.1.
Follow-up during the study...........................................................72
8.4.2.
Follow-up after the subject is discharged from the study..............72
8.5.
Treatment of adverse events ......................................................................73
8.6.
Subject card................................................................................................73
8.7.
Holding rules and safety monitoring............................................................73
8.7.1.
iSRC Review ...............................................................................73
8.7.2.
Holding Rules – primary series ....................................................74
8.7.3.
Impact of sample size on holding rule assessment ......................74
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................76
9.1.
Subject completion .....................................................................................76
9.2.
Subject withdrawal......................................................................................76
9.2.1.
Subject withdrawal from the study................................................76
9.2.2.
Subject withdrawal from investigational vaccine...........................77
10. STATISTICAL METHODS......................................................................................77
10.1.
Primary Endpoints ......................................................................................77
10.1.1.
Immunogenicity-fever indices.......................................................77
10.1.2.
Immune response to a booster dose............................................78
10.2.
Secondary Endpoints..................................................................................78
10.3.
Determination of sample size......................................................................81
10.4.
Cohorts for Analyses...................................................................................82
10.4.1.
Total Vaccinated Cohort ..............................................................82
10.4.2.
Cohort for according-to-protocol (ATP) immunogenicity 
analyses ......................................................................................82
10.4.3.
Cohort for analysis of the immunogenicity-fever score.................83
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
17
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
18
10.5.
Derived and transformed data.....................................................................83
10.6.
Statistical analyses .....................................................................................84
10.6.1.
Analysis of demographics ............................................................84
10.6.2.
Analyses of primary objectives.....................................................85
10.6.2.1.
Immunogenicity-fever indices .....................................85
10.6.2.2.
Immune Response to a booster dose .........................86
10.6.3.
Analysis for the secondary objectives ..........................................86
10.6.3.1.
Analysis for immunogenicity .......................................86
10.6.3.2.
Analysis for CMI .........................................................86
10.6.3.3.
Analysis for safety ......................................................87
10.7.
Interpretation of analyses............................................................................88
10.8.
Conduct of analysis ....................................................................................88
10.8.1.
Sequence of analyses..................................................................88
10.8.1.1.
iSRC analyses............................................................88
10.8.1.2.
Analysis at Day 42......................................................88
10.8.1.3.
Final analysis..............................................................89
10.8.2.
Statistical considerations for interim analyses..............................89
11. ADMINISTRATIVE MATTERS ...............................................................................89
11.1.
electronic Case Report Form instructions ...................................................89
11.2.
Study Monitoring by GSK Biologicals..........................................................90
11.3.
Record retention .........................................................................................90
11.4.
Quality assurance.......................................................................................91
11.5.
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................91
11.6.
Provision of study results to investigators ...................................................93
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................93
13. REFERENCES.......................................................................................................94
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
18
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
19
LIST OF TABLES
PAGE
Table 1
Risk Assessment....................................................................................31
Table 2
Study groups and epochs foreseen in the study.....................................35
Table 3
Study groups and treatments foreseen in the study:...............................35
Table 4
Blinding of study epochs ........................................................................36
Table 5
Sub-cohorts............................................................................................36
Table 6
List of study procedures .........................................................................42
Table 7
Intervals between study visits.................................................................43
Table 8
Biological samples .................................................................................48
Table 9
Humoral immunity (antibody determination) (Amended: 27-MAR-
2017)......................................................................................................48
Table 10
Cell-Mediated Immunogenicity (CMI) ) (Amended: 27-MAR-2017).........49
Table 11
Immunological read-outs (Amended: 27-MAR-2017)..............................50
Table 12
Study vaccine.........................................................................................52
Table 13
Dosage and administration.....................................................................55
Table 14
Solicited local adverse events ................................................................60
Table 15
Solicited general adverse events............................................................60
Table 16
List of potential immune-mediated diseases...........................................62
Table 17
Reporting periods for collecting safety information : ...............................65
Table 18
Intensity scales for solicited symptoms in infants/toddlers and 
children less than 6 years of age............................................................67
Table 19
Timeframes for submitting serious adverse events and pIMDs 
reports to GSK Biologicals .....................................................................70
Table 20
Holding Rules.........................................................................................74
Table 21
Lower limit of 95%CI for GMT ratio of vaccine group to the 
reference group 21- days after second vaccination ................................81
Table 22
Probability to detect fever during 7-day follow-up after 
vaccination.............................................................................................81
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
19
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
20
Table 23
Power to meet LL of 95% CI for SCR>40% and LL of 95%CI for 
SPR>70% in one of the vaccine group (without Type I error 
adjustment) ............................................................................................82
Table 24
GSK Biologicals’ laboratories .................................................................97
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
20
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
21
LIST OF FIGURES
PAGE
Figure 1
Design Overview....................................................................................34
Figure 2
Probability to conclude that a specific formulation is safe 
according to safety holding rule 2 with N = 37 ........................................75
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
21
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
22
LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .......................................................................95
APPENDIX B CLINICAL LABORATORIES ..................................................................97
APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL...........................................................................................98
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
22
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
23
LIST OF ABBREVIATIONS (Amended 27-MAR-2017)
AE:
Adverse Event
AESI:
Adverse Event of Special Interest
AS:
Adjuvant System
AS03:
AS03 is an Adjuvant System containing -tocopherol and 
squalene in an oil and water emulsion
AS03A:
The approved adult dose of AS03 (approximately 11.86 
mg tocopherol in 0.25 mL, i.e., 47.44 mg tocopherol per 
mL)
AS03B:
Half the approved adult dose of AS03 (approximately 
5.93 mg tocopherol). In this study, AS03B may equal 
0.125mL of the “AS03A” product, or may be provided as 
a separate formulation containing 23.72 mg tocopherol 
per mL, depending on dose preparation requirements.
AS03C:
Approximately one-fourth the approved adult dose of 
AS03 (2.96 mg tocopherol). In this study AS03C may 
equal 0.0625 mL of the “AS03A” product; or 0.125 mL of 
the “AS03B” product, or be provided as a separate 
formulation containing 11.86 mg tocopherol per mL, 
depending on the dose preparation requirements.
AS03D:
Approximately one-eighth the approved adult dose of 
AS03 (1.48 mg tocopherol). In this study AS03D equals 
0.125 mL of the “AS03C” product.
ATP:
According-To-Protocol
CHMP:
Committee for Medicinal Products for Human Use
CI:
Confidence Interval
CMI:
CD40L:
CD-3, 4 or 8:
Cell mediated Immunity
CD-40 Ligand
Cluster Differentiation 3, 4 or 8
CDC:
CFC:
Centers for Disease Control
Cytokine Flow Cytometry
eCRF:
Case Report Form/electronic Case Report Form
eTDF:
Electronic Temperature excursion Decision Form
GCP:
Good Clinical Practice
GMT:
Geometric Mean Titer
GSK:
GlaxoSmithKline
HA:
Hemagglutinin
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
23
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
24
HAI or HI:
Hemagglutination Inhibition
IB:
Investigator Brochure
ICF:
ICS:
Informed Consent Form
Intracellular Cytokine Staining (Amended: 27-MAR-
2017)
ICH:
International Conference on Harmonisation
IEC:
Independent Ethics Committee
IMP:
Investigational Medicinal Product
IDMC:
Independent Data Monitoring Committee
IRB:
Institutional Review Board
iSRC:
IFN:
IL-2:
Internal Safety Review Committee
Interferon 
Interleukin-2
LAR:
Legally Acceptable Representative
LSLV:
Last Subject Last Visit
MAEs:
Medically Attended Events (Amended: 27-MAR-2017)
MedDRA:
Medical Dictionary for Regulatory Activities
MGI:
Mean Geometric Increase
MN:
Microneutralization
pIMD:
Potential Immune-Mediated Disease
PT:
Preferred Term
SAE:
Serious Adverse Event
SCR:
Seroconversion Rate
SBIR:
Randomisation System on Internet
SDV:
Source Document Verification
SmPC:
Summary of Product Characteristics
SMQs:
Standardized MedDRA Queries
SPM:
Study Procedures Manual
TNF-:
Tumor necrosis factor-(Amended: 27-MAR-2017)
VRR:
Vaccine Response Rate
WB:
Whole Blood
WHBST:
Whole Blood – stimulated cells
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
24
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
25
GLOSSARY OF TERMS
Adverse event:
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product. An adverse event (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. For marketed medicinal 
products, this also includes failure to produce expected 
benefits (i.e. lack of efficacy), abuse or misuse.
Adverse events of special 
interest
A subset of adverse events defined in the Committee for 
Medicinal Products for Human Use (CHMP) Risk
Management Plan for Pandemic Vaccines for safety 
monitoring.
Blinding:
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. In an 
observer-blind study, the subject’s parent(s)/LAR(s) and 
the site and sponsor personnel involved in the clinical 
evaluation of the subjects are blinded while other study 
personnel may be aware of the treatment assignment.
Child in care:
A child who has been placed under the control or 
protection of an agency, organisation, institution or entity 
by the courts, the government or a government body, 
acting in accordance with powers conferred on them by 
law or regulation. The definition of a child in care can 
include a child cared for by foster parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted or has an 
appointed legal guardian.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
Epoch:
An epoch is a self-contained set of consecutive timepoints 
or a single timepoint from a single protocol. Self-
contained means that data collected for all subjects at all 
timepoints within that epoch allows to draw a complete 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
25
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
26
conclusion to define or precise the targeted label of the 
product (e.g. primary, booster, yearly immunogenicity 
follow-ups, and surveillance periods for efficacy or 
safety.
eTrack:
GSK’s tracking tool for clinical trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis.
Geometric mean titer:
The anti-log of the mean of the log (base 10) transformed 
inverse titers (the number X would denote the inverse of a 
titer expressed as “1:X”). Antibody titers below the cut-
off of the assay are given an arbitrary value of half the 
cut-off for the purpose of GMT calculation. 
Immunological correlate 
of protection:
The defined immune response above which there is a 
high likelihood of protection in the absence of any host 
factors that might increase susceptibility to the infectious 
agent.
Internal Safety Review 
Committee:
The internal safety review committee is a group of 
internal GSK experts not directly involved with the 
conduct of the study, who assess the progress of the study 
and the safety and efficacy data in an unblinded (on a 
subject level or treatment group level) fashion. Based on 
its review, the iSRC gives recommendations to the 
Clinical Project Team regarding study modification, 
continuation or termination.
Investigational vaccine:
(Synonym of 
Investigational Medicinal 
Product)
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorisation when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use. 
Legally acceptable 
representative:
(The terms legal representative or legally authorized 
representative are used in some settings.) An individual 
or juridical or other body authorized under applicable law 
to consent, on behalf of a prospective subject, to the 
subject's participation in the clinical trial.
Mean geometric 
increase:
Also known as the Geometric Mean Fold Rise and 
Seroconversion Factor. The geometric mean of the 
within-subject ratios of the post-vaccination reciprocal HI 
titer to the pre-vaccination reciprocal HI titer for the 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
26
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
27
vaccine virus. 
Medically attended 
event:
An event for which the subject received medical attention 
defined as hospitalization, an emergency room visit or a 
visit to or from medical personnel (medical doctor) for 
any reason
Potential Immune-
Mediated Disease:
Potential immune-mediated diseases (pIMDs) are a subset 
of AEs that include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology.
Randomisation:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
Self-contained study:
Study with objectives not linked to the data of another 
study.
Serious adverse event:
Any untoward medical occurrence in a patient or clinical 
investigation subject that: results in death, is life-
threatening, requires inpatient hospitalization or 
prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or is a 
congenital anomaly/birth defect.
Seroconversion rate:
The proportion of subjects who have either a pre-
vaccination reciprocal HI titer < 10 and a post-
vaccination reciprocal titer ≥ 40, or a pre-vaccination 
reciprocal HI titer ≥ 10 and at least a 4-fold increase in 
post vaccination reciprocal titer against the vaccine virus.
Seropositivity rate:
The proportion of subjects with a reciprocal titer above 
the cut-off value.
potential Seroprotection 
rate:
The proportion of subjects with H5N1 reciprocal HI titers 
≥ 40 against the tested vaccine virus.
Solicited adverse event:
Adverse events to be recorded as endpoints in the clinical 
study. The presence/occurrence/intensity of these events 
is actively solicited from the subject or an observer 
during a specified post-vaccination follow-up period.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
27
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
28
Study Delivery Lead:
An individual assigned by GSK Biologicals Headquarters 
who is responsible for assuring the co-ordination of the 
operational aspects and proper conduct of a clinical study, 
including compliance with International Conference on 
Harmonisation (ICH) Harmonised Tripartite Guideline 
for Good Clinical Practice (GCP) and GSK policies and 
standard operating procedures.
Sub-cohort:
A group of subjects for whom specific study procedures 
are planned as compared to other subjects.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccine(s)/product(s) or as a control.
Treatment:
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomisation or treatment allocation.
Unsolicited adverse 
event:
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event.
Vaccine response rate for 
microneutralization 
titers:
The incidence rate of subjects with at least a 4-fold 
increase in post vaccination reciprocal titer relative to 
pre-vaccination titers). Titers less than the cut-off titer are 
considered to be one-half the cut-off titer.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
28
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
29
1.
INTRODUCTION
Please refer to the current Investigator Brochure for information regarding the pre-clinical 
and clinical studies for AS03-adjuvanted pandemic influenza vaccines.
1.1.
Background
Avian influenza viruses of several subtypes, but most notably H5N1, have been 
associated with hundreds of identified human cases since 1997. From 2003 through 31 
March 2015, 826 laboratory confirmed human cases of H5N1 virus infection have been 
officially reported to WHO from 16 countries in Asia, Africa, Europe, America and the 
Near East with an overall confirmed case fatality rate (CFR) of 53% [WHO, 2015]. The 
majority of H5N1 infections occurred in children and adults younger than 40 years of 
age [CDC, 2015]. The highest CFR has been in the 10-19 years age group (74%) and the 
lowest CFR has been in those older than 70 years of age (25%) [WHO WPRO, 2013].
(Amended: 27-MAR-2017)
1.2.
Rationale for the study
GSK’s AS03-adjuvanted monovalent pandemic H5N1 influenza program in children 
includes three clinical studies (two uncontrolled, one controlled) using its Dresden 
manufactured D-Pan H5N1 vaccine and one placebo-controlled clinical study using its 
Quebec manufactured Q-Pan H5N1 vaccine. 
In the first D-Pan H5N1 trial, 3.75 or 1.9 µg of hemagglutinin (HA) antigen mixed with 2 
concentrations of adjuvant, AS03A and AS03B, were evaluated. An H5N1 vaccine 
containing 1.9 g of HA combined with AS03B (half the adult dose of 3.75 µg HA+
AS03A), administered as a 2-dose regimen 21 days apart, was chosen for further clinical
development in children. This regimen has been shown to elicit strong immunogenicity 
with an acceptable safety profile. (Amended: 27-MAR-2017)
In some subsequent clinical studies of D-Pan H5N1 vaccines containing 1.9 µg HA 
antigen and AS03B, children below 6 years of age showed an increase in reactogenicity 
(especially fever) after a second (or third) dose. In the clinical trial of Q-Pan H5N1 
vaccine containing 1.9 µg HA and AS03B, increased incidences of fever after a second 
dose were not observed in 607 children, 6 months to 17 years of age. However the overall 
incidence of local solicited and unsolicited symptoms 7 days after vaccination increased 
relative to saline placebo. As known from adjuvanted vaccines, there was an increase in 
solicited local and some general AEs within 7 days post vaccination in H5N1 vaccine 
recipients compared to placebo recipients. (Amended: 27-MAR-2017)
The aim of this dose ranging study is to assess whether reactogenicity can be reduced 
while maintaining adequate immunogenicity in a pediatric population. This study will 
either confirm that the current pediatric formulation represents an acceptable balance 
between immunogenicity and reactogenicity, or will suggest that the adjuvant or antigen 
dose, or both, could be modified.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
29
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
30
Study Flu Q-Pan-023 is part of the clinical development plan for D-H5N1 vaccine 
supporting both Prepandrix and Adjupanrix licenses in EU and is included in the current 
approved Paediatric Investigation Plan (PIP) of both products.
1.3.
Rationale for the study design
This study will assess the balance between immune responses and adverse effects
associated with different amounts of AS03 adjuvant and Q-Pan H5N1 antigen in 
combination. In previous pediatric studies, 1.9 g HA combined with AS03B was highly 
immunogenic and had an acceptable safety profile [Kosalaraksa, 2015]; it has therefore 
been defined as the reference dose for this study. Alternative doses will include 0.9 µg,
1.9 µg, or 3.75 µg HA in combination with AS03C (approximately one-fourth the adult 
dose of AS03) or 3.75 µg HA antigen in combination with AS03D (approximately one-
eighth the adult dose of AS03).
The schedule for the priming regimen in this study (2 doses, 21 days apart) is consistent 
with the schedule used in all prior pediatric studies. 
The study will plan to enrol 37 children per group to achieve 34 evaluable subjects per 
group with an overall target of 185 children. Power calculations are given in Section
10.3.
Experience with D-Pan H5N1 vaccines suggests that fever, in addition to being 
objectively measurable, is a relevant parameter indicative of reactogenicity in children 
below 6 years of age. Accordingly, this study will use fever (defined as a body 
temperature ≥38°C /100.4°F) by any route; axillary is preferred in this study) within 3 
days after each dose to assess the balance between reactogenicity and immunogenicity. 
This will be evaluated via immunogenicity-fever indices constructed using Day 42 
immune response either by hemagglutination inhibition (HI) assay or by 
microneutralization (MN) assay and reactogenicity as assessed by fever score.
The 6 – 35 month age group, which has had both the highest rates of fever and the highest 
post-vaccination antibody titers in previous clinical trials, will be studied. Reactogenicity 
and immune response in this age group will inform dose selection across the entire 
pediatric population.
For a pandemic vaccine, which might have to protect against a second or third wave of 
H5N1 infections, the quality and persistence of the immune response after priming are 
important parameters. 
The quality of the 2-dose priming will be assessed through the anamnestic response 
elicited by an antigen challenge administered 12 months later. All subjects will receive an 
unadjuvanted booster dose of 3.75 µg HA which was selected to this effect in an effort to 
(a) minimize reactogenicity in these young children, and (b) facilitate an assessment of 
the anamnestic response to each priming regimen by increasing the potential of detecting 
differences between groups, which may be masked by a vigorous response to an AS03 
adjuvanted booster dose rather than unadjuvanted antigen. The persistence of the 
immune response approximately 12 months after dose 2 (Day 385) will also be evaluated.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
30
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
31
Dose regimen selection will be based on all these factors, any safety concerns not 
captured in the immunogenicity-fever indices, and the logistics of dose distribution and 
preparation for a pandemic vaccine (a fraction of the dose licensed for use in adults 
(3.75 µg HA+AS03A) will also be considered in the dose selection procedure. (Amended: 
27-MAR-2017)
1.4.
Benefit : Risk Assessment
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of AS03-adjuvanted pandemic influenza vaccines in children.
The following section outlines the risk assessment and mitigation strategy for this study 
protocol.
1.4.1.
Risk Assessment
Overall, the reactogenicity and safety profile of AS03 adjuvanted H5N1 pandemic 
vaccines is acceptable and no safety concerns have been identified in clinical trials. This 
clinical trial aims to evaluate whether a reduction in adjuvant content may increase 
vaccine tolerability in children. The vaccine that will be used in the reference dose 
regimen in this study has been given to more than 750 children, of whom 274 were less 
than 3 years old.
Specific risks associated with study participation are described below.
Table 1
Risk Assessment
Important Potential/Identified Risk
Data/Rationale for Risk
Mitigation Strategy
Investigational FLU-Q-Pan H5N1 study vaccine
Immediate allergic reactions
Refer to the Investigator 
Brochure, Section 6.0
Subject Selection (Sections 4.2 and 
4.3) 
Subject Monitoring (Section 5.6)
Contraindications to subsequent 
vaccination (Section 6.5)
Adverse events requiring medical 
attention, Serious adverse events, 
Potentially immune mediated 
diseases (pIMDs), Adverse events of 
special interest (AESIs)
Refer to the Investigator 
Brochure, Sections 5.2 and 6.0
Subject Selection (Sections 4.2 and 
4.3) 
Subject Monitoring (Section 5.6)
Safety Data Review (Section 8)
Contraindications to subsequent 
vaccination (Section 6.5)
Study Procedures
Venipuncture
Pain or bruising at the site 
where blood is drawn. 
An infection at the site where 
blood is drawn. 
Fainting.
Procedure to be performed by qualified 
personnel.
A topical analgesic may be applied to 
the site where blood will be taken.
A topical disinfectant will be applied.
Subject Monitoring (Section 5.6)
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
31
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
32
1.4.2.
Benefit Assessment
Study participation may not have a direct benefit for individual subjects. Even if the Q-
Pan H5N1/AS03 vaccine is protective, the duration of protection or clinical benefit of 
immunological priming is unknown and the current risk of H5N1 infection is expected to 
be low in countries where the study is performed.
As part of the study, subjects receive the study vaccine, all the study tests and procedures 
and follow-up by the Investigator at no cost. 
Information collected during the study may increase knowledge about 

how to optimize immunization strategies to mitigate morbidity and mortality in the 
event of an H5N1 influenza pandemic 

how to optimize the pediatric dose for pandemic influenza vaccines.
1.4.3.
Overall Benefit - Risk Conclusion
The minimal potential or identified risks associated with Q-Pan H5N1 vaccine are in 
proportion to the minimal potential benefits of immunization against pandemic H5N1 
influenza.
2.
OBJECTIVES
2.1.
Co-Primary Objectives
2.1.1.
Primary Doses

To assess the performance of alternative dosing regimens for primary immunization 
with Q-Pan H5N1 vaccine using an immunogenicity-fever index that considers:

immunogenicity by HI assay 21 days after the second priming dose, and 

fever scores after the first and second priming doses.

