Persistence of Immune Response to GSK Biologicals' HPV Vaccine in Healthy Chinese Female Subjects From the HPV-058 Study
Phase: PHASE3
Conditions: Cervical Intraepithelial Neoplasia
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals SA
Rue de l’Institut 89
B-1330 Rixensart, Belgium
Primary Study vaccine and 
number
GlaxoSmithKline (GSK) Biologicals’ human 
papillomavirus (HPV) vaccine containing HPV-16/18 
L1 virus-like particles (VLPs) and AS04 adjuvant 
(GSK 580299)
eTrack study number and 
Abbreviated Title
207347 (HPV-093 EXT 058)
Date of protocol
Final Version 1: 19 May 2017
Title
Persistence of immune response to GSK Biologicals’ 
HPV vaccine in healthy Chinese female subjects from 
the HPV-058 study.
Detailed Title
A phase III, open-label, mono-centre, follow-up 
extension study to evaluate the persistence of immune 
response to GSK Biologicals’ HPV vaccine in healthy 
Chinese female subjects who received three doses of 
the vaccine in the HPV-058 study.
Co-ordinating author
, Scientific Writer
Contributing authors
!
, Clinical and Epidemiology R&D 
Project Lead
!
, Clinical Research and 
Development Lead 
!
, Project Statistician
!
 Lead Statistician
!
, Study Delivery Lead
!
and 
, 
Clinical Safety representative
!
, Study Data Manager
!
, Oversight Data Manager
!
, Clinical Read Out Team Leader
!
, Clinical Laboratory Sciences 
Study Manager
!
, Global Patents representative
!
, Clinical Trial Supply Manager
!
, Regulatory Affairs 
representative
!
, Head of Clinical Research and 
Development, China/Hong Kong

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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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eTrack study number and 
Abbreviated Title
207347 (HPV-093 EXT 058)
Detailed Title
A phase III, open-label, mono-centre, follow-up 
extension study to evaluate the persistence of immune 
response to GSK Biologicals’ HPV vaccine in healthy 
Chinese female subjects who received three doses of 
the vaccine in the HPV-058 study.
Contributing authors
!
, Local Delivery Lead Clinical 
Operations Senior Manager, China
!
, Local Medical Lead, China
!
 Local Delivery Lead, China
GSK Biologicals’ Protocol DS v 15.0
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited.

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PPD
PPD
PPD

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Protocol Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
207347 (HPV-093 EXT 058)
Date of protocol
Final Version 1: 19 May 2017
Detailed Title 
A phase III, open-label, mono-centre, follow-up 
extension study to evaluate the persistence of immune 
response to GSK Biologicals’ HPV vaccine in 
healthy Chinese female subjects who received three 
doses of the vaccine in the HPV-058 study
Sponsor signatory
Frank Struyf, M.D., Ph.D.,
Director, Clinical and Epidemiology R&D Project 
Lead, HPV and Hepatitis vaccines,
GlaxoSmithKline Biologicals SA.
Signature
Date
 
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Protocol 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’ study vaccine 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, 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.
 
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eTrack study number and 
Abbreviated Title
207347 (HPV-093 EXT 058)
Date of protocol
Final Version 1: 19 May 2017
Detailed Title
A phase III, open-label, mono-centre, follow-up 
extension study to evaluate the persistence of 
immune response to GSK Biologicals’ HPV vaccine 
in healthy Chinese female subjects who received 
three doses of the vaccine in the HPV-058 study
Investigator name
Signature
Date
 
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut 89
B-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 8.3.2.
 
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SYNOPSIS
Detailed Title
A phase III, open-label, mono-centre, follow-up extension 
study to evaluate the persistence of immune response to GSK 
Biologicals’ HPV vaccine in healthy Chinese female subjects 
who received three doses of the vaccine in the HPV-058 study
Indication
In China, Cervarix is approved for use in females 9 through 
25 years of age for the prevention of cervical cancer, cervical 
intraepithelial neoplasia grade 2, grade 3 (CIN 2/3) and 
adenocarcinoma in situ and cervical intraepithelial neoplasia 
grade 1 (CIN 1) caused by high risk human papillomavirus 
(HPV) types 16 and 18.
Rationale for the 
study and study 
design