To assess the performance of alternative dosing regimens for primary immunization 
with Q-Pan H5N1 vaccine using an immunogenicity-fever index that considers:

immunogenicity by MN assay 21 days after the second priming dose and 

fever scores after the first and second priming doses.
The reference dose for each of these assessments will be 1.9 µg HA with AS03B (half the 
approved adult dose).
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
32
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
33
2.1.2.
Booster Dose

To assess the performance of dosing regimens for booster immunization with Q-Pan 
H5N1 vaccine considering:

immune response by HI assay 7 days after a 12-month booster dose of 3.75 µg 
HA Q-Pan H5N1 unadjuvanted antigen. (Amended: 27-MAR-2017)

To assess the performance of dosing regimens for booster immunization with Q-Pan 
H5N1 vaccine considering:

immune response by MN assay 7 days after a 12-month booster dose of 3.75 µg 
HA Q-Pan H5N1unadjuvanted antigen. (Amended: 27-MAR-2017)
Refer to Section 10.1 for the definition of the primary endpoints.
2.2.
Secondary objectives

To describe the HI immune response to the vaccine-homologous virus 21 days after 
the second dose for each dosing regimen

To assess the performance of alternative dosing regimens for primary immunization 
with Q-Pan H5N1 vaccine considering persistence of immune response by HI and 
MN assay at Day 385 in terms of persistence index.

To assess the performance of the H5N1 vaccine regimens in terms of vaccine-
homologous HI and MN antibody titers on Days 0 ,42, 385 and Day 392.

To assess the immunogenicity of the H5N1 vaccine regimens in terms of vaccine-
heterologous HI and MN antibody titers on Days 0, 42, 385 and Day 392.
(Amended: 27-MAR-2017)

To assess vaccine induced cell-mediated immune responses on Days 0, 42, 385 and 
Day 392.

To describe reactogenicity and safety of the different priming regimens in terms of 
solicited (7-days after each vaccination) and unsolicited (21 days after each 
vaccination) adverse events (AEs).

To describe safety of the unadjuvanted booster dose in terms of solicited (7 days post 
boost) and unsolicited (30 days post boost) AEs.

To describe safety in terms of medically attended events (MAEs), potential immune-
mediated diseases (pIMDs), and serious adverse events (SAEs), adverse events of 
special interest (AESIs), during the entire study period.
Refer to Section 10.2 for the definition of the secondary endpoints.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
33
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
34
3.
STUDY DESIGN OVERVIEW
Figure 1
Design Overview
Randomisation 
1:1:1:1:1
190_B (FLU Q-Pan H5N1 1.9 µg + AS03B )– N=37
090_C (FLU Q-Pan H5N1 0.9 µg + AS03C ) – N= 37
190_C (FLU Q-Pan H5N1 1.9 µg + AS03C ) – N= 37
375_C (FLU Q-Pan H5N1 3.75 µg + AS03C ) – N= 37
375_D (FLU Q-Pan H5N1 3.75 µg + AS03D ) – N= 37
Visit 1
Day 0
V 1
BS
Visit 2
Day 21
V 2
Visit 3
Day 42
BS
Visit 6
Day 385
BV*
BS
Visit 5 
(TC 2)
Day 240
Visit 4 
(TC 1)
Day 90
Visit 7*
Day 392
BS
Visit 8 
(TC 3*
Day 415
Epoch001
PRIMARY
Epoch002
BOOSTER
NOTES: 
D=Day; TC = telephone contact, V = Primary Vaccination, *BV = Unadjuvanted booster vaccination (3.75 µg HA); 
BS = Blood sample,
FLU Q-Pan H5N1 = A/Indonesia/05/2005 hemagglutinin antigen
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 outline of study procedures (Section 5.5), are essential and required for 
study conduct.

Experimental design: phase II, observer blind, randomized, multi-center, multi-
country study, parallel groups.

Duration of the study: approximately 415 days after vaccination on Day 0. 

The Primary Epoch encompasses data collected from Visit 1 (Day 0) through 
Visit 5-TC2 (Day240) and ending at the start of Visit 6 (Day 385).

The Booster Epoch encompasses data collected from Visit 6 (Day 385) through 
Visit 8-TC 3 (Day 415)
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
34
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
35

Study groups: Approximately 37 subjects are planned to be enrolled in each of the 5 
following study groups:

190_B: 
1.9 g H5N1 HA antigen adjuvanted with AS03B 

090_C: 
0.9 g H5N1 HA antigen adjuvanted with AS03C 

190_C: 
1.9 g H5N1 HA antigen adjuvanted with AS03C 

375_C: 
3.75 g H5N1 HA antigen adjuvanted with AS03C 

375_D: 
3.75 g H5N1 HA antigen adjuvanted with AS03D 
Table 2
Study groups and epochs foreseen in the study
Study groups
Number of 
subjects
Epochs
Epoch 001 (Primary Series)
Epoch 002 (Booster)
190_B
37 
● 
● 
090_C
37 
● 
● 
190_C 
37 
● 
● 
375_C 
37 
● 
● 
375_D
37 
● 
● 
Table 3
Study groups and treatments foreseen in the study: 
Treatment 
name
Vaccine/Product name
(Formulation)
Study Groups
190_B
090_C 
190_C 
375_C
375_D
1.9 mcg 
H5N1 HA + 
AS03B
FLU-Q-PAN
(A/Indonesia/05/2005 H5N1 HA, 15 µg/mL) 
● 
AS03A 
(AS03 47.44 mg/mL , final vaccine dose 
contains 5.93 mg tocopherol)
● 
0.9 mcg 
H5N1 HA + 
AS03C 
FLU-Q-PAN
(A/Indonesia/05/2005 H5N1 HA, 15 µg/mL) 
● 
AS03A 
(AS03 47.44 mg/mL, final vaccine dose 
contains 2.97 mg tocopherol)
● 
1.9 mcg 
H5N1 HA + 
AS03C 
FLU-Q-PAN  
(A/Indonesia/05/2005 H5N1 HA, 15 µg/mL)
● 
AS03B 
(AS03 23.72 mg/mL; final vaccine dose 
contains 2.97 mg tocopherol
● 
3.75 mcg 
H5N1 HA + 
AS03C 
FLU-Q-PAN
(A/Indonesia/05/2005 H5N1 HA, 30 µg/mL)
● 
AS03B 
(AS03 23.72 mg/mL; final vaccine dose 
contains 2.97 mg tocopherol
● 
3.75 mcg
H5N1 HA + 
AS03D 
FLU-Q-PAN
(A/Indonesia/05/2005 H5N1 HA, 30 µg/mL)
● 
AS03C 
(AS03 11.86 mg/mL; final vaccine dose 
contains 1.48 mg tocopherol)
● 
3.75 mcg 
H5N1 HA *
FLU-Q-PAN
(A/Indonesia/05/2005 H5N1 HA, 15 µg/mL)
● 
● 
● 
● 
● 
*Booster vaccination to subjects in all study groups
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
35
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
36

Vaccination schedule:

All subjects are to receive an AS03 adjuvanted H5N1 vaccine given as a two-
dose primary series at a 21 day interval.

All subjects are to receive a 3.75 g HA, unadjuvanted H5N1 vaccine as a 
booster dose at Day 385.
Table 4
Blinding of study epochs
Study Epochs
Blinding
Epoch 001 
observer-blind
Epoch 002 
observer-blind

Sampling schedule:

All study groups: Day 0 (before vaccination); Day 42 (post primary course); 
Day 385 (persistence) and Day 392 (booster response)

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF).

Safety monitoring 

Ongoing monitoring of reactogenicity and safety data will be performed by an 
internal safety review committee (iSRC). Details of the data review will be further 
explained in a separate iSRC charter.
Refer to Section 8.7 for detailed description of holding rules and safety monitoring.
4.
STUDY COHORT
4.1.
Number of subjects/centres
A total of approximately 185 subjects will be enrolled at multiple study centers 
The estimated time to complete enrollment is approximately 3 months (the Sponsor may 
re-evaluate as needed). SBIR will be used to monitor progress against the recruitment 
plan. Enrollment will be terminated when approximately 185 subjects have been 
randomised/enrolled.
Table 5
Sub-cohorts
Sub-cohort name
Description
Estimated number of subjects
Cell Mediated Immunity (CMI) 
CMI on Days 0, 42, 385 and Day 392
100 
The CMI sub-cohort will be comprised of approximately 100 subjects, representing
approximately 20 subjects enrolled in each group. Within the participating country(ies), 
these subjects will be enrolled in only selected/qualified sites. For any site designated to 
enrol subjects in the CMI sub-cohort, efforts will be made to enrol the CMI subjects first, 
prior to initiating enrollment in the non-CMI sub-cohort. If fewer sites than planned are 
able to participate, or if sites cannot enrol enough CMI subjects, the remaining subjects 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
36
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
37
may be selected from one or more of the other sites or additional sites may be added if 
needed.
4.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:

Subject's parent(s)/ Legally Acceptable Representative(s) [LAR(s) who, in the 
opinion of the investigator, can and will comply with the requirements of the 
protocol (e.g., expressed availability for the required study period, ability and 
willingness to complete the diary cards and bring the study subject to protocol-
mandated visits).

Male or female children 6 months to less than 36 months old at the time of the first 
vaccination. Children who are not 36 months old as of Day 0, the day of first vaccine 
dose under this protocol, can be enrolled.

Written informed consent obtained from the parent(s)/legally acceptable 
representative(s) (LAR(s) of the subject prior to performance of any study specific 
procedure.

Healthy subjects as established by medical history and standard physical examination 
before entering into the study.

Born full-term (i.e., after a gestation period of 37 to less than 42 completed weeks) to 
be confirmed by interview with parent/LAR or available medical records.
4.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Child in care
Please refer to the glossary of terms for the definition of child in care. 

Medical history of physician-confirmed infection with an A/Indonesia/5/2005 
(H5N1) virus.

Previous vaccination at any time with an H5N1 vaccine.

Concurrently participating in another clinical study, or use of an investigational or a 
non-registered vaccine, pharmaceutical product, or device within 30 days preceding 
the first dose of study vaccine, or planned use during the study period.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
37
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
38

Presence in the parent(s) / LAR(s) of evidence of substance abuse or of neurological 
or psychiatric diagnoses which, even if stable, are deemed by the investigator to 
render the parent(s)/LAR(s) unable/unlikely to provide accurate safety reports.

Acute disease and/or fever at the time of enrolment. 

Fever is defined as temperature 38.0°C/100.4°F by any route (axillary 
preferred in this study). NOTE: The subject may be vaccinated at a later date, 
provided symptoms have resolved and all other eligibility criteria continue to be 
satisfied.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator. 

Administration of immunoglobulins, any blood products, or long-acting immune-
modifying drugs (e.g. infliximab) during the period starting 3 months before the first 
dose of study vaccine, or planned administration during the study period.

History of any neurological disorders or seizures, or Guillain-Barré Syndrome.

Diagnosed with excessive daytime sleepiness (unintended sleep episodes during the 
day present almost daily for at least one month), or narcolepsy; or history of 
narcolepsy in a subject’s parent or sibling.

Administration of an inactive vaccine within 14 days or of a live attenuated vaccine 
within 30 days before the first vaccination.

Planned administration of any vaccine not foreseen by the study protocol between 
Day 0 and Day 42 or planned administration of an inactive vaccine within 14 days or 
of a live attenuated vaccine within 30 days before through 30 days after the booster 
vaccination. Note: routine vaccinations may be provided on Day 42 after all study 
assessments have been performed.

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine (including egg proteins or mercurial preservatives); a 
history of anaphylactic-type reaction to consumption of eggs; or a history of severe 
adverse reaction to a previous influenza vaccine. 

Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe.

Chronic administration (defined as 14 or more days in total) of immunosuppressants 
or other immune-modifying drugs during the period starting six months prior to the 
first vaccine. For corticosteroids, this will mean a dose of prednisone or equivalent of 
> 2 mg/kg/day of body weight (for persons who weigh < 10 kg), or ≥ 20 mg/day (for 
persons who weigh ≥ 10 kg). Inhaled and topical steroids are allowed.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required). 

Family history of congenital or hereditary immunodeficiency. 

Major congenital defects
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
38
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
39

Any condition which, in the opinion of the investigator, prevents the subject from 
participating in the study.
5.
CONDUCT OF THE STUDY
5.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki. 
The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
paediatric population (ICH E11) and all other applicable ethical guidelines.
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject’s parent(s)/LAR(s) informed consent, as appropriate. 

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written or witnessed/ thumb printed (or as applicable per local 
guidelines) informed consent must be obtained from each subject’s parent(s)/LAR(s), as 
appropriate, prior to participation in the study. 
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF. 
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
39
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
40
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
5.2.
Subject identification and randomisation of treatment
5.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification
numbers allocated to each study centre.
5.2.2.
Randomisation of treatment
5.2.2.1.
Randomisation of supplies
The randomisation of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the study centres /warehouse(s).
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centres in this multi-centre study and to thus reduce the overall 
study recruitment period, an over-randomisation of supplies will be prepared. 
5.2.2.2.
Treatment allocation to the subject
The treatment numbers will be allocated by dose. Throughout the study, a single 
treatment number will identify the vaccine doses to be administered to the same subject.
5.2.2.2.1.
Study group and randomization/treatment number allocation
Target enrolment for the study will be approximately 185 healthy children (6 to less than
36 months of age) who will be randomised into 5 groups (n=37 per group) in a 1:1:1:1:1
ratio (see Figure 1).
Allocation of the subject to a study group at the investigator site will be performed using 
a central randomisation system on the internet (SBIR). The randomisation algorithm will 
use a minimisation procedure accounting for age (6-<12 months; 12 – less than 36
months), study centre, and the pre-study seasonal influenza vaccine history the subjects to 
ensure balanced representation of the combination of the minimisation factors among the 
study groups. 
After obtaining the signed and dated ICF from the subject and having checked the 
eligibility of the subject, the study staff in charge of the vaccine administration will 
access SBIR. Upon providing the subject’s age and the subject identification number, the 
randomisation system will provide the treatment number to be used for each dose.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
40
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
41
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
5.2.2.2.2.
Treatment number allocation for subsequent doses 
For each dose, the study staff in charge of vaccine administration will access SBIR, 
provide the subject identification number, and the system will provide a treatment 
number consistent with the allocated study group.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
5.3.
Method of blinding 
The study will be conducted in an observer-blind fashion.
Data will be collected in an observer-blind manner. By observer-blind, it is meant that 
during the course of the study, the vaccine recipient, the subject’s parent(s)/LAR(s) and 
the site and sponsor personnel involved in the clinical evaluation of the subjects are 
blinded while other study personnel may be aware of the treatment assignment.
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
41
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
42
5.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM provides the 
investigator and the site personnel with administrative and detailed technical information 
that does not impact the safety of the subjects.
5.5.
Outline of study procedures
Table 6
List of study procedures
Epoch 001 
Epoch 002
Type of contact
Visit 1 Visit 2 Visit 3 
Visit 4 
(TC1) 
Visit 5 
(TC2) 
Visit 6 
Visit 7 
Visit 8 
(TC3) 
Time point (s)
Day 0 Day 21 Day 42 Day 90
Day 
240
Day 
385
Day 392
Day 415
Sampling timepoint(s)
Pre-
Vacc 1
Pre 
Vacc 2
Post-
Vacc 2
Post 
Vacc 2
Post 
Vacc 3
Informed consent 
●
Check inclusion / exclusion criteria 
●
Check contraindications to vaccination *
●
●
● 
Medical history 
●
Seasonal influenza vaccination history 1
●
Collect demographic data 
●
Physical examination
●
Measure/record height and weight 
●
Brief (symptom directed) physical 
examination
○
○
○
○
Record concomitant medications and 
vaccinations 
●
●
●
●
●
●
●
●
Pre-vaccination body temperature /vital 
signs
●
●
● 
Study group and treatment number 
allocation
●
Treatment number allocation for 
subsequent doses
●
● 
Blood sampling for assessment of 
humoral immune response (approx. 2.5
mL venous blood)
●
●
● 
● 
Blood sampling for assessment of CMI 
response (approx. 2.0 mL venous blood)
●
●
● 
● 
Vaccine dose preparation by unblinded 
staff
○
○
○ 
Vaccine administration (record treatment 
number)
●
●
● 
Provide training / Distribute diary cards 2
○
○
○ 
○ 
Parent/LAR records solicited AEs 3
(beginning on the day of the dose and for 
the following six days; e.g., Day 0 – 6)
○
○
○ 
Parent/LAR records unsolicited AEs 
beginning with day of vaccination and 
continuing for next 20 (doses 1 and 2) or 
29 (booster dose) days
○
○
○
○ 
○ 
Parent/LAR returns diary cards 
○
○
○ 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
42
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
43
Epoch 001 
Epoch 002
Type of contact
Visit 1 Visit 2 Visit 3 
Visit 4 
(TC1) 
Visit 5 
(TC2) 
Visit 6 
Visit 7 
Visit 8 
(TC3) 
Time point (s)
Day 0 Day 21 Day 42 Day 90
Day 
240
Day 
385
Day 392
Day 415
Sampling timepoint(s)
Pre-
Vacc 1
Pre 
Vacc 2
Post-
Vacc 2
Post 
Vacc 2
Post 
Vacc 3
Investigator transcribes diary card data 
●
●
● 
● 
Report all non-serious adverse events 4
●
●
●
● 
● 
● 
Report non-serious adverse events 
leading to study withdrawal 
●
●
●
●
●
● 
● 
● 
Report current/intercurrent medical 
conditions 
●
●
●
●
● 
● 
Report medically attended events 4
●
●
●
●
●
●
● 
● 
Report serious adverse events 4
●
●
●
●
●
●
● 
● 
Report pIMDs 4
●
●
●
●
●
●
● 
● 
Report SAEs related to study 
participation or GSK concomitant product 
or any fatal SAE 
●
●
●
●
●
●
●
●
Study conclusion 
● 
Note: The double-line border following Day 42 indicates analyses will be performed on all data obtained up to this time 
point; Pre-Vacc: Pre-vaccination. Post-Vacc: Post-vaccination.. TC = telephone contact. ● is used to indicate a study 
procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF
* If any, it has to be recorded in medical history (prior first vaccination) or in AE/SAE.
1. Influenza vaccination history will include all previous seasonal influenza vaccination(s)]
2. Diary cards used to capture both solicited (for 7 days following each dose) and unsolicited events (for 21 days after 
doses 1 and 2; for 30 days after booster dose) are provided at the time of each vaccination and collected at the next 
visit after each vaccination.
3. Recording of intensity and duration of solicited local symptoms and of occurrence, intensity, duration, and 
relationship of each solicited general AE and unsolicited AE;
4. Recording of intensity, duration and relationship to vaccination of each event reported. Reported events will be 
searched for AESIs.
Table 7
Intervals between study visits
Interval 
(by visit number)
Interval
(by visit name)
Optimal length of 
interval1
Allowed interval
Visit 1 Visit 2 
Visit Day 0 Visit Day 21
21 days 
18 - 25 days2
Visit 1 Visit 3
Visit Day 0 Visit Day 42
42 days 
38 - 46 days2
Visit 1 Visit 4 (TC1)
Visit Day 0 TC Day 90 
90 days
80 - 100 days
Visit 1 Visit 5 (TC2)
Visit Day 0 TC Day 240 
240 days
220 - 260 days
Visit 1 Visit 6
Visit Day 0 Visit Day 385
385 days 
375 - 395 days2
Visit 6 Visit 7
Visit Day 385 Visit Day 392 
7 days 
6 - 10 days 2
Visit 6 Visit 8 (TC3) 
Visit Day 385 Visit Day 415 
30 days
30 – 45 days
1Whenever possible the investigator should arrange study visits within this interval. 
2 Subjects will not be eligible for inclusion in the ATP cohort for immunogenicity analysis for that specific interval if 
vaccine administration and blood collections are outside these intervals.
TC = telephone contact
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
43
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
44
5.6.
Detailed description of study procedures
5.6.1.
Informed consent
The signed/witnessed/thumb printed (or as applicable per local guidelines) informed 
consent of the subject’s parent(s)/LAR(s) must be obtained before study participation. 
Refer to Section 5.1 for the requirements on how to obtain informed consent. (Amended: 
27-MAR-2017)
5.6.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrolment. 
5.6.3.
Collect demographic data
Record demographic data date of birth, gender, geographic ancestry and ethnicity in the 
subject’s eCRF.
5.6.4.
Medical history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the study vaccination in the eCRF.
5.6.5.
Physical examination
Perform a history directed physical examination of the subject. Measure the subject’s 
height and weight. Record collected information in the eCRF. 
Physical examination at each study visit subsequent to the first vaccination will be 
performed only if the subject’s parent(s)/LAR(s) indicate(s) during questioning that there 
might be some underlying pathology(ies) or if deemed necessary by the Investigator or 
delegate.
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
5.6.6.
Pre-vaccination vital signs
Before each vaccination, evaluate body temperature, and heart and respiratory rates and 
record in the eCRF.
Temperature may be recorded by any route or method; however the preferred route for 
recording temperature in this study will be axillary, using a digital thermometer provided 
by GSK.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
44
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
45
5.6.7.
Check contraindications, warnings and precautions to 
vaccination 
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of each/the vaccination visit. Refer to Sections 6.5 and 6.6 for more details. 
5.6.8.
Study group and randomization/treatment number allocation
Study group and randomization/treatment number allocation will be performed as 
described in Section 5.2.2. The number of each administered treatment must be recorded 
in the eCRF.
5.6.9.
Blood sampling for immune response assessment
As indicated in Table 6, approximately 2.5 mL of whole blood should be drawn from all 
subjects at Visits 1,3,6 and 7. Also for those in the CMI sub-cohort (n=20 per group) an 
additional 2.0 mL of whole blood should be drawn at Visits 1,3,6 and 7.
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of blood samples. (Amended: 27-MAR-2017)
5.6.10.
Study Vaccine administration