Rationale for the study
In China, the burden of cervical cancer is most likely 
underestimated with over 61,000 new cases of cervical cancer 
being diagnosed annually, responsible for more than 29,000 
deaths [HPV Information Centre, 2016]. In the last decade, 
the mortality rates of cervical cancer have significantly 
slowed down, presumably due to the implementation of 
screening programs, development of cervical cancer 
treatments and prevention strategies like vaccination. 
However, the incidence of cervical cancer among younger 
women is increasing, and the mortality rates in rural China are 
still high [Yang, 2003; Shi, 2012]. HPV prophylactic 
vaccination would efficiently reduce the incidence of cervical 
cancer in China, where it is difficult to implement effective 
and regular screening programs due to the size of the 
population [Zhu, 2014a; Zhu, 2014b; Zhao, 2014].
The safety, immunogenicity and efficacy of the HPV-16/18 
vaccine were assessed in four clinical trials, involving over 
8000 Chinese females between 9 through 45 years of age 
[Zhu, 2011; Cervarix Product Information, 2016]. The HPV-
058 study was designed to evaluate the safety and 
immunogenicity of the HPV-16/18 vaccine in Chinese female 
subjects aged 9 through 17 years. Similarly, the HPV-039 
study was designed to assess the vaccine efficacy, 
immunogenicity and safety in healthy Chinese female subjects 
aged 18 through 25 years. The primary objective of the HPV-
058 study was to demonstrate the non inferiority of the 
immune response to the HPV-16/18 vaccine in subjects from 
the HPV-058 study compared to the immune response in 
subjects from the HPV-039 study, one month after the last 
dose.
 
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This extension study (HPV-093 EXT 058) is being conducted 
to evaluate the persistence of immune response in subjects 
who received the HPV-16/18 vaccine, seven to eight years 
after the last dose of primary vaccination in the HPV-058 
study. In addition, the study will describe the immune 
responses in subjects who received the HPV-16/18 vaccine in 
the HPV-058 study to the responses observed at a comparable 
time-point (Year 6) in subjects who belonged to the 
immunogenicity subset in the HPV-039 study.

Rationale for the study design
All subjects who received three doses of the HPV-16/18 
vaccine administered according to 0, 1 and 6 months schedule 
in the HPV-058 study will be invited to participate in this 
study. In order to assess the persistence of immune responses 
seven to eight years after the last vaccine dose against HPV-
16/18, a blood sample will be taken from all the subjects. 
The study will be open-label, uncontrolled and non-
randomised as no vaccine will be administered during the 
study. In order to fulfil international reporting obligations, 
serious adverse events (SAEs) that are related to study 
participation (i.e. protocol-mandated procedures) 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 is discharged from the study.
Objectives
Primary

To assess the immune response against HPV types 16 and 
18 [as determined by Enzyme Linked Immunosorbent 
Assay (ELISA)] seven to eight years after completion of 
the vaccination schedule in the HPV-058 study.
Secondary

To describe the immune response against HPV types 16 
and 18 (as determined by ELISA) observed seven to eight 
years after completion of the vaccination schedule in the 
HPV-058 study to the response observed (at Year 6) in 
subjects aged 18-25 years at vaccination in the HPV-039 
study.
Study design

Experimental design: Phase III, open-label, mono-
centric, single country study with a single group.

Duration of the study: One day

Epoch 001: starting at Visit 1 (Day 1) and ending at 
Visit 1 (Day 1)
 
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
Primary completion Date (PCD): Visit 1 (Day 1).

End of Study (EoS): Last testing results released for
samples collected at Visit 1.

Study group: The study group is as follows:

HPV group: Subjects from HPV-058 study who 
received all three doses of the HPV-16/18 vaccine 
will be eligible to take part in this extension study.
Synopsis Table 1
Study group and epoch foreseen in the study
Study group
Number of subjects
Age (Min/Max)
Epoch
Epoch 001
HPV group
Up to 369
17 years and above (i.e., 9-17 
years old at the time of first 
vaccination in HPV-058 study)
x

Control: none, i.e. uncontrolled.

Vaccination schedule and Treatment allocation: No 
vaccine will be administered in this extension study.

Blinding: Open-label
Synopsis Table 2
Blinding of study epoch
Study Epoch
Blinding
Epoch 001
open-label

Sampling schedule: One blood sample (approximately 5
ml) will be drawn from all subjects at the study visit 
(Visit 1) for HPV-16/18 antibody concentrations 
determination by ELISA.

Type of study: self-contained and extension of HPV-058 
study.