If, after completing all required pre-vaccination assessments, the subject is 
determined to be eligible for vaccination(s), study vaccine will be administered 
intramuscularly (IM) in the anterolateral thigh (Section 6.3).

If the subject has fever [defined as temperature 38.0°C/100.4°F by any route, 
(axillary preferred in this study)] on the day of vaccination, or the investigator 
determines that the subject’s health on the day of vaccination temporarily precludes 
vaccination for any other reason, the visit will be rescheduled within the allowed 
interval for this visit (Table 7).

Each subject will be observed closely for at least 30 minutes following the 
administration of the vaccine, with appropriate medical treatment readily available in 
case of anaphylaxis.
5.6.11.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions 
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.7.
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.8.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
45
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
46
5.6.12.
Recording of AEs

Refer to Section 8.2 for procedures for the investigator to record AEs. Refer to 
Section 8.3 for special requirements for reporting SAEs and pIMDs to GSK 
Biologicals.

The subject’s parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should the subject manifest any signs or symptoms they perceive as 
serious. 

At each vaccination visit, diary cards will be provided to subject’s parent(s)/LAR(s). 
The subject’s parent(s)/LAR(s) will record body temperature and any solicited 
local/general AEs (i.e. on the day of vaccination and during the next 6 days) or any 
unsolicited AEs (i.e. on the day of vaccination and during the next 20 days)
occurring after primary vaccinations and for 29 days after booster dose visit. The 
subject’s parent(s)/LAR(s) will be instructed to return the completed diary card to the 
investigator at the next study visit.

Collect and verify completed diary cards as well as information collected via 
telephone contacts during discussion with the subject’s parent(s)/LAR(s) at 
visits/TCs listed in Table 6.

Any unreturned diary cards will be sought from the subject’s parent(s)/LAR(s) 
through telephone call(s) or any other convenient procedure. The investigator will 
transcribe the collected information into the eCRF in English.
5.6.13.
Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness

complete the Study Conclusion page/screen in the eCRF.
5.7.
Biological sample handling and analysis
Please refer to the SPM for guidance/details on biospecimen management (handling, 
storage and shipment).
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number).

Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
46
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
47
all subjects in countries where this is allowed, will be asked to give a specific 
consent to allow GSK or a contracted partner to use the samples for future research. 
Future research will be subject to the laws and regulations in the respective countries 
and will only be performed once an independent Ethics Committee or Review Board 
has approved this research.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals. 
Any sample testing will be done in line with the consent of the individual subject’s 
parent(s)/LAR(s). 
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s). 
If additional testing is performed, the marker priority ranking given in Section 5.7.4 may 
be changed.
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals.
5.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the ATP analysis (See Section 10.4 for the definition of 
cohorts to be analysed). The investigator must ensure that his/her personnel and the 
laboratory(ies) under his/her supervision comply with this requirement. However, when 
GSK Biologicals does not provide material for collecting and storing clinical samples, 
appropriate materials from the investigator’s site must be used. Refer to the Module on 
Clinical Trial Supplies in the SPM.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
47
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
48
5.7.2.
Biological samples
Table 8
Biological samples
Sample 
type
Quantity
Unit
Timepoint
Group
Blood
Approx 2.5
ml
Visit 1 (Day 0)
All subjects
Visit 3 (Day 42)
Visit 6 (Day 385)
Visit 7 (Day 392)
Blood
Approx 2.0-
ml
Visit 1 (Day 0)
CMI sub-cohort
Visit 3 (Day 42)
Visit 6 (Day 385)
Visit 7 (Day 392)
5.7.3.
Laboratory assays
Please refer to APPENDIX A for a detailed description of the assay performed in the 
study. Please refer to APPENDIX B for the address(es) of the clinical laboratory(ies)
used for sample analysis.
All immunogenicity assessments supporting primary and secondary objectives will be 
performed by GlaxoSmithKline Biologicals’ laboratories or in a validated laboratory 
designated by GlaxoSmithKline Biologicals using standardized, validated procedures 
with adequate controls (see Table 9 and Table 10).
Table 9
Humoral immunity (antibody determination) (Amended: 27-MAR-
2017)
System
Component
Scale
Method
Kit / 
Manufacturer
Unit
Cut-
off
Laboratory
Serum
Vaccine-Homologous
Influenza Virus 
A/Indonesia/05/2005 
(H5N1) HA
Quantitative
HI
In-house 
assay
1/DIL
10
GSK 
Biologicals1
Serum
Vaccine-Homologous
Influenza Virus 
A/Indonesia/05/2005 
(H5N1)
Quantitative
MN
In-house 
assay
1/DIL
28
GSK 
Biologicals1
Serum
H5N1 virus heterologous 
or other H5 subtypes
Quantitative
HI
In-house 
assay
1/DIL
10
GSK 
Biologicals1
Serum
H5N1 virus heterologous 
or other H5 subtypes
Quantitative
MN
In-house 
assay
1/DIL
28
GSK 
Biologicals1
1 GSK Biologicals laboratory or validated laboratory designated by GSK Biologicals.
2 This testing will depend on adequate specimens and resources.
HI = hemagglutination inhibition; MN = microneutralization; DIL = dilution
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
48
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
49
Table 10
Cell-Mediated Immunogenicity (CMI) ) (Amended: 27-MAR-2017)
System
Component
Challenge
Method
Unit
Laboratory
WHBST 
(Whole 
Blood 
Stimulated) 
Cells
Cells CD4+CD8 (CD40L+Interleukin-
2+Tumor Necrosis Factor alpha+Interferon 
gamma)
(T cells stained with probes for various 
cytokines and activation marker (IFNγ, TNFα,, 
IL-2, CD40L)
BKG 
(None), H5N1 
split, SEB
ICS (CFC) Events/10E6 
cells 
(polypositive 
CD4+/CD8+ T 
cells per 
million 
CD4+/CD8+ T 
cells)
GSK 
Biologicals
WHBST = Whole Blood Stimulated; BKG = Background; SEB = staphylococcal enterotoxin b
CFC = cell flow cytometry; ICS = Intracellular cytokine staining.
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
49
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
50
5.7.4.
Biological samples evaluation
Immunological read-outs are described in Table 11.
Table 11
Immunological read-outs (Amended: 27-MAR-2017)
Blood sampling timepoint
Sub-cohort Name
No. 
subjects
Component
Priority 
rank
Type of contact 
and time point
Sampling 
time point
Visit 1 (Day 0)
Pre Vacc 1 
Vaccine homologous 
185 
Influenza Virus 
A/Indonesia/05/2005 
(H5N1) HI
1
Visit 3 (Day 42)
Post Vacc 2 
Vaccine homologous 
185
Visit 6 (Day 385)
Post Vacc 2 
Vaccine homologous 
185
Visit 7 (Day 392)
Post Vacc 3 
Vaccine homologous 
185
Visit 1 (Day 0)
Pre Vacc 1 
Vaccine homologous 
185
Influenza Virus 
A/Indonesia/05/2005 
(H5N1) MN
2
Visit 3 (Day 42)
Post Vacc 2 
Vaccine homologous 
185
Visit 6 (Day 385)
Post Vacc 2 
Vaccine homologous 
185
Visit 7 (Day 392)
Post Vacc 3 
Vaccine homologous 
185
Visit 1 (Day 0)
Pre Vacc 1 
Vaccine heterologous 
185 
H5N1 virus 
heterologous or 
other H5 subtypes
(marker = 
heterologous MN)
3
Visit 3 (Day 42)
Post Vacc 2 
Vaccine heterologous 
185
Visit 6 (Day 385)
Post Vacc 2 
Vaccine heterologous 
185
Visit 7 (Day 392)
Post Vacc 3 
Vaccine heterologous 
185
Visit 1 (Day 0)
Pre Vacc 1 
Vaccine heterologous 
185 
H5N1 virus 
heterologous or 
other H5 subtypes
(marker = 
heterologous HI)
4
Visit 3 (Day 42)
Post Vacc 2 
Vaccine heterologous 
185
Visit 6 (Day 385)
Post Vacc 2 
Vaccine heterologous 
185
Visit 7 (Day 392)
Post Vacc 3 
Vaccine heterologous 
185
Visit 1 (Day 0)
Pre Vacc 1 
Cell Mediated Immunity (CMI) 
100
T cells stained with 
probes for various 
cytokines and 
activation marker 
(IFN, TNF, IL-2
1
Visit 3 (Day 42)
Post Vacc 2 
Cell Mediated Immunity (CMI) 
100
Visit 6 (Day 385)
Post Vacc 2 
Cell Mediated Immunity (CMI) 
100
Visit 7 (Day 392)
Post Vacc 3 
Cell Mediated Immunity (CMI) 
100
HI = hemagglutination inhibition; MN = microneutralization; CMI=cell-mediated immunity 
For humoral antibody tests, priority rank 1 and 2 read-outs (HI and MN vaccine-
homologous testing) will be attempted for all subjects; priority rank 3 and 4 read-outs 
(MN and HI vaccine-heterologous testing) may be attempted for fewer than the specified 
number of subjects per treatment group if necessitated by resource or sample constraints
and availability of suitable strains. (Amended: 27-MAR-2017)
5.7.5.
Immunological correlates of protection
Although there is no accepted correlate of protection against influenza, either seasonal or 
pandemic, the protective role of antibodies against the HA and, to a lesser extent, 
neuraminidase, is well established and has been demonstrated both in experimentally 
infected animals and humans [Rimmelzwaan, 2008]. 
For this reason, the induction of HA-specific antibodies is used as a marker of potential 
vaccine efficacy and the serum HI assay is used to demonstrate this humoral response. HI 
antibody titers of 1:40 or greater have been associated with protection from influenza 
illness in at least 50% of subjects in challenge studies [Hannoun, 2004] as well as to 
correlate with vaccine effectiveness [Beyer, 1989].
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
50
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
51
6.
STUDY VACCINE ADMINISTRATION
6.1.
Description of study vaccine(s)/product(s)
The Q-Pan H5N1 vaccine has been developed and manufactured by GSK Biologicals.
The Quality Control Standards and Requirements the candidate vaccine are described in 
separate Quality Assurance documents (e.g. release protocols, certificate of analysis) and 
the required approvals have been obtained. 
The vaccine components are labelled and packed according to applicable regulatory 
requirements. Refer to Table 12.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
51
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
52
Table 12
Study vaccine
Treatment 
name
Vaccine 
/product 
name
Formulation
Presentation
Vial 
Volume* 
Final Dose: 
Volume per 
product (mL)**
No. doses 
per subject
Final Dose: 
Total Volume 
(mL)***
1.9 mcg 
H5N1 HA + 
AS03B
FLU-Q-PAN
A/Indonesia/05/2005(H5N1)=1.9µg 
(15 g/mL vial)
translucent to 
whitish suspension 
3.1 ml
0.125 ml
2
0.25 ml
AS03A 
Emulsion containing 
tocopherol,tocopherol=47,44mg/ml 
Final vaccine dose = emulsion containing 
tocopherol, tocopherol = 5.93 mg)
whitish to yellowish 
homogenous milky 
liquid emulsion 
3.1 ml
0.125 ml
0.9 mcg 
H5N1 HA + 
AS03C
FLU-Q-PAN 
A/Indonesia/05/2005(H5N1)=0.9µg
(15 g/mL vial)
translucent to 
whitish suspension 
3.1 ml
62.5 µL 
2
0.125ml
AS03A 
Emulsion containing 
tocopherol,tocopherol=47,44mg/ml 
Final vaccine dose = emulsion containing tocopherol,
tocopherol = 2.97 mg)
whitish to yellowish 
homogenous milky 
liquid emulsion 
3.1 ml
62.5 µL
1.9 mcg 
H5N1 HA + 
AS03C
FLU-Q-PAN 
A/Indonesia/05/2005(H5N1)=1.9µg
(15 g/mL vial)
translucent to 
whitish suspension 
3.1 ml
0.125 ml 
2
0.25ml
AS03B 
Emulsion containing tocopherol, tocopherol = 23.72 
mg/mL 
Final vaccine dose = Emulsion containing 
tocopherol, tocopherol=2.97mg 
whitish to yellowish 
homogenous milky 
liquid emulsion 
3.1 ml
0.125 ml
3.75 mcg 
H5N1 HA + 
AS03C
FLU-Q-PAN 
A/Indonesia/05/2005(H5N1)=3.75µg
(30 g/mL vial)
translucent to 
whitish suspension 
3.1 ml
0.125 ml 
2
0.25 ml
AS03B 
Emulsion containing tocopherol, tocopherol = 23.72 
mg/mL 
Final vaccine dose = Emulsion containing 
tocopherol, tocopherol=2,97 mg
whitish to yellowish 
homogenous milky 
liquid emulsion 
3.1 ml
0.125 ml
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
52
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
53
Treatment 
name
Vaccine 
/product 
name
Formulation
Presentation
Vial 
Volume* 
Final Dose: 
Volume per 
product (mL)**
No. doses 
per subject
Final Dose: 
Total Volume 
(mL)***
3.75 mcg 
H5N1 HA + 
AS03D
FLU-Q-PAN
A/Indonesia/05/2005(H5N1)=3.75µg
(30 g/mL vial)
translucent to 
whitish suspension 
3.1 ml
0.125 ml
2
0.25 ml
AS03C
Emulsion containing tocopherol, tocopherol=2.97mg 
per 0.25 mL dose
Final vaccine dose = emulsion containing 
tocopherol, tocopherol = 1.48 mg)
whitish to yellowish 
homogenous milky 
liquid emulsion 
3.1 ml
0.125 ml
3.75 mcg 
H5N1 HA 
FLU-Q-PAN 
A/Indonesia/05/2005=3.75µg
(15 g/mL vial)
translucent to 
whitish suspension 
3.1 ml
0.25 ml 
1
0.25 ml
*for adjuvanted vaccines, full vials of antigen and adjuvant are mixed.; ** The volume of each component (antigen, adjuvant) 
administered in a final vaccine dose ***Total target volume of the antigen/adjuvant mixture to be administered to the subject. Syringes 
may only be calibrated to two decimal places.
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
53
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
54
6.2.
Storage and handling of study vaccine
The study vaccine components must be stored at the respective label storage temperature 
conditions in a safe and locked place. Access to the storage space should be limited to 
authorized study personnel. The storage conditions will be assessed during pre-study 
activities under the responsibility of the sponsor study contact. The storage temperature 
should be continuously monitored with calibrated (if not validated) temperature 
monitoring device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the 
SPM for more details on storage of the study vaccine(s)/product(s).
Temperature excursions must be reported in degrees Celsius.
Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) impacting investigational medicinal products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form ([e]TDF). 
The impacted IMPs must not be used and must be stored in quarantine at label 
temperature conditions until usage approval has been obtained from the sponsor.
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to 
+8°C/+36 to +46°F label storage temperature conditions. The impacted IMP(s) may still 
be administered, but the site should avoid re-occurrence of such temperature excursion.
Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to 
take.
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccine components.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
54
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
55
6.3.
Dosage and administration of study vaccine(s)/product(s)
Table 13
Dosage and administration
Type of contact 
and timepoint
Dose
Study 
Group
Vaccine/Product
Route 1
Site 
Side
Antigen
Adjuvant vial*
Visit 1 Day 0 )
1 
190_B
FLU-Q-PAN 
AS03A 
IM 
Anterolateral thigh
Left
Visit 2 (Day 21 )
2
190_B
FLU-Q-PAN 
AS03A 
IM 
Anterolateral thigh
Right
Visit 6 (Day 385)
3
190_B
FLU-Q-PAN 
None
IM 
Anterolateral thigh
Left
Visit 1 Day 0 )
1 
090_C
FLU-Q-PAN 
AS03A 
IM 
Anterolateral thigh 
Left
Visit 2 (Day 21 )
2
090_C
FLU-Q-PAN 
AS03A 
IM 
Anterolateral thigh 
Right
Visit 6 (Day 385)
3
090_C
FLU-Q-PAN 
None
IM 
Anterolateral thigh
Left
Visit 1 Day 0 )
1 
190_C
FLU-Q-PAN 
AS03B 
IM 
Anterolateral thigh
Left
Visit 2 (Day 21 )
2
190_C
FLU-Q-PAN 
AS03B 
IM 
Anterolateral thigh
Right
Visit 6 (Day 385)
3
190_C
FLU-Q-PAN 
None
IM 
Anterolateral thigh
Left
Visit 1 Day 0 )
1 
375_C
FLU-Q-PAN 
AS03B 
IM 
Anterolateral thigh
Left
Visit 2 (Day 21 )
2
375_C
FLU-Q-PAN 
AS03B 
IM 
Anterolateral thigh
Right
Visit 6 (Day 385)
3
375_C
FLU-Q-PAN 
None
IM 
Anterolateral thigh
Left
Visit 1 Day 0 )
1 
375_D
FLU-Q-PAN 
AS03C 
IM 
Anterolateral thigh 
Left
Visit 2 (Day 21 )
2
375_D
FLU-Q-PAN 
AS03C 
IM 
Anterolateral thigh 
Right
Visit 6 (Day 385)
3
375_D
FLU-Q-PAN 
None
IM 
Anterolateral thigh
Left
1Intramuscular (IM); *adjuvant vial to be used
6.4.
Replacement of unusable vaccine/product doses
In addition to the vaccine/product doses provided for the planned number of subjects 
(including over-randomisation when applicable), at least 10% additional vaccine/product
doses will be supplied to replace those that are unusable. 
The investigator will use SBIR to obtain the replacement vial number. The replacement 
numbers will be allocated by kit/dose/component. The system will ensure, in a blinded 
manner, that the replacement vial matches the formulation the subject was assigned to by 
randomisation.
6.5.
Contraindications to subsequent vaccination
The following events constitute absolute contraindications to further administration of Q-
Pan H5N1 vaccine. If any of these events occur during the study, the subject must not 
receive additional doses of vaccine but may continue other study procedures at the 
discretion of the investigator (Section 9).

Anaphylaxis following study vaccine administration.

Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe, or discovery of a change in the subject’s status which renders 
his/her parent(s)/LAR(s) unable to comply with protocol-mandated safety follow-up.
The following events constitute contraindications to administration of Q-Pan H5N1 
vaccine at that point in time; if any of these events occur at the time scheduled for 
vaccination, the subject may be vaccinated at a later date, within the time window 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
55
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
56
specified in the protocol (Section 5.5), or the subject may be withdrawn at the discretion 
of the investigator (Section 9). 

Acute disease and/or fever at the time of vaccination. 

Fever is defined as temperature 38.0°C/100.4°F by any route (axillary 
assessment preferred). 

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines/products.
6.6.
Warnings and precautions
Refer to the approved product label/package insert.
6.7.
Concomitant medications/products and concomitant 
vaccinations
At each study visit/contact, the investigator should question the subject and/or the 
subject’s parent(s)/LAR(s) about any medications/products taken and vaccinations
received by the subject.
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF.

All concomitant medications /products except vitamins and dietary supplements, 
administered in the period starting 30 days before the first dose of study vaccine and 
continuing for at least 21 days after each priming dose and for 30 days after the 
booster (Day 0 to Day 21; Day 21 to Day 42; Day 385 to Day 415). 

Any prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).

Any antipyretics administered in the period starting 6 hours before vaccination and 
ending 12 hours after vaccination (there is a specific eCRF page where this 
information is captured).

Any concomitant medications/products/vaccines listed in Section 6.7.2.

Any concomitant medications/products/vaccines administered during the study 
period for the treatment of a SAE /pIMD, or relevant to a SAE/pIMD that is to be 
reported as per protocol. In addition, concomitant medications relevant to SAEs and 
pIMDs need to be recorded on the expedited Adverse Event report.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
56
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
57
6.7.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP analyses
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
ATP analysis. See Section 10.4 for cohorts to be analysed.

A vaccine not foreseen by the study protocol administered in the period starting 30 
days before the first dose of study vaccine through Day 42 visit (Day -30 to Day 42 
visit); and for the booster, administration of an inactive vaccine within 14 days or of 
a live attenuated vaccine within 30 days before through 30 days after the booster 
vaccination (note: routine vaccinations may be administered on Day 42 visit only 
after all study assessments are made).

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period. 

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. for 14 or more days) during the entire study period. For corticosteroids, this will 
mean a dose of prednisone or equivalent of > 2 mg/kg/day of body weight (for
persons who weigh < 10 kg), or ≥ 20 mg/day (for persons who weigh ≥ 10 kg).
Inhaled and topical steroids are allowed.

Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab).

Immunoglobulins or any blood products for 3 months before any protocol-mandated 
blood sampling.
A detailed, comprehensive list of reasons for elimination from ATP analyses will be 
established at the time of data cleaning.
In case an emergency mass vaccination for an unforeseen public health threat (e.g.: a 
pandemic) is organised by the public health authorities, outside the routine immunisation 
program, the time period described above can be reduced if necessary for that vaccine 
provided it is licensed and used according to its Prescribing Information and according to 
the local governmental recommendations and provided a written approval of the Sponsor 
is obtained.
6.8.
Intercurrent medical conditions that may lead to elimination 
of a subject from ATP analyses
At each study visit subsequent to the first vaccination, it must be verified if the subject 
has experienced or is experiencing any intercurrent medical condition. If it is the case, the 
condition(s) must be recorded in the eCRF.
7.
HEALTH ECONOMICS
Not applicable.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
57
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
58
8.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an adverse event (AE) or serious 
adverse event (SAE) as provided in this protocol. 
Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should the subject manifest any signs or symptoms they perceive as serious.
8.1.
Safety definitions
8.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
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. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 
Examples of an AE include:

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 investigational vaccine administration 
even though they may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either the 
investigational vaccine or a concurrent medication (overdose per se should not be 
reported as an AE/SAE).

Signs and/or symptoms temporally associated with vaccine administration.

Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen).
AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All other 
AEs will be recorded as UNSOLICITED AEs.
Examples of an AE DO NOT include:

Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.

Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).

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. 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
58
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
59

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first vaccination. These events will be recorded in the medical history section of the 
eCRF.
8.1.2.
Definition of a serious adverse event 
A SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalisation or prolongation of existing hospitalisation,
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE.
d.
Results in disability/incapacity, OR
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, 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 in the offspring of a study subject.
Medical or scientific judgement 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 hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
59
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
60
8.1.3.
Solicited adverse events
The following local (injection-site) AEs will be solicited:
Table 14
Solicited local adverse events
All age groups
Pain at injection site
Redness at injection site
Swelling at injection site
The following general AEs will be solicited:
Table 15
Solicited general adverse events
Drowsiness
Fever
Irritability/Fussiness
Loss of appetite
Note: Temperature (by axillary route preferred) will be recorded in the evening. Should 
additional temperature measurements be performed at other times of day, the highest 
temperature will be recorded in the eCRF.
8.1.4.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments that are judged by the 
investigator to be clinically significant will be recorded as AEs or SAEs if they meet the 
definition of an AE or SAE (refer to Sections 8.1.1 and 8.1.2). Clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline 
and significantly worsen following the start of the study will also be reported as AEs or 
SAEs. However, clinically significant abnormal laboratory findings or other abnormal 
assessments that are present or detected at the start of the study and do not worsen, will 
not be reported as AEs or SAEs.
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
8.1.5.
Other adverse events
8.1.5.1.
Potential immune-mediated diseases
Potential immune-mediated diseases (pIMDs) are a subset of AEs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology. AEs that need to be recorded and 
reported as pIMDs include those listed in Table 16.
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other diseases have an autoimmune origin (i.e. pathophysiology 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
60
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
61
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
61
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
62
Table 16
List of potential immune-mediated diseases 
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve disorders, including 
paralyses/paresis (e.g. Bell’s palsy) 

Optic neuritis

Multiple sclerosis

Transverse myelitis

Guillain-Barré syndrome, including 
Miller Fisher syndrome and other 
variants

Acute disseminated 
encephalomyelitis, including site 
specific variants: e.g. non-infectious 
encephalitis, encephalomyelitis, 
myelitis, myeloradiculoneuritis

Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome 

Immune-mediated peripheral 
neuropathies and plexopathies, 
(including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy and 
polyneuropathies associated with 
monoclonal gammopathy).

Narcolepsy

Systemic lupus erythematosus 
and associated conditions

Systemic scleroderma (Systemic 
sclerosis), including diffuse 
systemic form and CREST 
syndrome
Idiopathic inflammatory 
myopathies, including 
dermatomyositis 

Polymyositis 

Antisynthetase syndrome

Rheumatoid arthritis, and 
associated conditions including 
juvenile chronic arthritis and 
Still’s disease

Polymyalgia rheumatica

Spondyloarthritis, including 
ankylosing spondylitis, reactive 
arthritis (Reiter's Syndrome) and 
undifferentiated spondyloarthritis 

Psoriatic arthropathy

Relapsing polychondritis

Mixed connective tissue disorder

Psoriasis

Vitiligo

Erythema nodosum

Autoimmune bullous 
skin diseases 
(including 
pemphigus, 
pemphigoid and 
dermatitis 
herpetiformis)

Alopecia areata

Lichen planus

Sweet’s syndrome

Localised 
Scleroderma 
(Morphoea)
Vasculitides
Blood disorders
Others

Large vessels vasculitis including: 
giant cell arteritis such as 
Takayasu's arteritis and temporal 
arteritis. 

Medium sized and/or small 
vessels vasculitis including: 
polyarteritis nodosa, Kawasaki's 
disease, microscopic polyangiitis, 
Wegener's granulomatosis, 
Churg–Strauss syndrome (allergic 
granulomatous angiitis), Buerger’s 
disease (thromboangiitis 
obliterans), necrotizing vasculitis 
and anti-neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type unspecified), 
Henoch-Schonlein purpura, 
Behcet's syndrome, 
leukocytoclastic vasculitis.

Autoimmune 
hemolytic 
anemia

Autoimmune 
thrombocytopeni
a

Antiphospholipid 
syndrome

Pernicious 
anemia

Autoimmune 
aplastic anaemia

Autoimmune 
neutropenia 

Autoimmune 
pancytopenia

Autoimmune glomerulonephritis 
(including IgA nephropathy, 
glomerulonephritis rapidly progressive, 
membranous glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis)

Ocular autoimmune diseases (including 
autoimmune uveitis and autoimmune 
retinopathy)

Autoimmune 
myocarditis/cardiomyopathySarcoidosi
s

Stevens-Johnson syndrome

Sjögren’s syndrome

Idiopathic pulmonary fibrosis

Goodpasture syndrome

Raynaud’s phenomenon
Liver disorders
Gastrointestinal disorders
Endocrine disorders

Autoimmune hepatitis

Primary biliary cirrhosis

Primary sclerosing 
cholangitis

Autoimmune cholangitis

Inflammatory Bowel 
disease, including Crohn’s 
disease, ulcerative colitis, 
microscopic colitis, 
ulcerative proctitis 

Celiac disease

Autoimmune pancreatitis

Autoimmune thyroiditis (including 
Hashimoto thyroiditis)

Grave's or Basedow’s disease

Diabetes mellitus type I

Addison’s disease

Polyglandular autoimmune syndrome

Autoimmune hypophysitis
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
62
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
63
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD, as per Section 8.3.3. Symptoms, signs or conditions which might (or 
might not) represent the above diagnoses, should be recorded and reported as AEs but not 
as pIMDs until the final or definitive diagnosis has been determined, and alternative 
diagnoses have been eliminated or shown to be less likely.
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the above 
diagnoses will be available to investigators at study start.
8.1.5.2.
CHMP-defined adverse events of special interest (AESIs)
AESIs are a subset of AEs that are defined in the Committee for Medicinal Products for 
Human Use (CHMP) Risk Management Plan for Pandemic Vaccines for safety 
monitoring. 
Reports of AESIs will be identified by searching the clinical database using MedDRA 
Preferred Terms (PTs) or Standardized MedDRA Queries (SMQs) as recommended by 
CHMP. SMQs are groupings of MedDRA terms, usually at the PT level, that relate to a 
defined medical condition or event of interest and are intended to aid in the identification 
of case reports of these events. AESIs include the events listed below and the MedDRA 
PT or SMQ used to identify reports of these events is provided in parentheses:

Anaphylaxis (narrow SMQs “Anaphylactic reaction” and “Angioedema”)

Bell’s palsy (MedDRA PT “VIIth nerve palsy”)

Convulsion (narrow SMQ “Convulsions”)

Demyelination (narrow SMQ “Demyelination”)

Encephalitis (narrow SMQ “Non-infectious encephalitis”)

Guillain-Barré syndrome (narrow SMQ “Guillain-Barré syndrome”)

Neuritis (MedDRA PT “Neuritis”)

Vasculitis (narrow SMQ “Vasculitis”)
With the exception of anaphylaxis and convulsion, all AESIs and associated preferred 
terms are also considered to be pIMDs (Section 8.1.5.1) and will be reported as such 
(Section 8.3.3).
8.2.
Detecting and recording adverse events/SAEs
Types of adverse events to be collected during this study are as follows.

Solicited local and general adverse events (Table 14 and Table 15), and

Unsolicited adverse events, including (but not limited to) those which:

are medically attended (“MAEs,” see glossary of terms), 

are potential immune mediated diseases (“pIMDs,” Table 16), and/or 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
63
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
64

meet the definition of a serious adverse event (“SAEs,” see glossary of terms).
Methods used to detect and record both solicited and unsolicited adverse events include:

Diary cards,

Scripted telephone interviews,

Interactions with site personnel at study visits, and

Searching database for pIMDs as per list in Table 16 (see Section 8.1.5.1) and for 
AESIs according to defined PTs and SQMs (see Section 8.1.5.2).
8.2.1.
Time periods for detecting and recording adverse events/SAEs
All solicited and unsolicited AEs must be recorded into the appropriate section of the 
eCRF, irrespective of intensity or whether or not they are considered vaccination-related.
Solicited AEs must be recorded for 7 days, i.e. on the day of each study vaccination and 
for the next 6 days after (i.e., Day 0 to Day 6 (dose 1); Day 21 to Day 27 (dose 2); Day 
385 to Day 392 (booster dose )).
The time period for collecting and recording information about occurrences of AEs 
leading to withdrawal from the study, MAEs, pIMDs and SAEs will begin with the first
study vaccine dose and will end when the subject is discharged from the study. See 
Section 8.3 for special instructions on reporting of pIMDs and SAEs.
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study.
Occurrences of all other unsolicited AEs must be recorded from the time of the first 
receipt of study vaccine through completion of the Day 42 visit (Day 0 to Day 42) as well 
as on day of booster dose (Day 385 and 30 days after booster to Day 415) or until the 
subject is withdrawn or lost to follow-up.
The clinical database will be searched for events corresponding to AESIs; this will 
include any AEs reported from Day0 to Day42 or within 30 days post-booster, as well as 
any MAEs, SAEs or pIMDs reported during the entire study period. 
Table 17 provides an overview of the protocol-required reporting periods for collecting 
safety information.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
64
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
65
Table 17
Reporting periods for collecting safety information : 
All groups
Study activity
Visit 1
V1
-
Visit 2
V2
-
Visit 3 
V3
Visit 4 
(TC 1) 
Visit 5 
(TC 2)
Visit 6
Visit 7
Visit 8 
(TC 3)
D01
D0 –D6
D7-D20
D21
D21-D27 D28 – D41
D42
D90
D240
D385
D392
D415
Solicited AEs (local 
and general)
DC, SP
DC
DC, 
SP
DC
DC, SP
Unsolicited MAEs, 
SAEs and pIMDs *
DC, SP
DC
DC
DC, 
SP
DC
DC
DC, SP
I
I
DC, SP
DC, SP
TC, I
Unsolicited SAEs 
related to study 
participation 
or concurrent GSK 
medication/vaccine *
DC, SP
DC
DC
DC, 
SP
DC
DC
DC, SP
I
I
DC, SP
DC, SP
TC, I
Unsolicited AEs 
related to study 
withdrawal *
DC, SP
DC
DC
DC, 
SP
DC
DC
DC, SP
I
I
DC, SP
DC, SP
TC, I
All other unsolicited 
AEs *
DC, SP
DC
DC
DC, 
SP
DC
DC
DC, SP
DC, SP
DC, SP
TC, I
V: vaccination;; D: Day, AE= adverse event; MAE = medically attended adverse event; SAE = serious adverse event, DC = diary card, TC, I = phone contact scripted interview, SP = 
interaction with site personnel at study visit. Data will be reported to GSK via electronic Case Report Form.
Solicited AE diary card data collected for 7 days after dose 1 to be reviewed at Day 21 visit. Solicited AE diary card data collected for 7 days after dose 2 to be reviewed at Day 42 visit.
Events that occur prior to vaccination are only to be reported if they are SAEs related to study participation or to a GSK concomitant product.
* Reported events will be searched for AESIs.
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
65
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
66
8.2.2.
Post-Study adverse events/SAEs
A post-study AE is defined as any event that occurs outside of the AE reporting period 
defined in Table 17. Investigators are not obligated to actively seek AEs in former study 
participants. However, if the investigator learns of any SAE at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably related to the 
investigational vaccine(s)/product(s), the investigator will promptly notify the Study 
Contact for Reporting SAEs.
8.2.3.
Evaluation of adverse events/SAEs
8.2.3.1.
Active questioning to detect adverse events/SAEs
As a consistent method of collecting AEs, the subject or the subject’s parent(s)/LAR(s)
should be asked a non-leading question such as:
‘Have you felt different in any way since receiving the vaccine(s)/product(s) or since the 
previous visit?’
‘Has your child acted differently or felt different in any way since receiving the 
vaccine(s)/product(s) or since the last visit?’
When an AE 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 in 
the eCRF. The investigator is not allowed to send photocopies of the subject’s medical 
records to GSK Biologicals instead of appropriately completing the eCRF. However, 
there may be instances when copies of medical records for certain cases are requested by 
GSK Biologicals. In this instance, all subject identifiers will be blinded on the copies of 
the medical records prior to submission to GSK Biologicals.
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and not the individual signs/symptoms.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
66
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
67
8.2.3.2.
Assessment of intensity
8.2.3.2.1.
Solicited AEs
The intensity of the following solicited AEs will be assessed as described:
Table 18
Intensity scales for solicited symptoms in infants/toddlers and 
children less than 6 years of age
Adverse Event
Intensity grade
Parameter
Pain at injection site
0
None
1
Mild: Minor reaction to touch
2
Moderate: Cries/protests on touch
3
Severe: Cries when limb is moved/spontaneously painful
Redness at injection site
Record greatest surface diameter in mm
Swelling at injection site
Record greatest surface diameter in mm
Fever*
Record temperature in °C/°F
Irritability/Fussiness
0
Behaviour as usual
1
Mild: Crying more than usual/no effect on normal activity
2
Moderate: Crying more than usual/interferes with normal activity
3
Severe: Crying that cannot be comforted/prevents normal 
activity
Drowsiness
0
Behaviour as usual
1
Mild: Drowsiness easily tolerated
2
Moderate: Drowsiness that interferes with normal activity
3
Severe: Drowsiness that prevents normal activity
Loss of appetite
0
Appetite as usual
1
Mild: Eating less than usual/no effect on normal activity
2
Moderate: Eating less than usual/interferes with normal activity
3
Severe: Not eating at all
*Fever is defined as temperature 38.0°C / 100.4°F assessed by any route (axillary preferred)
The maximum intensity of local injection site redness or swelling will be scored at GSK 
Biologicals as follows:
0
:
≤ 20 mm
1
:
> 20 to 50 mm
2
:
> 50 to 100 mm
3
:
> 100 mm
Body temperatures will be scored at GSK Biologicals as follows:
0
< 38.0°C (< 100.4°F)
1
≥ 38.0 – 38.4°C (≥100.4 – 101.2°F)
2
≥ 38.5 – 38.9°C (≥ 101.3 – 102.1°F)
3
≥ 39.0 - 40°C (≥ 102.2 – 104.0°F)
4
>40.0°C (>104.0°F)
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
67
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
68
8.2.3.2.2.
Unsolicited AEs
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
The intensity should be assigned to one of the following categories:
1 (mild)
=
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An AE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
=
An AE which prevents normal, everyday activities 
(in a young child, such an AE would, for example, prevent 
attendance at school/kindergarten/a day-care centre and would 
cause the parent(s)/LAR(s) to seek medical advice. 
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 8.1.2.
8.2.3.3.
Assessment of causality
The investigator is obligated to assess the relationship between the investigational 
vaccine and the occurrence of each AE. The investigator will use clinical judgement to 
determine the relationship. Alternative plausible causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal relationship 
of the event to the investigational vaccine will be considered and investigated. The 
investigator will also consult the IB and/or SmPC and/or Prescribing Information for 
marketed products to determine his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements.
In case of concomitant administration of multiple vaccines/products, it may not be 
possible to determine the causal relationship of general AEs to the individual 
vaccine/product administered. The investigator should, therefore, assess whether the AE 
could be causally related to vaccination rather than to the individual vaccines/products.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
68
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
69
All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question:
Is there a reasonable possibility that the AE may have been caused by the investigational 
vaccine/product?
YES
:
There is a reasonable possibility that the vaccine(s)/product(s)
contributed to the AE. 
NO
:
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine(s)/product(s). There are other, 
more likely causes and administration of the study 
vaccine(s)/product(s) is not suspected to have contributed to the AE.
The definitions for ‘NO’ and ‘YES’ have been written in such a way that all events that 
have been attributed a ‘NO’ can be pooled with events which in the primary vaccination 
study were determined to be ‘not related’ or ‘unlikely to be related’ to vaccination. Those 
events that are attributed a ‘YES’ can be pooled with those events that in the past were 
determined to have a ‘suspected’ or ‘probable’ relationship to vaccination in the primary 
vaccination study.
If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccine(s)/product(s), if applicable.