Data collection: electronic Case Report Form (eCRF).
Number of subjects
Up to 369 healthy Chinese female subjects of age 17 years 
and above at the time of enrolment are expected to participate 
in this extension study. Subjects from HPV-058 study who 
completed the vaccination schedule (0, 1 and 6 months) will 
be eligible to take part in this study.
Endpoints
Primary

Anti-HPV-16/18 seropositivity rates and antibody 
concentrations assessed by ELISA at Visit 1 (Day 1).
 
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Secondary

Anti-HPV-16/18 seropositivity rates and antibody 
concentrations assessed by ELISA at Visit 1 (Day 1) 
compared with anti-HPV-16/18 seropositivity rates and 
antibody concentrations at Year 6 in subjects from the 
immunogenicity subset in study HPV-039.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................6
SYNOPSIS......................................................................................................................7
LIST OF ABBREVIATIONS...........................................................................................16
GLOSSARY OF TERMS ...............................................................................................18
TRADEMARK................................................................................................................21
1.
INTRODUCTION....................................................................................................22
1.1.
Background ................................................................................................22
1.2.
Rationale for the study and study design ....................................................22
1.2.1.
Rationale for the study.................................................................22
1.2.2.
Rationale for the study design......................................................23
1.3.
Benefit : Risk Assessment ..........................................................................23
2.
OBJECTIVES.........................................................................................................23
2.1.
Primary objective ........................................................................................23
2.2.
Secondary objective ...................................................................................24
3.
STUDY DESIGN OVERVIEW ................................................................................24
4.
STUDY COHORT...................................................................................................25
4.1.
Number of subjects/centres ........................................................................25
4.2.
Inclusion criteria for enrolment....................................................................26
4.3.
Exclusion criteria for enrolment...................................................................26
5.
CONDUCT OF THE STUDY ..................................................................................27
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................27
5.2.
Subject identification and randomisation.....................................................28
5.2.1.
Subject identification....................................................................28
5.3.
Method of blinding ......................................................................................28
5.4.
General study aspects ................................................................................28
5.5.
Outline of study procedures ........................................................................29
5.6.
Detailed description of study procedures ....................................................29
5.6.1.
Informed consent and Informed assent........................................29
5.6.2.
Check inclusion and exclusion criteria .........................................29
5.6.3.
Collect demographic data ............................................................29
5.6.4.
Medical history.............................................................................30
5.6.5.
Compare subject information .......................................................30
5.6.6.
Study group and subject number allocation .................................30
5.6.7.
Sampling......................................................................................30
5.6.7.1.
Blood sampling for antibody determination.................30
5.6.8.
Check and record concomitant medication/vaccination................30
5.6.9.
Recording of SAEs ......................................................................30
5.6.10.
Study conclusion..........................................................................30
 
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5.7.
Biological sample handling and analysis.....................................................31
5.7.1.
Use of specified study materials ..................................................32
5.7.2.
Biological samples.......................................................................32
5.7.3.
Laboratory assays .......................................................................32
5.7.4.
Biological samples evaluation......................................................33
5.7.4.1.
Immunological read-outs ............................................33
5.7.5.
Immunological correlates of protection.........................................33
6.
STUDY VACCINE AND ADMINISTRATION...........................................................33
6.1.
Concomitant medications/products and concomitant vaccinations..............33
6.1.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................34
6.1.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses............34
7.
HEALTH ECONOMICS ..........................................................................................34
8.
SAFETY.................................................................................................................34
8.1.
Safety definitions ........................................................................................35
8.1.1.
Definition of an adverse event......................................................35
8.1.2.
Definition of a serious adverse event ...........................................36
8.1.3.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................37
8.2.
Detecting and recording serious adverse events.........................................37
8.2.1.
Time period for detecting and recording serious adverse 
events..........................................................................................37
8.2.2.
Post-Study serious adverse events..............................................37
8.2.3.
Evaluation of serious adverse events...........................................38
8.2.3.1.
Assessment of outcomes............................................38
8.3.
Reporting of serious adverse events...........................................................38
8.3.1.
Prompt reporting of serious adverse events.................................38
8.3.2.
Contact information for reporting serious adverse events ............39
8.3.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................39
8.3.3.1.
Back-up system in case the electronic 
reporting system does not work..................................39
8.3.4.
Updating of SAE information after removal of write access 
to the subject’s eCRF...................................................................40
8.3.5.
Regulatory reporting requirements for serious adverse 
events..........................................................................................40
8.4.
Follow-up of serious adverse events...........................................................40
8.4.1.
Follow-up of serious adverse events............................................40
8.4.1.1.
Follow-up during the study..........................................40
8.4.1.2.
Follow-up after the subject is discharged from 
the study.....................................................................40
8.5.
Treatment of serious adverse events..........................................................41
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................41
9.1.
Subject completion .....................................................................................41
9.2.
Subject withdrawal......................................................................................41
9.2.1.
Subject withdrawal from the study ...............................................41
 