Erroneous administration.

Other cause (specify).
8.2.3.4.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
69
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
70

Fatal (SAEs only).
8.2.3.5.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/LAR(s) will be asked if the subject received medical attention defined as 
hospitalisation, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded in the eCRF. 
8.3.
Prompt reporting of serious adverse events and other 
events to GSK Biologicals
SAEs that occur in the time period defined in Section 8.2 will be reported promptly to 
GSK within the timeframes described in Table 19, once the investigator determines that 
the event meets the protocol definition of a SAE.
pIMDs that occur in the time period defined in Section 8.2 will be reported promptly to 
GSK within the timeframes described in Table 19, once the investigator determines that 
the event meets the protocol definition of a pIMD.
Table 19
Timeframes for submitting serious adverse events and pIMDs
reports to GSK Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a 
Previous Report
Timeframe
Documents
Timeframe
Documents
SAEs
24 hours*‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events Report
pIMDs 
24 hours**‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events Report
* Timeframe allowed after receipt or awareness of the information.
**Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMD.
‡ The investigator will be required to confirm review of the SAE/pIMD causality by ticking the ‘reviewed’ box in the 
electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/pIMD.
8.3.1.
Contact information for reporting serious adverse events and 
pIMDs
Study Contact for Reporting SAEs and pIMDs
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs, pIMDs
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Fax: +
 or +
Email address: 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
70
27-MAR-2017
PPD
PPD
PPD

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
71
8.3.2.
Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE.
8.3.2.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours. 
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system. 
8.3.3.
Reporting of pIMDs to GSK Biologicals
Once a pIMD is diagnosed in a study subject (whether serious or non-serious), the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS after he/she becomes aware of the 
diagnosis. The report allows to specify that the event is a pIMD and whether it is serious 
or non-serious. The report will always be completed as thoroughly as possible with all 
available details of the event, in accordance with the pIMD standard questionnaire 
provided. Even if the investigator does not have all information regarding a pIMD, the 
report should still be completed within 24 hours. Once additional relevant information is 
received, the report should be updated WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the pIMD causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the pIMD.
Refer to Section 8.3.2.1 for back-up system in case the electronic reporting system does 
not work.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
71
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
72
8.3.4.
Updating of SAE and pIMD information after removal of write 
access to the subject’s eCRF
When additional SAE or pIMD information is received after removal of the write access 
to the subject’s eCRF, new or updated information should be recorded on the appropriate
paper report, with all changes signed and dated by the investigator. The updated report 
should be faxed to the Study Contact for Reporting SAEs (refer to the Sponsor 
Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance department 
within the designated reporting time frames specified in Table 19.
8.3.5.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.3. GSK Biologicals has a legal responsibility to promptly notify, as 
appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccine and unexpected. The 
purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation.
8.4.
Follow-up of adverse events/SAEs
8.4.1.
Follow-up during the study
After the initial AE report, the investigator is required to proactively follow each subject 
and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for pIMDs and SAEs; refer to Table 19).
All MAEs, pIMDs (serious or non-serious) SAEs and AEs leading to withdrawal from 
the study documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
subject is discharged from the study.
All other AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination through Day 415 (or until the subject is discharged from 
the study, whichever is earliest).
8.4.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects with SAEs, pIMDs (serious or non-serious), or 
subjects withdrawn from the study as a result of an AE, until the event has resolved, 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
72
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
73
subsided, stabilised, disappeared, or until the event is otherwise explained, or the subject 
is lost to follow-up. 
If the investigator receives additional relevant information on a previously reported SAE
or pIMD, he/she will provide this information to GSK Biologicals using a paper/ 
electronic Expedited Adverse Events Report as applicable.
Follow-up of other non-serious AEs is required during the study only, as specified in 
Section 8.4.1.
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE. The investigator is obliged to assist. If a subject 
dies during participation in the study or during a recognised follow-up period, GSK 
Biologicals will be provided with any available post-mortem findings, including 
histopathology.
8.5.
Treatment of adverse events
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an AE should 
be recorded in the subject’s eCRF (refer to Section 6.7).
8.6.
Subject card
Subjects’ parent(s)/LAR(s) must be provided with the address and telephone number of 
the main contact for information about the clinical study.
The investigator (or designate) must therefore provide a “subject card” to each subject’s 
parent(s)/LAR(s). In an emergency situation this card serves to inform the responsible 
attending physician that the subject is in a clinical study and that relevant information 
may be obtained by contacting the investigator.
Subjects’ parent(s)/LAR(s) must be instructed to keep subject cards in their possession at 
all times.
8.7.
Holding rules and safety monitoring
8.7.1.
iSRC Review
Periodic reviews of clinical safety data will be done by an internal Safety Review 
Committee (iSRC). 
The iSRC members will include a GSK Biologicals’ Global Clinical Research and 
Development Central Safety Physician, a Clinical Research and Development Lead, and a 
Senior Biostatistician as core members. These members will not be otherwise involved in 
the conduct of the study and will be independent from GSK’s Pandemic Influenza Safety 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
73
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
74
Review Team. The iSRC members will have access to all available safety data. Other 
operational details will be described in an iSRC charter.
8.7.2.
Holding Rules – primary series
Table 20 lists criteria which will lead to suspension of any further administration of 
priming doses of vaccine (termed “holding rules”) to any participant until a review of 
available study safety data has occurred. 
Table 20
Holding Rules
Holding Rule 
#
Event
# of subjects
Proportion of subjects 
1a‡
If one subject experiences death or a life-
threatening event
≥ 1
1b‡
If one subject experiences any vaccine-related* 
SAE 
≥ 1
1c‡
If one subject is diagnosed with a potential 
immune-mediated disease 
≥ 1
1d†
If one subject is withdrawn from the study (by 
investigator request) following a Grade 3 vaccine-
related AE* 
≥ 1
1e†
Any vaccine-related* local or general solicited AE 
leading to hospitalization, or vaccine-related* 
fever >40°C by any route, or necrosis at the 
injection site, within the 7-day post-vaccination 
period
≥ 1
2a
Subjects reporting any Grade 3 solicited local AE 
in an investigational group, within the 7-day post-
vaccination period 
≥ 30% 
2b
Subjects reporting any Grade 3 vaccine-related* 
solicited general AE in an investigational group, 
within the 7-day post-vaccination period 
≥ 20% 
2c
Subjects reporting any Grade 3 vaccine-related* 
unsolicited AE in an investigational group, within 
the 21-day post-vaccination period 
≥ 20% 
‡ Reported via eCRF within 24 hours
* vaccine related implies that there is a reasonable possibility that the vaccine(s) contributed to the SAE/AE as
determined by the Investigator.
† Investigators should refer to the local study contact information document to notify the study sponsor within 24 hours 
of any 1d or 1e events. 
8.7.3.
Impact of sample size on holding rule assessment
The likelihood that a particular holding rule is met varies according to the total number of 
subjects expected to be evaluated at the time of an iSRC review. With 37 enrolled 
subjects and a cut off of 8/37, there is 90% chance that the holding rule 2b/2c is met for a 
vaccine with a true incidence rate of an event triggering a holding rule of 30%, 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
74
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
75
representing an unacceptable safety profile, and 95 % chance that the holding rule is not 
met for a vaccine with a true incidence of 10%. Refer to Figure 2.
Figure 2
Probability to conclude that a specific formulation is safe according 
to safety holding rule 2 with N = 37
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
75
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
76
9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject completion
A subject who returns for the concluding visit/is available for the concluding contact 
foreseen in the protocol is considered to have completed the study.
9.2.
Subject withdrawal
Withdrawals will not be replaced.
9.2.1.
Subject withdrawal from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit/was not available for the concluding contact
foreseen in the protocol. 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis.
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up. 
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject’s parent(s)/LAR(s) or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.

Lost to follow-up.

Other (specify).
*In case a subject is withdrawn from the study because the subject’s parent(s)/LAR(s)
has/have withdrawn consent, the investigator will document the reason for withdrawal of 
consent, if specified by the subject/subject’s parent(s)/LAR(s), in the eCRF.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
76
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
77
Subjects who are withdrawn from the study because of AEs must be clearly distinguished 
from subjects who are withdrawn for other reasons. Investigators will follow subjects 
who are withdrawn from the study as result of an AE until resolution of the event (see 
Section 8.4.2).
9.2.2.
Subject withdrawal from investigational vaccine
A ‘withdrawal’ from the investigational vaccine refers to any subject who does not 
receive the complete treatment, i.e. when no further planned dose is administered from 
the date of withdrawal. A subject withdrawn from the investigational vaccine may not 
necessarily be withdrawn from the study as further study procedures or follow-up may be 
performed (safety or immunogenicity) if planned in the study protocol. 
Information relative to premature discontinuation of the investigational vaccine will be 
documented on the Vaccine Administration page/screen of the eCRF. The investigator 
will document whether the decision to discontinue further vaccination/treatment was 
made by the subject’s parent(s)/LAR(s), or by the investigator, as well as which of the 
following possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Other (specify).
10.
STATISTICAL METHODS
10.1.
Primary Endpoints
See glossary of terms for definitions of SPR, GMT.
10.1.1.
Immunogenicity-fever indices
Separate HI and MN immunogenicity-fever indices will be constructed based on the 
following endpoints:

Humoral immune response in terms of vaccine-homologous HI antibody for each 
group: 

LL (lower limit) of 95%CI of GMT group ratio at Day 42 using 1.9 µg HA with 
AS03B as reference 

Humoral immune response in terms of vaccine-homologous MN antibodies for each 
group: 

LL of 95%CI GMT group ratio at Day 42 using 1.9 µg HA with AS03B as 
reference 

Fever measurement (≥38°C) post dose 1 and dose 2
For each subject, a fever index will be calculated using temperature measurements 
3-days post Dose 1 (D0-D2) and 3-days post Dose 2 (D21-D23)
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
77
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
78
For details regarding construction of these indices refer to Section 10.6.2.1.
10.1.2.
Immune response to a booster dose
Following booster dose administered at Day 385 the following will be evaluated:

For immune response in terms of HI antibodies against vaccine-homologous antigen

Mean Geometric Increase (MGI) at Day 392 relative to Day 385 

For the immune response in terms of MN antibodies against vaccine-homologous 
antigen

MGI at Day 392 relative to Day 385 
10.2.
Secondary Endpoints
Immunogenicity

For humoral immune response in terms of HI antibodies against vaccine-
homologous/heterologous antigens post primary immunization, the following 
aggregate variables will be calculated for each group:
Seroconversion rates (SCR) at Day 42 
Seroprotection rates (SPR) at Day 42 
MGI at Days 42 relative to Day 0 

For humoral immune response in terms of vaccine-homologous MN antibody post 
the primary immunization, following aggregate variables will be calculated for each 
group. :
MGI at Day 385 relative to Day 0

For humoral immune response in terms of HI antibodies against vaccine-
homologous/heterologous antigens (at Days 0, 42 and 385 post the primary 
immunization, at Day 392 (7 days post booster dose)), the following aggregate 
variables will be calculated for each group:
Seropositivity rates at Days 0, 42, 385 and Day 392
Seroconversion rates (SCR) at Day 385 (relative to Day 0) and Day 392 (relative 
to Days 0 and 385)
Seroprotection rates (SPR) at Days 0, 385 and Day 392 
Geometric Mean Titer (GMT) at Days 0, 42, 385 and Day 392 
MGI at Day 385 (relative to Day 0), MGI at Day 392 (relative to Days 0 and 385) 

For humoral immune response in terms of vaccine-homologous/heterologous MN 
antibody, the following aggregate variables will be calculated for each group
(Amended: 27-MAR-2017):
Seropositivity rates at Days 0, 42,385 and Day 392
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
78
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
79
GMT at Days 0, 42,385 and Day 392
Vaccine response rate (VRR) at Days 42, 385 (relative to Day 0) and Day 392
(relative to Days 0 and 385)
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
79
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
80

For CMI in terms of frequencies of antigen-specific cells(CD3+/CD4+/CD8+) at 
Days 0, 42, 385 and 392: 

Frequencies of cytokine CD4+/CD8+ T-cells per million CD4+/CD8+ cells
producing two or more markers within CD40L, IL-2, TNF-, IFN-upon in 
vitro stimulation using A/Indonesia/05/2005 (H5N1) split virus as determined by 
ICS in a sub-cohort of approximately 20 subjects per group at Days 0, 42, 385 
and Day 392
Reactogenicity /Safety:

Solicited local and general AEs
Occurrence of each solicited local AEs during a 7-day follow-up period (i.e., day 
of vaccination and 6 subsequent days) after any vaccination.

Percentage, intensity and duration of solicited local AEs during a 7-day 
follow-up period (Day 0-Day 6) after any vaccination.
Occurrence of each solicited general AEs during a 7-day follow-up period (i.e.,
day of vaccination and 6 subsequent days) after any vaccination.

Percentage, intensity, duration and relationship to vaccination of solicited 
general AEs during a 7-day follow-up period (Day 0-Day 6) after any 
vaccination.

Unsolicited adverse events (AEs)
For the primary series: occurrence and relationship to vaccination of unsolicited 
AEs within 21 days after each vaccine dose.

Percentage, intensity and relationship to vaccination of unsolicited AEs 
during a 21-day follow-up period (Day 0-Day 20) after each vaccine dose.
For the booster dose [unadjuvanted]: occurrence and relationship to vaccination of 
unsolicited AEs within 30 days after vaccination

Percentage, intensity and relationship to vaccination of unsolicited AEs 
during a 30-day follow-up period.
Occurrence and relationship to vaccination of adverse events with MAEs during 
the entire study period.

Percentage and relationship to vaccination of MAEs during the entire study 
period.
Occurrence and relationship to vaccination of pIMDs, SAEs, AESIs during the 
entire study period.

Percentage and relationship to vaccination of pIMDs, SAEs, AESIs during 
the entire study period.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
80
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
81
10.3.
Determination of sample size
One of the objectives of the study is to assess the performance of alternative dosing 
regimens of Q-Pan H5N1 vaccine using a desirability function that considers 
immunogenicity by HI/MN assay 21 days after the second dose and fever scores after the 
first dose and the second dose with as reference half the adult dose [1.9 µg HA with 
AS03B]. All comparisons are descriptive.
The following tables provide (1) the LL of 95%CI for the GMT ratio based on various 
assumptions of standard deviation and point estimate of GMT ratio (Table 21); (2) 
probability to detect at least one subject with fever ≥ 38°C (Table 22); (3) power to meet 
LL of 95% CI for SCR>40% and LL of 95%CI for SPR>70% (Table 23).
Table 21
Lower limit of 95%CI for GMT ratio of vaccine group to the reference 
group 21- days after second vaccination
log GMT standard deviation
0.50
0.55
0.60
0.65
0.70
GMT ratio
0.25
0.14
0.13
0.13
0.12
0.11
0.29
0.16
0.16
0.15
0.14
0.13
0.34
0.19
0.18
0.17
0.16
0.15
0.4
0.23
0.21
0.20
0.19
0.18
0.5
0.28
0.27
0.25
0.24
0.23
0.67
0.38
0.36
0.34
0.32
0.30
1
0.57
0.54
0.51
0.48
0.45
Assumed non-evaluable rate is less than 10%, with a sample size of 34 evaluable 
subjects per group and SD (log value)=0.60, the LL of 95%CI for the GMT ratio would 
be 0.25 if the point estimate of GMT ratio of vaccine group to the reference group is 0.5 
(50% of GMT value deduction).
Table 22
Probability to detect fever during 7-day follow-up after vaccination
Endpoint
Incidence 
rate
Num of evaluable 
subjects 
at least X subjects with 
fever
Prob of detecting at 
least one subjects with 
fever*
Fever ≥38°C
22.4%
34
1
≥99.9%
Fever ≥38.5°C
10.7%
34
1
97.9%
Assumed a binomial distribution 
Based on incidence of fever observed in Q-Pan H5N1-021 in that age group, with 34 
evaluable subjects per group the probability of observing at least one subject with fever ≥
38°C is >99.9% assuming a fever incidence rate of 22.4%; and the probability of 
observing at least one subject with fever ≥38.5°C is 97.9% assuming the incidence rate 
of 10.7%.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
81
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
82
Table 23
Power to meet LL of 95% CI for SCR>40% and LL of 95%CI for 
SPR>70% in one of the vaccine group (without Type I error 
adjustment)
Endpoint
Success Criteria
N evaluable in 
each group
Reference value1
Power2
HI response: SCR
LL of 95% CI > 40%
34
90%
>99.99%
HI response: SPR
LL of 95% CI > 70%
34
90%
75.04%
Key: LL=Lower Limit; SP=Seroprotection (HI antibody titers > 1:40); SPR=Seroprotection rate; CI=confidence interval.
1Source of reference values: lower 95% confidence bound of SPR at Day 42 for Q-Pan-021 in children 6-35 months of 
age receiving 1.9 g H5N1 HA antigen adjuvanted with AS03B.
2PASS 2005 [Miettinen, 1985], 2-sided one proportion test, alpha=5%.
As one of the secondary objectives, HI responses in each vaccine regimen 21 days post 
dose 2 will be evaluated. The power to meet LL of 95% CI for SCR>40% and LL of 
95%CI for SPR>70% is 75.0% in one vaccine group (no type I error adjustment).
10.4.
Cohorts for Analyses
10.4.1.
Total Vaccinated Cohort
The total vaccinated cohort (TVC) will include all subjects who received at least one dose 
of vaccine (TVC cohort for booster safety analysis will include all the subjects who 
received the booster dose):

A safety analysis based on the Total vaccinated cohort will include- all vaccinated 
subjects.

An immunogenicity analysis based on Total vaccinated cohort will include-all 
vaccinated subjects for whom immunogenicity data are available.
The total vaccinated cohort analyses will be performed per investigational vaccine 
actually administered at the first dose.
The analysis of safety will be performed on the TVC.
10.4.2.
Cohort for according-to-protocol (ATP) immunogenicity analyses
The ATP cohort for immunogenicity analysis will include all vaccinated/eligible subjects:

who have received all study vaccine dose(s) (3-doses for booster immunogenicity 
analysis, 2-doses for other analyses) per protocol treatment assignment;

for whom the randomization code is unbroken during the relevant analysis interval;

who have not received any investigational or non-registered product (drug or 
vaccine) other than the study vaccine(s) during the relevant analysis interval;

who have not received any non-study vaccine during the relevant analysis interval
who have not received any immunoglobulins and/or any blood products during the 
relevant analysis interval 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
82
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
83

for whom there was no chronic administration of immunosuppressants) during the 
relevant analysis interval.

who develop a physician-confirmed infection with an A/Indonesia/5/2005 (H5N1) 
virus during the relevant analysis interval.

who have results available for the relevant assay (HI and MN) for all blood samples 
to be collected during the relevant analysis intervals for ATP-Day 42; for ATP-Day 
385 (persistence); for ATP-Day 392 post booster dose (ATP-booster).
10.4.3.
Cohort for analysis of the immunogenicity-fever score
The analysis cohort for combined immunogenicity and safety of the two-dose primary 
series will include all subjects in the ATP cohort for immunogenicity analysis at Day 42 
(Section 10.4.2) for whom temperature measurements are available during the first 3 days 
after both vaccine doses 1 and 2. 
Subjects without immunogenicity results at Day 42 or for whom one or more daily 
temperature measurements are missing during the first 3 days after either vaccine dose 
[dose 1 or dose 2] will be excluded from the immunogenicity/fever index calculation for 
the primary series.
10.5.
Derived and transformed data
The cut-off value for antibody titer is defined by the laboratory before the analysis. A 
seronegative subject is a subject whose antibody titer is below the cut-off value, and 
conversely, a seropositive subject is one whose antibody titer is greater than or equal to 
the cut-off value. For this study, it is assumed that HI titers of < 1:10 will be considered 
below the cut-off. For the calculations of GMT, HI titers of < 10 will be considered to 
take the value 5. It is also assumed that MN titers of < 1:28 will be considered below the 
cut-off. For the calculations of GMT, MN titers of < 28 will be considered to take the 
value 14.
Geometric Mean Titer (GMT) calculations are performed by taking the anti-log of the 
mean of the log (base 10) transformed inverse titers (the number X would denote the 
inverse of a titer expressed as “1:X”). Antibody titers below the cut-off of the assay are 
given an arbitrary value of half the cut-off for the purpose of GMT calculation.
Mean Geometric Increase (MGI) is defined as the geometric mean of the within-subject 
ratios of the post-vaccination reciprocal HI titer to the pre-vaccination HI titer.
Seroconversion Rate (SCR) is defined as the incidence rate of vaccinees who have 
either a pre-vaccination titer recorded as <1:10 for HI and a post-vaccination reciprocal 
titer ≥ 40 or a pre-vaccination reciprocal titer ≥10 and at least a 4-fold increase in post-
vaccination reciprocal titer.
Incidence Rate of HI Reciprocal Titers ≥ 40 (potential SPR), defined as the 
percentage of all vaccinees with a serum reciprocal HI antibody titer ≥ 40 post-
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
83
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
84
vaccination, a level of HI antibodies that may correlate with benefit in protection against 
influenza.
Vaccine Response Rate (VRR) by MN is defined as the post-vaccination reciprocal titer 
of vaccines that have at least 4-fold increase compared with their pre-vaccination 
reciprocal titer. Antibody titers below the cut-off of the assay are given an arbitrary value 
of half the cut-off for the purpose of VRR calculation. (Amended: 27-MAR-2017)
Incidence rates of AEs will be calculated as the number of subjects who experience the 
event, divided by the number of subjects in the safety analysis cohort (the TVC).
Handling of missing immunogenicity data: for a given subject and a given 
immunogenicity measurement, missing or non-evaluable measurements will not be 
replaced. Therefore, analyses will exclude subjects with missing or non-evaluable 
measurements.
Handling of missing safety data: For a given subject and the analysis of solicited 
symptom within 7 days post-vaccination (Days 0 through 6), missing or non-evaluable 
measurements will not be replaced. Therefore the analysis of the solicited AEs based on 
the TVC will include only vaccinated subjects and doses with documented safety data 
(i.e., symptom screen/sheet completed). Details of calculation of percentages of subjects 
with solicited or unsolicited AEs, as a percentage of doses or per subject, will be 
contained in the study Statistical Analysis Plan (SAP). In particular, for analysis of 
unsolicited AEs, such as SAEs or AEs by primary Medical Dictionary for Regulatory 
Activities (MedDRA) term, all vaccinated subjects will be considered. Subjects who did 
not report the event will be considered as subjects without the event.
For summaries reporting both solicited and unsolicited AEs, all vaccinated subjects will 
be considered. Subjects who did not report the event will be considered as subjects 
without the event.
10.6.
Statistical analyses
Detailed demographic, immunogenicity and safety analyses will be described in the 
Statistical Analysis Plan (SAP) and template Tables, Figures and Listings (TFLs). An 
overview of these analyses follows.
10.6.1.
Analysis of demographics
Demographic characteristics (e.g., age at first study vaccination in months; gender; 
ethnicity) will be summarised using descriptive statistics:

Frequency tables will be generated for categorical variables such as study centre.

Mean, median, and standard deviation will be provided for continuous data such as 
age. 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
84
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
85
10.6.2.
Analyses of primary objectives
10.6.2.1.
Immunogenicity-fever indices
These analyses will be performed on the cohort described in Section 10.4.2.
An analysis of covariance model (ANCOVA) will be fitted on the log10 transformed HI 
and MN antibody responses at Day 42, with the vaccine group as a fixed independent 
variable, adjusted by the log10 transformed pre-vaccination titer and age. (Amended: 27-
MAR-2017)
For vaccine-homologous HI and MN separately, an immunogenicity index (DGMT) will 
be constructed using a desirability function based on the computed GMT group ratio 
(alternative dose regimen to reference =1.9 µg HA with AS03B) and the 95%CI.
(Amended: 27-MAR-2017)

DGMT will be the LL of the 95% CI for GMT group ratio 

If the LL of the 95% CI for GMT group ratio is less than 0.25 (i.e., 4- fold less 
than that of the reference group), then DGMT =0.

If the LL of the 95% CI for GMT group ratio is greater than 1 (comparison 
group has higher GMT value than the reference group), DGMT =1. 
note DGMT =1 for the reference group
The fever index (DR) will be calculated according to body temperature measurements 
performed from Days 0-2 after each dose

Any temperature < 38°C (100.4 F)will be assigned a value of 0. Any 
temperature > 40.5°C will be assigned a value of 40.5).

The highest possible temperature value per subject is 243 (6 x 40.5°C; i.e. for 3 
days after dose 1 and dose 2); 

The lowest possible temperature value per subject is 0 (all measurements < 
38.0°C (100.4 F) for 3 days after dose 1 and dose 2).

For each subject, a temperature index will be constructed as follows:(243 minus 
the sum of recorded temperature values for 3 days after dose 1 and dose 2)/243. 
The average temperature measurement for each vaccine group will be calculated 
as the DR. A lower index value DR indicates a less desirable regimen in terms of 
reactogenicity.
An immunogenicity-fever index (D) at Day 42 will be computed for each group 
R
GMT
D
D
D


This index (D) will range between 0 and 1 (0 = not desirable; 1 = highly desirable) and 
the same weight (0.5) is assigned for immunogenicity index and reactogenicity (fever) 
index.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
85
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
86
Two immunogenicity-fever indices will be separately calculated for HI and MN assay 
against the vaccine-homologous virus. Each will be used to rank the different dosing 
regimens as a tool to guide dosing regimen selection. (Amended: 27-MAR-2017)
10.6.2.2.
Immune Response to a booster dose
There will be two separate evaluations, performed on evaluable subjects (ATP cohort-
booster) following a booster dose:

Point estimates and 95% CIs for MGIs relative to Day 385 will be computed for 
vaccine-homologous antibody titers assessed by HI at Day 392 for each vaccine 
regimen

Point estimates and 95% CIs for MGIs relative to Day 385 will be computed for 
vaccine-homologous antibody titers assessed by MN at Day 392 for each 
vaccine regimen
10.6.3.
Analysis for the secondary objectives
10.6.3.1.
Analysis for immunogenicity

Point estimates and 95% CIs for MGIs relative to Day 0 will be computed for 
vaccine-homologous antibody titers assessed by MN at Day 385 for each vaccine 
regimen. 

Using vaccine-homologous and vaccine-heterologous antibody titers assessed by HI, 
the point estimates for SCR, SPR, MGI, and the associated 95% CIs will be 
computed at 21 days after the second dose.

Using vaccine-homologous and vaccine-heterologous antibody titers assessed by HI,
the point estimates and 95% CIs for GMTs and seropositivity rates (at all 
timepoints), and SPRs, SCRs and MGIs at Day 385 will be computed for each 
vaccine regimen.

Point estimates and 95% CIs for seropositivity rates, GMTs, and VRRs for vaccine-
homologous/heterologous MN titers will be computed for all appropriate timepoints.
(Amended: 27-MAR-2017)
All comparisons will be descriptive.
The ATP immunogenicity cohorts (Day 42, persistence or booster) will be used for the 
related analysis of immunogenicity. The detailed analysis will be described in the 
Statistical Analysis Plan (SAP) and template Tables, Figures and Listings (TFLs).
10.6.3.2.
Analysis for CMI

Cell Mediated Immunity (CMI) parameters at Day 0, 42 , 385 and 392 will be 
evaluated:

Antigen-specific CD4+/CD8+ T Cells identified as CD4/CD8+ T-cells producing 
two or more markers within CD40L, IL-2, TNF-, IFN-upon in vitro
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
86
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
87
stimulation using A/Indonesia/05/2005 (H5N1) split virus, (Amended: 27-MAR-
2017)

The frequency of the response for CD4+/CD8+T-cells stained with probes for 
various cytokines and activation marker (IFN-, TNF-, IL-2, CD40L) and
elicited by vaccine components measured in a sub-cohort of approximately 20 
subjects per group at Days 0, 42, 385 and 392 will be described according to the 
technical specifications provided by R&D (Clinical Data – Information Sheet).

CMI analysis will be analyzed based on the TVC for the subjects with CMI results 
available.
10.6.3.3.
Analysis for safety

Safety data will be analyzed based on the TVC.

Analysis will be of subject incidence rates of solicited and unsolicited adverse (AEs) 
events, by solicited local and general AEs terms, and, for unsolicited AEs, by 
MedDRA preferred term and system organ class. Safety data will be summarized for 
all subjects by treatment group. The incidence of solicited local and general AEs 
occurring during 7 days after vaccination will be tabulated with exact 95% CI for 
each treatment group The same calculations will be performed for AEs of any 
intensity, those with intensity grade ≥ 2, and those with intensity of Grade 3, as well 
as for solicited general events assessed as related to vaccination. All solicited local 
AEs are considered to be related to vaccination.

The percentage of subjects with at least one report of an unsolicited AE classified by 
MedDRA (System Organ Class and Preferred Term) 21 days after each vaccination 
will be tabulated with exact 95% CI for each treatment group. The same tabulation 
will be performed for Grade 3 unsolicited AEs and for unsolicited AEs that are 
considered by the investigator to be possibly or probably related to vaccination.

The percentage of subjects with at least one report of an unsolicited AE classified by 
MedDRA (System Organ Class and Preferred Term) 30 days after the booster 
vaccination will be tabulated with exact 95% CI . The same tabulation will be 
performed for Grade 3 unsolicited AEs and for unsolicited AEs that are considered 
by the investigator to be possibly or probably related to vaccination.

The proportion of subjects who begin at least one new concomitant medication 
during the first 42 days after primary vaccination will be calculated with 95% CI.

MAEs, AESIs, SAEs, and pIMDs will be summarized through the entire study
period. In addition, serious AEs and withdrawals due to AE(s) will be described in 
detail.
Note: The pIMD listings will include pIMDs reported by the Investigator and those 
identified from the clinical database search using a list of pre-specified pIMD PTs.
The AESIs listings will include AESIs identified from the clinical database search using a 
list of pre-specified AESIs PTs and SMQs.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
87
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
88
The detailed safety analysis will be described in the Statistical Analysis Plan (SAP) and 
template Tables, Figures and Listings (TFLs).
10.7.
Interpretation of analyses
In this study, all the comparative analyses will be descriptive with the aim to rank 
alternative dosing regimens with respect to immunogenicity and reactogenicity at Day 42, 
persistence at Day 385, and anamnestic response to plain antigen booster dose at Day 
392. In order to evaluate all the effects at the same scale (values between 0-1), a 
persistence parameter and a booster effect parameter will be calculated for HI and MN:

Persistence index = (MGI – 4)/MGI for each group. 

Boostability index=(MGI – 4)/MGI for each group
If the MGI value is less than 4, the index will be set to 0, the immunogenicity- fever, 
persistence and boostability indices will be ranked for each vaccine group.
Given the complexity of possible outcomes, an algorithm for dose selection will not be 
proposed.
Dose selection will be based on Day 42 immunogenicity and fever as key indicator of 
reactogenicity, persistence of the immune response and anamnestic response to 
unadjuvanted antigen as well as any additional safety concerns. Additional practical 
matters related to the estimated incremental benefit versus the complexity of a pediatric 
specific dosing regimen, should it not be a fraction of the adult dose, will also be weighed 
for dose selection as this could lead to increased complexity from a manufacturing and 
delivery perspective in a pandemic response setting.
10.8.
Conduct of analysis
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
10.8.1.
Sequence of analyses
10.8.1.1.
iSRC analyses
iSRC analyses based on TVC will be performed for the purposes of safety data review.
These analyses will be described in detail in a separate iSRC Charter.
10.8.1.2.
Analysis at Day 42
An analysis will be performed on data collected through the Day 42 visit. Elements will
include:

An analysis of cleaned immunogenicity and solicited AEs data collected through the 
Day 42 visit will be conducted. 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
88
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
89

Analyses of unsolicited AEs reported up to the Day 42 visit and cleaned in so far as 
is possible will be carried out. 

Analyses of MAEs, AESIs, SAEs, pIMDs and withdrawals due to AEs collected up 
to the Day 42 visit will be carried out.

Results will be presented in a Day 42 statistical report. Access to individual 
treatment codes will be restricted to the designated statisticians in charge of the 
analysis. No individual listings or data with the subjects’ identifying information will 
be disseminated. Listings of final data will be provided with the Day 415 report.
10.8.1.3.
Final analysis
A final data analysis will be performed at the end of study (Day 415) of all primary and 
secondary endpoints based on the clean data, including evaluations of:

immunogenicity 

solicited AE data (Day 0-6) after each vaccination

unsolicited AEs reported up to the Day 42 visit (21 days after each dose), as well as 
30 days after the Day 385 booster dose

concomitant medications reported up to the Day 42 visit, as well as 30 days after the 
Day 385 booster dose

MAEs, AESIs, SAEs, pIMDs and withdrawals due to AEs collected throughout the 
entire study.
Results of the final analysis, as well as individual data listings, will be presented in a 
final, integrated clinical study report (CSR).
10.8.2.
Statistical considerations for interim analyses
Not applicable.
11.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled. 
11.1.
electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection. 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
89
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
90
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties.
11.2.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst others, the: 