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10. STATISTICAL METHODS......................................................................................42
10.1.
Primary endpoint.........................................................................................42
10.2.
Secondary endpoint....................................................................................42
10.3.
Determination of sample size......................................................................42
10.4.
Cohorts for Analyses ..................................................................................42
10.4.1.
Exposed Set ................................................................................42
10.4.2.
Per-protocol cohort for analysis of immunogenicity......................42
10.5.
Derived and transformed data.....................................................................43
10.6.
Analysis of demographics...........................................................................43
10.7.
Analysis of immunogenicity.........................................................................43
10.8.
Interpretation of analyses............................................................................43
10.9.
Conduct of analyses ...................................................................................44
10.9.1.
Sequence of analyses..................................................................44
10.9.2.
Statistical considerations for interim analyses..............................44
11. ADMINISTRATIVE MATTERS ...............................................................................44
11.1.
electronic Case Report Form instructions ...................................................44
11.2.
Study Monitoring by GSK Biologicals..........................................................45
11.3.
Record retention .........................................................................................45
11.4.
Quality assurance.......................................................................................46
11.5.
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................46
11.6.
Provision of study results to investigators ...................................................46
11.7.
Data Sharing...............................................................................................47
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................47
13. REFERENCES.......................................................................................................48
 
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LIST OF TABLES
PAGE
Table 1
Study group and epoch foreseen in the study ........................................25
Table 2
Blinding of study epoch ..........................................................................25
Table 3
List of study procedures .........................................................................29
Table 4
Biological samples .................................................................................32
Table 5
Humoral Immunity (Antibody determination)...........................................32
Table 6
Immunological read-outs.......................................................................33
Table 7
Reporting periods for collecting safety information .................................37
Table 8
Timeframes for submitting serious adverse events.................................38
Table 9
Outsourced laboratories.........................................................................51
 
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LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .......................................................................50
APPENDIX B CLINICAL LABORATORIES ..................................................................51
 
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LIST OF ABBREVIATIONS
AE
Adverse Event
ATP
According to Protocol
CI
Confidence Interval
CIN
Cervical Intraepithelial Neoplasia
eCRF
electronic Case Report Form
ELISA
Enzyme Linked Immunosorbent Assay
EoS
End of Study
ES
Exposed Set
GCP
Good Clinical Practice
GMC
Geometric Mean Concentration
GSK
GlaxoSmithKline
HPV
Human Papillomavirus 
ICF
Informed Consent Form
IAF
Informed Assent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LAR
Legally Acceptable Representative
LSLV
Last Subject Last Visit
MPL
3-O-desacyl-4’-monophosphoryl lipid A
NIFDC
National Institutes for Food and Drug Control
PCD
Primary Completion Date
PPS
Per Protocol Set
SAE
Serious Adverse Event
 
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SDV
Source Document Verification
SPM
Study Procedures Manual
VLP
Virus-like Particle
 
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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.
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 
open-label study, no blind is used. Both the investigator 
and the subject know the identity of the treatment 
assigned.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
End of Study 
(Synonym of End of 
Trial)
For studies without collection of human biologicals
samples or imaging data EoS is the Last Subject Last 
Visit (LSLV). 
For studies with collection of Human Biologicals 
Samples or imaging data, EoS is defined as the date of 
the last testing/reading released of the Human Biological 
Samples or imaging data, related to primary and 
secondary endpoints. EoS must be achieved no later than 
8 months after LSLV
Epoch:
An epoch is a set of consecutive time-points or a single 
time-point from a single protocol. Epochs are defined to 
support a main purpose which is either to draw 
conclusions on subject participation or to draw a 
complete conclusion to define or precise the targeted 
label of the product. Supporting means that data collected 
at the time-points included in an epoch must be sufficient 
to fulfil the purpose of the epoch.
 
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Typical examples of epochs are screening,
immunogenicity follow-ups, safety follow-up.
eTrack:
GSK’s tracking tool for clinical trials.
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.
Investigational 
vaccine/product:
(Synonym of 
Investigational Medicinal 
Product)
A pharmaceutical form of an active ingredient being 
tested 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 
authorised 
representative are used 
in some settings.)
An individual or juridical or other body authorised under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the clinical trial.
Primary completion 
date:
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for all primary outcomes, whether the clinical trial was 
concluded according to the pre-specified protocol or was 
terminated.
Protocol amendment:
The International Conference on Harmonisation (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, study design, or scientific 
integrity of the study.
Protocol administrative 
change:
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study.
Self-contained study:
Study with objectives not linked to the data of another 
study.
Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites.
 
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Study vaccine:
Any investigational vaccine being tested and/or any 
authorised use of a vaccine as a reference or administered 
concomitantly, in a clinical trial that evaluates the use of 
an investigational vaccine.
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 or as a control.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
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.
Treatment number:
A number identifying a treatment to a subject, according 
to treatment allocation.
 
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TRADEMARK
The following trademark is used in the present protocol.
Note: In the body of the protocol (including the synopsis), the name of the vaccine will 
be written without the superscript symbol ™ and in italics.
Trademark of the GlaxoSmithKline group 
of companies
Generic description
Cervarix™
Human papillomavirus vaccine types 16 and 
18 (recombinant, AS04-adjuvanted)
 
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1.
INTRODUCTION
1.1.
Background
Cervical cancer is the fourth most common cancer among women worldwide
[International Agency for Research on Cancer, 2012].A total of 4.5% of all cancers (with 
nearly 630,000 new cancer cases per year) are attributable to HPV [De Martel , 2017].
Infection with HPV has been clearly established as the central cause of cervical cancer 
[Walboomers, 1999]. Up to 71% of the cervical cancer cases are attributable to the high-
-risk HPV types (HR-HPV) 16 and 18 [de Sanjose, 2010]. Consequently, a vaccine which 
could prevent infection with HR-HPV types, or decrease their consequences, would be of 
great value.
GlaxoSmithKline (GSK) Biologicals has therefore developed a prophylactic HPV 
vaccine, Cervarix, based on L1 proteins of HPV-16 and HPV-18 formulated with AS04 
(comprising aluminium hydroxide [Al(OH)3] and 3-O-desacyl-4’-monophosphoryl lipid 
A [MPL]).
Cervarix was first licensed in Australia in May 2007 and in the European Union in 
September 2007. The vaccine is currently licensed in 136 countries and regions 
worldwide. In July 2016, Cervarix (hereafter referred to as the HPV-16/18 vaccine) was 
approved for use as a three-dose schedule at 0, 1, 6 months in females from 9 to 25 years 
in China.
To date, more than 60,000 adolescent and adult females aged nine years and above have 
received at least one dose of the HPV 16/18 vaccine in clinical studies. The vaccine is 
known to be immunogenic and generally well tolerated. Pooled safety analyses of girls 
and women aged nine years and above who received HPV vaccine have shown that the 
vaccine was generally well tolerated in women of all ages [Descamps, 2009; Angelo, 
2014].
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
In China, the burden of cervical cancer is most likely underestimated with over 61,000 
new cases of cervical cancer being diagnosed annually, responsible for more than 29,000 
deaths [HPV Information Centre, 2016]. In the last decade, the mortality rates of cervical 
cancer have significantly slowed down, presumably due to the implementation of 
screening programs, development of cervical cancer treatments and prevention strategies 
like vaccination. However, the incidence of cervical cancer among younger women is 
increasing, and the mortality rates in rural China are still high [Yang, 2003; Shi, 2012]. 
. HPV prophylactic vaccination would efficiently reduce the incidence of cervical cancer 
in China, where it is difficult to implement effective and regular screening programs due 
to the size of the population [Zhu, 2014a; Zhu, 2014b; Zhao, 2014].
 