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, 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.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a CRF/ eCRF review and a Source 
Document Verification (SDV). By SDV we understand verifying eCRF entries by 
comparing them with the source data that will be made available by the investigator for 
this purpose. 
The Source Documentation Agreement Form describes the source data for the different 
data in the CRF/ eCRF. This document should be completed and signed by the site 
monitor and investigator and should be filed in the monitor’s and investigator’s study file. 
Any data item for which the CRF/ eCRF will serve as the source must be identified, 
agreed and documented in the source documentation agreement form. 
For eCRF, the monitor freezes completed and approved screens at each visit.
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
11.3.
Record retention
Following closure of the study, the investigator 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 easily accessible, when needed (e.g. audit or 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
90
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
91
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated 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 that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site. 
11.4.
Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues.
11.5.
Posting of information on publicly available clinical trial 
registers and publication policy
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
Summaries of the results of GSK interventional studies (phase I-IV) are posted on 
publicly available results registers within 6 months /12 months of the primary completion 
date for studies of authorised vaccines and 18 months for studies of non-authorised 
vaccines. 
GSK also aims to publish the results of these studies in the searchable, peer reviewed 
scientific literature. Manuscripts are submitted for publication within 24 months of the 
last subject’s last visit. At the time of publication, this protocol will be fully disclosed.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
91
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
92
Interventional studies that do not evaluate vaccines/products are progressed for 
publication in the scientific literature when the results provide important scientific or 
medical knowledge.
Study information from this protocol will be posted on publicly available clinical trial 
registers following finalization of the protocol and, whenever possible, before the 
initiation of the analysis/study. 
Results are publicly registered within 8 months of the completion of the analysis. GSK 
also aims to publish the results of these studies in the searchable, peer reviewed scientific 
literature. Manuscripts are submitted within 18 months of the completion of the analysis.
At the time of publication, this protocol will be fully disclosed.
Study information from this protocol is not required to be posted unless the study results 
provide important scientific knowledge or are relevant for patient care.
Summary protocols or plans and results for analyses that are designed to inform the 
feasibility, conduct or design of other studies are not required to be posted or submitted 
for publication unless the results provide important scientific knowledge or are relevant 
for patient care.
Results of research studies, utilizing data or biological samples from previous GSK 
clinical studies that do not evaluate GSK (or other) vaccines/products are progressed for 
publication in the scientific literature when the results provide important scientific or 
medical knowledge.
Study information from this protocol will be posted on publicly available clinical trial 
registers following finalization of the protocol and, whenever possible, before initiation 
of the analysis/study.
Summary results of observational studies that are designed to inform the safety, efficacy 
or effectiveness, including cost-effectiveness, of GSK vaccines/products are publicly 
registered within 8 months of completion of the analysis. GSK also aims to publish the 
results of these studies in the searchable, peer reviewed scientific literature; manuscripts 
are submitted within 18 months of the completion of the analysis.
Study information from this protocol will be posted on publicly available clinical trial 
registers following finalization of the protocol and, whenever possible, before initiation 
of the analysis/study.
Summary results of observational studies that are designed to inform the safety, efficacy 
or effectiveness, including cost-effectiveness, of GSK vaccines/products (and other 
informative studies) are publicly registered within 8 months of completion of the 
analysis. GSK also aims to publish the results of these studies in the searchable, peer 
reviewed scientific literature; manuscripts are submitted within 18 months of the 
completion of the analysis.
Study information from this protocol is not required to be posted unless the study results 
provide important scientific knowledge or are relevant for subject care.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
92
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
93
Summary protocols and results of observational studies that are designed to inform the 
feasibility, conduct or design of other studies are not required to be posted or progressed 
for publication unless the results provide important scientific knowledge or are relevant 
for patient care. 
Observational studies that do not evaluate vaccines/products are progressed for 
publication in the scientific literature when the results provide important scientific or 
medical knowledge.
11.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
12.
COUNTRY SPECIFIC REQUIREMENTS
None.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
93
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
94
13.
REFERENCES
Beyer WEP, Palache AM, Baljet M, Masurel N. Antibody induction by influenza 
vaccines in elderly: a review of the literature. Vaccine. 1989; 7:385-94
Centers for Disease Control (CDC). Highly Pathogenic Asian-Origin Avian Influenza A 
(H5N1) in People. 2015. http://www.cdc.gov/flu/avianflu/h5n1-people.htm Accessed 1 
May 2015.
Crotty S., Aubert Rachael D, Glidewell J., Ahmeda R.T racking human antigen-specific 
memory B cells: a sensitive and generalized ELISPOT system. Journal of Immunological 
Methods 2004; 286: 111 –122. (Amended: 27-MAR-2017)
Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza 
vaccination. Vir Res. 2004; 103:133-8.
Kosalaraksa P, Jeanfreau R, Frenette L et. al. AS03B-Adjuvanted H5N1 Influenza 
Vaccine in Children 6 Months through 17 Years of Age: A Phase 2/3 Randomized, 
Placebo-Controlled, Observer-Blinded Trial. JID. 2015; 211: 801-810.
Miettinen O, Nurminen M, Comparative analysis of two rates. Stat Med. 1985;4:213-226.
Reed LJ, Muench H. A simple method of estimating fifty per cent endpoints. Am J Hyg. 
1938;27:493-497.
Rimmelzwaan GF, McElhaney JE. Correlates of protection: novel generations of 
influenza vaccines. Vaccine. 2008; 26 (Suppl 4): D41-4.
Western Pacific Regional Office of the World Health Organization (WHO WPRO). 
Avian Influenza A (H5N1) Weekly Update. 2013. Available at: 
http://www.wpro.who.int/emerging_diseases/AIWeekly384.24May2013.pdf?ua=1Access
ed May 2015.
World Health Organization (WHO). Cumulative Number of Confirmed Human Cases of 
Avian Influenza A/(H5N1) Reported to WHO. 31 March 2015. Available at: 
http://www.who.int/influenza/human_animal_interface/EN_GIP_201503031cumulativeN
umberH5N1cases.pdf?ua=1. Accessed May 2015.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
94
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
95
APPENDIX A
LABORATORY ASSAYS
Hemagglutination Inhibition
HI antibody response will be measured in paired serum specimens treated with receptor-
destroying enzyme to remove non-specific inhibitors; the assay will be a microplate
method using 2 HA units of the appropriate antigens, derived from the WHO 
Collaborating Center for Influenza, Centers for Disease Control, Atlanta, GA, USA 
(1991), with a 0.5% horse erythrocyte suspension. Starting with an initial dilution of 1:10 
(assay cut-off), a two-fold dilution series will be prepared up to 1:20,480. All samples
will be tested in duplicate. Antibody titers will be defined by the highest dilution of 
serum which shows complete inhibition of hemagglutination; for calculations of 
geometric means and fold-increases, titers will be expressed as reciprocals. Antibody 
titers below the cut-off of the assay (< 1:10) will be given an arbitrary value of 1:5, half 
the cut-off value, for the purpose of calculations.
Microneutralization (MN) assay 
Virus neutralization by antibodies contained in the serum is determined by a 
microneutralization assay on thawed frozen serum samples. The sera are used after heat 
inactivation for 30 min at 56°C. Each serum is tested in triplicate. A standardised amount 
of virus is mixed with serial dilutions of serum and incubated to allow binding of the 
antibodies to the virus. A cell suspension, containing a defined concentration of Madin-
Darby Canine Kidney (MDCK) cells is then added to the mixture of virus and antiserum 
and incubated at 37°C. After the incubation period, virus replication is visualised by 
hemagglutination of chicken red blood cells. The 50% neutralization titre of a serum is 
calculated by the method of Reed and Muench [Reed, 1938]. (Amended: 27-MAR-2017)
Intracellular Cytokine Staining Assay
Blood samples will be collected by venipuncture and Peripheral Blood Mononuclear 
Cells (PBMCs) will be prepared by centrifugation onto a LymphoprepTM cushion within 
24 hrs following collection. Cell density of the PBMC suspensions will be determined 
(using hemacytometer or other methods) and cells will be frozen according procedure 
described in GSK Biologicals SOPs and stored in liquid nitrogen. Frozen cell suspensions 
will be shipped to GSK Biologicals facilities for testing. To measure T cell responses 
elicited by the vaccine candidates, samples will be thawed. Cell suspension density and 
cell viability will be assessed by an adequate counting method and the cell density will be 
adjusted according to the relevant SOP. PBMCs will be re-stimulated overnight with 
relevant antigens either in the form of split virions or synthetic peptides. Re-stimulated 
cells will then be immunostained for surface markers such as CD4 and CD8 followed by 
cell permeabilization and immunostaining for effector molecules (cytokines/activation 
marker) such as IL-2, IFN-, TNF-and CD40L. Other effectors could also be explored.
Analysis will then be performed by multiparametric flow cytometry. Results will be 
expressed as frequencies of T cells producing various combinations of the 
cytokine/activation markers assessed.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
95
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
96
ELISPOT (Memory B cell detection assay)
The B Cell ELISPOT allows the quantification of antigen specific memory B cells. The 
protocol is adapted from the assay developed by Crotty, 2004, and involves the 
incubation of PBMC that have been differentiated into antibody secreting cells in micro-
plates coated with either the antigen of interest (for the detection of antigen-specific 
memory B cells) or anti-human Ig (for the detection of total memory B cells). A 
conventional immuno-enzymatic procedure [Crotty, 2004] is applied to detect 
antibody/antigen spots enumerating memory B cells and the results are expressed as the 
frequencies of antigen-specific memory B cells within the total memory B cell 
population. (Amended: 27-MAR-2017)
Intracellular Cytokine Staining Assay on Stimulated Whole Blood
Blood samples will be collected by venepuncture and shipped within 4 hours to a GSK 
designated processing lab. To measure T cell responses elicited by the vaccine 
candidates, whole blood will be stimulated overnight with relevant antigens (either in the 
form of split virions or synthetic peptides) and frozen according to SOP 9000005440. 
Frozen stimulated whole blood will be shipped to GSK Biologicals facilities for testing. 
Samples will be thawed and immunostained for surface markers such as CD4 and CD8 
followed by cell permeabilization and immunostaining for effector molecules 
(cytokines/activation marker) such as IL-2, IFN-, TNF-and CD40L as described in 
SOP 900028001. Other effector molecules could also be explored. Analysis will then be 
performed by multiparametric flow cytometry. Results will be expressed as frequencies 
of T cells producing various combinations of the cytokine/activation markers assessed.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
96
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
97
APPENDIX B
CLINICAL LABORATORIES
The clinical laboratory(ies) to be used in this study have not yet been finalized; labs will 
be finalized prior to study start.
Below are laboratories that may be used (the labs are to be specified in SPM).
Table 24
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biologicals Global Vaccine 
Clinical Laboratory, Rixensart
Biospecimen Reception - B7/44
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium
GSK Biologicals Global Vaccine 
Clinical Laboratory, Wavre-Nord 
Noir Epine
Avenue Fleming, 20 - B-1300 Wavre - Belgium
GlaxoSmithKline Biologicals
Branch of SmithKline Beecham 
Pharma GmbH & Co. KG
Zirkusstrasse 40, D-01069 Dresden
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
97
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
98
APPENDIX C
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 1
eTrack study number 
and Abbreviated Title(s)
116938 (FLU Q-PAN H5N1=AS03-023)
Amendment number:
Amendment 1
Amendment date:
20 January 2016
Co-ordinating author:
, Scientific Writer, XPE Pharma for GSK 
Biologicals
Rationale/background for changes: 
This Protocol Amendment corrects a typographical errors and clarifies methodology 
for assessment of Adverse Events of Special Interest (AESIs) in Protocol:

The sponsor’s address in the protocol was indicated in North America rather 
than the address in Belgium. The sponsor is now correctly listed as 
GlaxoSmithKline Biologicals S.A., Rue de l'Institut 89, 1330, Rixensart, 
Belgium.

A typographical error was corrected for one of the formulations (group 3.75 µg 
HA + AS03c) in Table 12. In the table the adjuvant and antigen strengths to be 
used were correct but there was a typographical error for the calculation of the 
final adjuvant content. Table 12 indicates now the correct tocopherol content as 
2.97mg (rather than 5.93mg) as the final dose.

Lists of AESIs was added to Section 8.1.5, and the methodology of AESIs 
collection was clarified.

Minor edits in other sections were made for clarification.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Cover page:
Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals S.A.
Rue de l’Institut 89,
1330, Rixensart, Belgium
GlaxoSmithKline Vaccines North America,
2301 Renaissance Blvd. King of Prussia PA
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
98
27-MAR-2017
PPD

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
99
LIST OF ABBREVIATIONS
CHMP:
Committee for Medicinal Products for Human Use
EMA
European Medicines Agency
FDA:
Food and Drug Administration, United States of America
GMT:
Geometric Mean Titer
MGI:
Mean Geometric Increase
PT:
Preferred Term
SCR:
Seroconversion Rate
SMQs:
Standardized MedDRA Queries
VRR:
Vaccine Response Rate
GLOSSARY OF TERMS
Adverse events of special 
interest
A subset of adverse events defined in the Committee for 
Medicinal Products for Human Use (CHMP) Risk 
Management Plan for Pandemic Vaccines for safety 
monitoring.
Section 1.4.1. Risk Assessment
Important Potential/Identified Risk
Data/Rationale for Risk
Mitigation Strategy
Investigational FLU-Q-Pan H5N1 study vaccine
Immediate allergic reactions
Refer to the Investigator 
Brochure, Section 6.0
Subject Selection (Sections 4.2 and 
4.3) 
Subject Monitoring (Section 5.6)
Contraindications to subsequent 
vaccination (Section 6.5)
Adverse events requiring medical 
attention, Serious adverse events, 
Potentially immune mediated 
diseases (pIMDs), Adverse events of 
special interest (AESIs)
Refer to the Investigator 
Brochure, Sections 5.2 and 6.0
Subject Selection (Sections 4.2 and 
4.3) 
Subject Monitoring (Section 5.6)
Safety Data Review (Section 8)
Contraindications to subsequent 
vaccination (Section 6.5)
Study Procedures
Venipuncture 
Pain or bruising at the site 
where blood is drawn. 
An infection at the site where 
blood is drawn. 
Fainting.
Procedure to be performed by qualified 
personnel.
A topical analgesic may be applied to 
the site where blood will be taken.
A topical disinfectant will be applied.
Subject Monitoring (Section 5.6)
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
99
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
100
Section 3.
Study design overview
Figure1
Design Overview
NOTES: 
D=Day; TC = telephone contact, V = Primary Vaccination, *BV = Unadjuvanted booster vaccination (3.75 µg HA); 
BS = Blood sample,
FLU Q-Pan H5N1 = A/Indonesia/05/2005 hemagglutinin antigen
Section 5.5
Outline of study procedures
Table 6
List of study procedures
Epoch 001
Epoch 002
Type of contact
Visit 1 Visit 2 Visit 3
Visit 4 
(TC1)
Visit 5 
(TC2)
Visit 6
Visit 7
Visit 8 
(TC3)
Time point (s)
Day 0 Day 21 Day 42 Day 90
Day 
240
Day 
385
Day 392
Day 415
Sampling timepoint(s)
Pre-
Vacc 1
Pre 
Vacc 2
Post-
Vacc 2
Post 
Vacc 2
Post 
Vacc 3
Report pIMDs / AESIs4
●
●
●
●
●
●
●
●
4. Recording of intensity, duration and relationship to vaccination of each event reported. Reported events will be 
searched for AESIs.
Section 5.6.12.
Recording of AEs
Refer to Section 8.2 for procedures for the investigator to record AEs. Refer to Section 
8.3 for special requirements for reporting SAEs, AESIs and pIMDs to GSK 
Biologicals.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
100
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
101
Section 6.1.
Description of study vaccine(s)/product(s)
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
101
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
102
Table 12
Study vaccine
Treatment 
name
Vaccine 
/product 
name
Formulation
Presentation
Vial 
Volume* 
Final Dose: 
Volume per 
product (mL)**
No. doses 
per subject
Final Dose: 
Total Volume 
(mL)***
3.75 mcg 
H5N1 HA + 
AS03C
FLU-Q-PAN 
A/Indonesia/05/2005(H5N1)=3.75µg
(30 g/mL vial)
translucent to 
whitish suspension 
3.1 ml
0.125 ml 
2
0.25 ml
AS03B 
Emulsion containing tocopherol, tocopherol = 23.72 
mg/mL 
Final vaccine dose = Emulsion containing 
tocopherol, tocopherol=2,97 5.93mg 
whitish to yellowish 
homogenous milky 
liquid emulsion 
3.1 ml
0.125 ml
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
102
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
103
Section 6.5.
Contraindications to subsequent vaccination
The following events constitute contraindications to administration of Q-Pan H5N1 
vaccine at that point in time; if any of these events occur at the time scheduled for 
vaccination, the subject may be vaccinated at a later date, within the time window 
specified in the protocol (Section 5.5), or the subject may be withdrawn at the discretion 
of the investigator (Section 9). 

Acute disease and/or fever at the time of vaccination. 

Fever is defined as temperature 38.0°C/100.4°F by any route (by any route 
(oral, axillary, rectal or tympanic; axillary assessment preferred).
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) 
without fever can be administered all vaccines/products.
Section 8.1.5. Other adverse events
Section 8.1.5.2.
CHMP-defined adverse events of special interest (AESIs)
AESIs are a subset of AEs that are defined in the Committee for Medicinal Products 
for Human Use (CHMP) Risk Management Plan for Pandemic Vaccines for safety 
monitoring. 
Reports of AESIs will be identified by searching the clinical database using MedDRA 
Preferred Terms (PTs) or Standardized MedDRA Queries (SMQs) as recommended by 
CHMP. SMQs are groupings of MedDRA terms, usually at the PT level, that relate to a 
defined medical condition or event of interest and are intended to aid in the 
identification of case reports of these events. AESIs include the events listed below and 
the MedDRA PT or SMQ used to identify reports of these events is provided in 
parentheses:

Anaphylaxis (narrow SMQs “Anaphylactic reaction” and “Angioedema”)

Bell’s palsy (MedDRA PT “VIIth nerve palsy”)

Convulsion (narrow SMQ “Convulsions”)

Demyelination (narrow SMQ “Demyelination”)

Encephalitis (narrow SMQ “Non-infectious encephalitis”)

Guillain-Barré syndrome (narrow SMQ “Guillain-Barré syndrome”)

Neuritis (MedDRA PT “Neuritis”)

Vasculitis (narrow SMQ “Vasculitis”)
With the exception of anaphylaxis and convulsion, all AESIs and associated preferred 
terms are also considered to be pIMDs and will be reported as such (Section 8.3.3).
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
103
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
104
Section 8.2.
Detecting and recording adverse events/SAEs
Methods used to detect and record both solicited and unsolicited adverse events include:

Diary cards,

Scripted telephone interviews, and

Interactions with site personnel at study visits, and

Searching database for pIMDs as per list in Table 16 (see Section 8.1.5.1) and for 
AESIs according to defined PTs and SQMs (see Section 8.1.5.2).
Section 8.2.1. Time periods for detecting and recording adverse events/SAEs
The time period for collecting and recording information about occurrences of AEs 
leading to withdrawal from the study, MAEs, pIMDs, AESIs and SAEs will begin with 
the first study vaccine dose and will end when the subject is discharged from the study. 
See Section 8.3 for special instructions on reporting of pIMDs, AESIs and SAEs.
The clinical database will be searched for events corresponding to AESIs; this will 
include any AEs reported from Day0 to Day42 or within 30 days post-booster, as well 
as any MAEs, SAEs or pIMDs reported during the entire study period.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
104
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
105
Table 17
Reporting periods for collecting safety information: 
All groups
Study activity
Visit 1
V1
-
Visit 2
V2
-
Visit 3 
V3
Visit 4 
(TC 1) 
Visit 5 
(TC 2)
Visit 6
Visit 7
Visit 8 
(TC 3)
D01
D0 –D6
D7-D20
D21
D21-D27 D28 – D41
D42
D90
D240
D385
D392
D415
Solicited AEs (local 
and general)
DC, SP
DC
DC, 
SP
DC
DC, SP
Unsolicited MAEs, 
SAEs and pIMDs, 
AESIs *
DC, SP
DC
DC
DC, 
SP
DC
DC
DC, SP
I
I
DC, SP
DC, SP
TC, I
Unsolicited SAEs 
related to study 
participation 
or concurrent GSK 
medication/vaccine *
DC, SP
DC
DC
DC, 
SP
DC
DC
DC, SP
I
I
DC, SP
DC, SP
TC, I
Unsolicited AEs 
related to study 
withdrawal *
DC, SP
DC
DC
DC, 
SP
DC
DC
DC, SP
I
I
DC, SP
DC, SP
TC, I
All other unsolicited 
AEs *
DC, SP
DC
DC
DC, 
SP
DC
DC
DC, SP
DC, SP
DC, SP
TC, I
V: vaccination;; D: Day, AE= adverse event; MAE = medically attended adverse event; SAE = serious adverse event, DC = diary card, TC, I = phone contact scripted interview, SP = 
interaction with site personnel at study visit. Data will be reported to GSK via electronic Case Report Form.
Solicited AE diary card data collected for 7 days after dose 1 to be reviewed at Day 21 visit. Solicited AE diary card data collected for 7 days after dose 2 to be reviewed at Day 42 visit.
Events that occur prior to vaccination are only to be reported if they are SAEs related to study participation or to a GSK concomitant product.
* Reported events will be searched for AESIs.
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
105
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
106
Section 10.5. Derived and transformed data
Mean Geometric Increase (MGI) is defined as the geometric mean of the within-subject 
ratios of the post-vaccination reciprocal HI titer to the pre-vaccinationDay 0 reciprocal 
HI titer.
Seroconversion Rate (SCR) is defined as the incidence rate of vaccines who have either 
a pre-vaccination (Day 0) titer recorded as <1:10 for HI and a post-vaccination reciprocal 
titer ≥ 40 or a pre-vaccination reciprocal titer ≥10 and at least a 4-fold increase in post-
vaccination reciprocal titer.
Vaccine Response Rate (VRR) by MN is defined as the post-vaccination reciprocal titer 
of vaccines that have at least 4-fold increase compared with their pre-vaccination 
reciprocal titer. Seronegative subjects (i.e., those with no detectable neutralizing 
activity at a 1:28 antibody titer) will be assigned reciprocal titers of 14, which is half 
the minimal reciprocal titer detectable in the assay system.
Handling of missing safety data: For a given subject and the analysis of solicited 
symptom within 7 days post-vaccination (Days 0 through 6), missing or non-evaluable 
measurements will not be replaced. Therefore the analysis of the solicited AEs based on 
the TVC will include only vaccinated subjects and doses with documented safety data 
(i.e., symptom screen/sheet completed). Details of calculation of percentages of subjects 
with solicited or unsolicited AEs, as a percentage of doses or per subject, will be 
contained in the study Statistical Analysis Plan (SAP). In particular, for analysis of 
unsolicited AEs, such as SAEs or AEs by primary Medical Dictionary for Regulatory 
Activities (MedDRA) term, all vaccinated subjects will be considered. Subjects who did 
not report the event will be considered as subjects without the event. For safety laboratory 
results, missing or non-evaluable measurements will not be replaced.
Section 10.6.3.3.
Analysis for safety

MAEs, AESIs, SAEs, and pIMDs will be collected and summarized through the 
entire study period. In addition, serious AEs and withdrawals due to AE(s) will be 
described in detail.
Note: The pIMD/AESIs listings will include pIMDs/AESIs reported by the Investigator 
and those identified from the clinical database search using a list of pre-specified 
pIMD/AESIs PTs.
The AESIs listings will include AESIs identified from the clinical database search 
using a list of pre-specified AESIs PTs and SMQs.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
106
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
107
GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 2
eTrack study number 
and Abbreviated Title(s)
116938 (FLU Q-PAN H5N1=AS03-023)
Amendment number:
Amendment 2
Amendment date:
27-March 2017
Co-ordinating author:
, Senior Scientific Writer
Rationale/background for changes: 

The heterologous immunogenicity testing described as secondary study 
objective will be assessed by microneutralization (MN) assay in addition to HI 
assay. MN provides additional relevant information to evaluate cross reactivity 
being a more sensitive and less HA antigen-specific assay than the HI assay. In 
addition, updated EMA guidance [EMA/CHMP/VWP/457259/2014 Guideline 
on Influenza Vaccines. Non-clinical and Clinical Module] requires both HI and 
neutralization data for cross-reactivity assessment.

Minor edits in other sections were made for clarification.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Cover page
Co-ordinating author
, Science Writer
 
Science Writer
Contributing authors
Clinical Research and Development Lead
Project Statistician
Lead Statistician
 
Study Delivery Lead, SynteractHCR for GSK
Study Delivery Manager, SynteractHCR for GSK
 
Clinical Read-outs Team Lead Immunology
representative
 
Clinical Safety representatives
 
Project Data Manager; Keyrus Biopharma for GSK
Vaccine Supply Coordinator
Clinical Trial Supply Manager
Global Regulatory Leader
Regulatory Affairs
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
107
27-MAR-2017
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
108
Copyright 2015-20167 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited
Synopsis Objectives and Section 2.2 Secondary Objectives
Secondary: 

To assess the immunogenicity of the H5N1 vaccine regimens in terms of vaccine-
heterologous HI and MN antibody titers on Days 0, 42, 385 and Day 392.

To describe safety in terms of medically attended events AEs (MAEs), AEs of 
special interest (AESIs), potential immune-mediated diseases (pIMDs), and serious 
adverse events (SAEs) during the entire study period
Synopsis Secondary Endpoints, Section 10.2 Secondary Endpoints, and Section 
10.6.3.2 Analysis of CMI
Immunogenicity

For humoral immune response in terms of vaccine-
homologous/heterologous MN antibody post the primary 
immunization, following aggregate variables will be 
calculated for each group

For humoral immune response in terms of vaccine-
homologous/heterologous MN antibodies, the 
following aggregate variables will be calculated for 
each group: 

For CMI in terms of frequencies of antigen-specific 
(CD3+/CD4+/CD8+) cells at Days 0, 42, 385 and 392;

Frequencies of cytokine CD4+/CD8+ T-cells per 
million CD4+/CD8+ cells producing two or more 
markers within CD40L, IL-2, TNF-, IFN-upon in
vitro in vitro stimulation using A/Indonesia/05/2005 
(H5N1) split virus as determined by intracellular 
cytokine staining (ICS) in a sub-cohort of 
approximately 20 subjects per group at Days 0, 42, 385 
and Day 392
List of Abbreviations and Glossary of Terms
ICS:
Intracellular Cytokine Staining
IFNg:
Interferon 
MAEs:
Medically Attended Adverse Events
TNF-:
Tumor necrosis factor-
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
108
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
109
Background
The majority of H5N1 infections occurred in children and adults younger than 40 years 
of age [CDC, 2015].
Rationale for the Study
In the first D-Pan H5N1 trial, 3.75 or 1.9 µg of Hhemagglutinin (HA) antigen mixed with 
2 concentrations of adjuvant, AS03A and AS03B, were evaluated. An H5N1 vaccine 
containing 1.9 g of HA combined with AS03B (half the adult dose of 3.75 µg HA+
AS03A), administered as a 2-dose regimen 21 days apart, was chosen for further H5N1 
clinical development in children.
As known from adjuvanted vaccines, there was an increase in solicited local and some 
general AEs within 7 days post vaccination in Q-Pan H5N1 vaccine recipients compared 
to placebo recipients.
Rationale for the study design and Section 2.1.2 Booster Dose
All subjects will receive an unadjuvanted booster dose of 3.75 µg HA which was selected 
to this effect in an effort to (a) minimize reactogenicity in these young children, and (b) 
facilitate an assessment of the anamnestic response to each priming regimen by 
increasing the potential of detecting differences between groups, which may be masked 
by a vigorous response to an AS03 adjuvanted booster dose rather than plain
unadjuvanted antigen.
Section 5.5 Outline of study procedures
Table 6
List of study procedures
Epoch 001 
Epoch 002
Type of contact
Visit 1 Visit 2 Visit 3 
Visit 4 
(TC1) 
Visit 5 
(TC2) 
Visit 6 
Visit 7 
Visit 8 
(TC3) 
Time point (s)
Day 0 Day 21 Day 42 Day 90
Day 
240
Day 
385
Day 392
Day 415
Sampling timepoint(s)
Pre-
Vacc 1
Pre 
Vacc 2
Post-
Vacc 2
Post 
Vacc 2
Post 
Vacc 3
Informed consent 
●
Check inclusion / exclusion criteria 
●
Check contraindications to vaccination *
●
●
● 
Medical history 
●
Seasonal influenza vaccination history 1
●
Collect demographic data 
●
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
109
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
110
Epoch 001 
Epoch 002
Type of contact
Visit 1 Visit 2 Visit 3 
Visit 4 
(TC1) 
Visit 5 
(TC2) 
Visit 6 
Visit 7 
Visit 8 
(TC3) 
Time point (s)
Day 0 Day 21 Day 42 Day 90
Day 
240
Day 
385
Day 392
Day 415
Sampling timepoint(s)
Pre-
Vacc 1
Pre 
Vacc 2
Post-
Vacc 2
Post 
Vacc 2
Post 
Vacc 3
Physical examination
●
Measure/record height and weight 
●
Brief (symtpom symptom directed) 
physical examination
○
○
○
○
Record concomitant medications and 
vaccinations 
●
●
●
●
●
●
●
●
Pre-vaccination body temperature /vital 
signs
●
●
● 
Study group and treatment number 
allocation
●
Treatment number allocation for 
subsequent doses
●
● 
Blood sampling for assessment of 
humoral immune response (approx. 2.5 
mL venous blood)
●
●
● 
● 
Blood sampling for assessment of CMI 
response (approx. 2.0 mL venous blood)
●
●
● 
● 
Vaccine dose preparation by unblinded 
staff
○
○
○ 
Vaccine administration (record treatment 
number) 
●
●
● 
Provide training / Distribute diary cards 2
○
○
○ 
○ 
Parent/LAR records solicited AEs 3
(beginning on the day of the dose and for 
the following six days; e.g., Day 0 – 6)
○
○
○ 
Parent/LAR records unsolicited AEs 
beginning with day of vaccination and 
continuing for next 20 (doses 1 and 2) or 
29 (booster dose) days
○
○
○
○ 
○ 
Parent/LAR returns diary cards 
○
○
○ 
Investigator transcribes diary card data 
●
●
● 
● 
Report all non-serious adverse events 4
●
●
●
● 
● 
● 
Report non-serious adverse events 
leading to study withdrawal 
●
●
●
●
●
● 
● 
● 
Report current/intercurrent medical 
conditions 
●
●
●
●
● 
● 
Report medically attended events 4
●
●
●
●
●
●
● 
● 
Report serious adverse events 4
●
●
●
●
●
●
● 
● 
Report pIMDs 4
●
●
●
●
●
●
● 
● 
Report SAEs related to study 
participation or GSK concomitant product 
or any fatal SAE 
●
●
●
●
●
●
●
●
Study conclusion 
● 
Note: The double-line border following Day 42 indicates analyses will be performed on all data obtained up to this time 
point; Pre-Vacc: Pre-vaccination. Post-Vacc: Post-vaccination.. TC = telephone contact. ● is used to indicate a study 
procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF
* If any, it has to be recorded in medical history (prior first vaccination) or in AE/SAE.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
110
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
111
1. Influenza vaccination history will include all previous seasonal influenza vaccination(s)]
2. Diary cards used to capture both solicited (for 7 days following each dose) and unsolicited events (for 21 days after 
doses 1 and 2; for 30 days after booster dose) are provided at the time of each vaccination and collected at the next 
visit after each vaccination.
3. Recording of intensity and duration of solicited local symptoms and of occurrence, intensity, duration, and 
relationship of each solicited general AE and unsolicited AE;
4. Recording of intensity, duration and relationship to vaccination of each event reported. Reported events will be 
searched for AESIs.
Section 5.6.1 Informed consent
The signed/witnessed/thumb printed printed (or as applicable per local guidelines) 
informed consent of the subject’s parent(s)/LAR(s) must be obtained before study 
participation.
Section 5.6.9 Blood sampling for immune response assessment
Refer to the Module on Biospecimen Management in the Study Procedures Manual
(SPM) for detailed instructions
Section 5.7.3
Laboratory assays
Table 9
Humoral immunity (antibody determination)
System
Component
Scale
Method
Kit / 
Manufacturer
Unit
Cut-
off
Laboratory
Serum
Vaccine-Homologous
Influenza Virus 
A/Indonesia/05/2005 (H5N1) 
HA
Quantitative
HI
In-house 
assay
1/DIL
10
GSK 
Biologicals1
Serum
Vaccine-Homologous
Influenza Virus 
A/Indonesia/05/2005 (H5N1)
Quantitative
MN
In-house 
assay
1/DIL
28
GSK 
Biologicals1
Serum
H5N1 virus heterologous 
or other H5 subtypes2
A/Indonesia/05/2005 
(H5N1)drift variant(s)
Quantitative
HI
In-house 
assay
1/DIL
10
GSK 
Biologicals1
Serum
H5N1 virus heterologous 
or other H5 subtypes2
Quantitative
MN
In-house 
assay
1/DIL
28
GSK 
Biologicals1
1 GSK Biologicals laboratory or validated laboratory designated by GSK Biologicals.
2 This testing will depend on adequate specimens and resources.
HI = hemagglutination inhibition; MN = microneutralization; DIL = dilution
Table 10
Cell-Mediated Immunogenicity (CMI)
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
111
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
112
System
Component
Challenge
Method
Unit
Laboratory
WHBST 
(Whole 
Blood 
Stimulated) 
Cells
Cells CD4.CD40L(+)+Interleukin-2(-)+Tumor 
Necrosis Factor alpha(-)+Interferon gamma(-)
Cells CD4+CD8 (CD40L+Interleukin-
2+Tumor Necrosis Factor alpha+Interferon 
gamma)
(T cells stained with probes for various 
cytokines and activation marker (IFNγ, TNFα, 
IL-2, CD40L)
BKG 
(None), H5N1 
split, SEB
ICS (CFC) Events/10E6 
cells 
(polypositive 
CD4+/CD8+ T 
cells per 
million 
CD4+/CD8+ T 
cells)
GSK 
Biologicals
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
112
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
113
Section 5.7.4 Biological samples evaluation
Table 11
Immunological read-outs
Blood sampling timepoint
Sub-cohort Name
No. 
subjects
Component
Priority 
rank
Type of contact 
and time point
Sampling 
time point
Visit 1 (Day 0)
Pre Vacc 1 
Vaccine homologous 
185 
Influenza Virus 
A/Indonesia/05/2005 
(H5N1) HI
1
Visit 3 (Day 42)
Post Vacc 2 
Vaccine homologous 
185
Visit 6 (Day 385)
Post Vacc 2 
Vaccine homologous 
185
Visit 7 (Day 392)
Post Vacc 3 
Vaccine homologous 
185
Visit 1 (Day 0)
Pre Vacc 1 
Vaccine homologous 
185
Influenza Virus 
A/Indonesia/05/2005 
(H5N1) MN
2
Visit 3 (Day 42)
Post Vacc 2 
Vaccine homologous 
185
Visit 6 (Day 385)
Post Vacc 2 
Vaccine homologous 
185
Visit 7 (Day 392)
Post Vacc 3 
Vaccine homologous 
185
Visit 1 (Day 0)
Pre Vacc 1 
Vaccine heterologous 
185 
H5N1 virus 
heterologous or 
other H5 subtypes
(marker = 
heterologous MN)
3
Visit 3 (Day 42)
Post Vacc 2 
Vaccine heterologous 
185
Visit 6 (Day 385)
Post Vacc 2 
Vaccine heterologous 
185
Visit 7 (Day 392)
Post Vacc 3 
Vaccine heterologous 
185
Visit 1 (Day 0)
Pre Vacc 1 
Vaccine heterologous 
185 
H5N1 virus 
heterologous or 
other H5 subtypes
(marker = 
heterologous HI)
3 4
Visit 3 (Day 42)
Post Vacc 2 
Vaccine heterologous 
185
Visit 6 (Day 385)
Post Vacc 2 
Vaccine heterologous 
185
Visit 7 (Day 392)
Post Vacc 3 
Vaccine heterologous 
185
Visit 1 (Day 0)
Pre Vacc 1 
Cell Mediated Immunity (CMI) 
100
T cells stained with 
probes for various 
cytokines and 
activation marker 
(IFNg, TNFa, 
IL-2
1
Visit 3 (Day 42)
Post Vacc 2 
Cell Mediated Immunity (CMI) 
100
Visit 6 (Day 385)
Post Vacc 2 
Cell Mediated Immunity (CMI) 
100
Visit 7 (Day 392)
Post Vacc 3 
Cell Mediated Immunity (CMI) 
100
HI = hemagglutination inhibition; MN = microneutralization; CMI=cell-mediated immunity 
For humoral antibody tests, priority rank 1 and 2 read-outs (HI and MN vaccine-
homologous testing) will be attempted for all subjects; priority rank 3 and 4 read-outs 
(MN and HI vaccine-heterologous testing) may be attempted for fewer than the specified 
number of subjects per treatment group if necessitated by resource or sample constraints 
and availability of suitable strains.
Section 5.7.5 
Immunological correlates of protection
Although there is no accepted correlate of protection against influenza, either seasonal or 
pandemic, the protective role of antibodies against the HA hemagglutinin and, to a lesser 
extent.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
113
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
114
Section 8.7.2. Holding Rules – primary series 
Table 20
Holding Rules
Holding Rule 
#
Event
# of subjects
Proportion of subjects 
1a‡
If one topic subject experiences death or a life-
threatening event
≥ 1
1b‡
If one subject experiences any vaccine-related* 
SAE 
≥ 1
1c‡
If one subject is diagnosed with a potential 
immune-mediated disease 
≥ 1
1d†
If one subject is withdrawn from the study (by 
investigator request) following a Grade 3 vaccine-
related AE* 
≥ 1
1e†
Any vaccine-related* local or general solicited AE 
leading to hospitalization, or vaccine-related* 
fever >40°C by any route, or necrosis at the 
injection site, within the 7-day post-vaccination 
period
≥ 1
2a
Subjects reporting any Grade 3 solicited local AE 
in an investigational group, within the 7-day post-
vaccination period 
≥ 30% 
2b
Subjects reporting any Grade 3 vaccine-related* 
solicited general AE in an investigational group, 
within the 7-day post-vaccination period 
≥ 20% 
2c
Subjects reporting any Grade 3 vaccine-related* 
unsolicited AE in an investigational group, within 
the 21-day post-vaccination period 
≥ 20% 
‡ Reported via eCRF within 24 hours
* vaccine related implies that there is a reasonable possibility that the vaccine(s) contributed to the SAE/AE as
determined by the Investigator.
† Investigators should refer to the local study contact information document to notify the study sponsor within 24 hours 
of any 1d or 1e events. 
Section 10.4.2 
Cohort for according-to-protocol (ATP) immunogenicity 
analyses
The ATP cohort for immunogenicity analysis will include all vaccinated/eligible subjects:

who have results available for the relevant assay assay (HI and MN) for all blood 
samples to be collected during the relevant analysis intervals for ATP-Day 42; for 
ATP-Day 385 (persistence); for ATP-Day 392 post booster dose (ATP-booster).
10.5
Derived and transformed data
Mean Geometric Increase (MGI) is defined as the geometric mean of the within-subject 
ratios of the post-vaccination reciprocal HI titer to the pre-vaccination HI titer.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
114
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
115
Vaccine Response Rate (VRR) by MN is defined as the post-vaccination reciprocal titer 
of vaccinees that have at least 4-fold increase compared with their pre-vaccination 
reciprocal titer.
Section 10.6.2.1
Immunogenicity-fever indices 
An analysis of covariance model (ANCOVA) will be fitted on the log1010 transformed HI 
and MN antibodyies responses at Day 42, with the vaccine group as a fixed independent 
variable, adjusted by the log1010 transformed pre-vaccination titer and age.
For vaccine-homologous HI and MN separately, an immunogenicity index (DGMT) will 
be constructed using a desirability function based on the computed GMT group ratio 
(alternative dose regimen to reference =1.9 µg HA with AS03B) and the 95%CI.
Two immunogenicity-fever indicesexes will be separately calculated for HI and MN 
assay against the vaccine-homologous virus. Each will be used to rank the different 
dosing regimens as a tool to guide dosing regimen selection. 
Section 10.6.3.1
Analysis for immunogenicity

Point estimates and 95% CIs for seropositivity rates, GMTs and VRRs for vaccine-
homologous/heterologous MN titers will be computed for all appropriate timepoints.
References
Crotty S., Aubert Rachael D, Glidewell J., Rafi Ahmeda R.T racking human antigen-
specific memory B cells: a sensitive and generalized ELISPOT system. Journal of 
Immunological Methods 2004; 286: 111 –122.
Appendix B
ELISPOT (Memory B cell detection assay)
The B Cell Elispot allows the quantification of antigen specific memory B cells.  The 
protocol is adapted from the assay developed by Crotty, 2004, and involves the 
incubation of PBMC that have been differentiated into antibody secreting cells in nitro-
plates coated with either the antigen of interest (for the detection of antigen-specific 
memory B cells) or anti-human Ig (for the detection of total memory B cells).  A 
conventional immuno-enzymatic procedure [Crotty, 2004] is applied to detect 
antibody/antigen spots enumerating memory B cells and the results are expressed as the 
frequencies of antigen-specific memory B cells within the total memory B cell 
population.
The B Cell Elispot allows the quantification of antigen specific memory B cells.  The 
protocol is adapted from the assay developed by Crotty, 2004, and involves the 
incubation of PBMC that have been differentiated into antibody secreting cells in nitro-
plates coated with either the antigen of interest (for the detection of antigen-specific 
memory B cells) or anti-human Ig (for the detection of total memory B cells). A 
conventional immuno-enzymatic procedure [Crotty, 2004] is applied to detect 
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
115
27-MAR-2017

CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
27-MAR-2017
116
antibody/antigen spots enumerating memory B cells and the results are expressed as the 
frequencies of antigen-specific memory B cells within the total memory B cell 
population.
 
CONFIDENTIAL
116938 (FLU Q-PAN H5N1=AS03-023)
Protocol Amendment 2 Final
f9b8ce5d3bd6bfffdc386a71b6a5626b1f9a63ff
116
27-MAR-2017

PPD