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The safety, immunogenicity and efficacy of the HPV-16/18 vaccine were assessed in four 
clinical trials, involving over 8000 Chinese females between 9 through 45 years of age 
[Zhu, 2011; Cervarix Product Information, 2016]. The HPV-058 study was designed to 
evaluate the safety and immunogenicity of the HPV-16/18 vaccine in Chinese female 
subjects aged 9 through 17 years. Similarly, the HPV-039 study was designed to assess 
the vaccine efficacy, immunogenicity and safety in healthy Chinese female subjects aged 
18 through 25 years. The primary objective of the HPV-058 study was to demonstrate the 
non inferiority of the immune response to the HPV-16/18 vaccine in subjects from the 
HPV-058 study compared to the immune response in subjects from the HPV-039 study, 
one month after the last dose.
This extension study (HPV-093 EXT 058) is being conducted to evaluate the persistence 
of immune response in subjects who received the HPV-16/18 vaccine, seven to eight 
years after the last dose of primary vaccination in the HPV-058 study. In addition, the 
study will describe the immune responses in subjects who received the HPV-16/18 
vaccine in the HPV-058 study to the responses observed at a comparable time-point 
(Year 6) in subjects who belonged to the immunogenicity subset in the HPV-039 study.
1.2.2.
Rationale for the study design
All subjects who received three doses of the HPV-16/18 vaccine administered according 
to 0, 1 and 6 months schedule in the HPV-058 study will be invited to participate in this 
study. In order to assess the persistence of immune responses seven to eight years after 
the last vaccine dose against HPV-16/18, a blood sample will be taken from all the 
subjects. 
The study will be open-label, uncontrolled and non-randomised as no vaccine will be 
administered during the study. In order to fulfil international reporting obligations, 
serious adverse events (SAEs) that are related to study participation (i.e. protocol-
mandated procedures) 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 is discharged from the study.
1.3.
Benefit : Risk Assessment
Please refer to the Prescribing Information for information regarding the summary 
potential risks and benefits of HPV-16/18 vaccine.
2.
OBJECTIVES
2.1.
Primary objective

To assess the immune response against HPV types 16 and 18 [as determined by 
Enzyme Linked Immunosorbent Assay (ELISA)] seven to eight years after 
completion of the vaccination schedule in the HPV-058 study.
Refer to Section 10.1 for the definition of the primary endpoint.
 
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2.2.
Secondary objective

To describe the immune response against HPV types 16 and 18 (as determined by 
ELISA) observed seven to eight years after completion of the vaccination schedule 
in the HPV-058 study to the response observed (at Year 6) in subjects aged 18-25
years at vaccination in the HPV-039 study.
Refer to Section 10.2 for the definition of the secondary endpoint.
3.
STUDY DESIGN OVERVIEW
N = Number of subjects
BS = Blood sample
Protocol waivers or exemptions are not allowed unless necessary for the management 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 III, open-label, mono-centric, single country study with 
a single group.

Duration of the study: One day.

Epoch 001: starting at Visit 1 (Day 1) and ending at Visit 1 (Day 1).

Primary completion date (PCD): Visit 1 (Day 1).
Refer to glossary of terms for the definition of PCD.
 
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
End of study (EoS): Last testing results released for samples collected at Visit 1.
Refer to glossary of terms for the definition of EoS.

Study group: The study group is as follows:

HPV group: Subjects from HPV-058 study who received all three doses of the 
HPV-16/18 vaccine will be eligible to take part in this extension study.
The study group and epoch foreseen in the study are presented in Table 1
Table 1
Study group and epoch foreseen in the study
Study group
Number of subjects
Age (Min/Max)
Epoch
Epoch 001
HPV group
Up to 369
17 years and above (i.e., 9-17 years old at the 
time of first vaccination in HPV-058 study)
x

Control: none, i.e. uncontrolled.

Vaccination schedule and treatment allocation: No vaccine will be administered 
in this extension study.

Blinding: Open-label.
Table 2
Blinding of study epoch
Study Epoch
Blinding
Epoch 001 
Open-label

Sampling schedule: One blood sample (approximately 5 ml) will be drawn from all 
subjects at the study visit (Visit 1) for HPV-16/18 antibody concentrations 
determination by ELISA.

Type of study: self-contained and extension of HPV-058 study.

Data collection: electronic Case Report Form (eCRF).
4.
STUDY COHORT
4.1.
Number of subjects/centres
Up to 369 healthy Chinese female subjects of age 17 years and above at the time of 
enrolment are expected to participate in this extension study.
Overview of the recruitment plan

This study will be conducted in China.

The study will be monitored by the study monitor.

At the time of initiation of the extension study, the investigator will contact all
subjects from the HPV group who completed the primary vaccination study (HPV-
058). The reason for non-participation in the extension study will be documented in 
the site’s screening log.
 
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
Enrolment will be terminated when all eligible subjects either have been enrolled, or 
have refused participation or have been lost to follow-up. The reasons for subjects 
who have been lost to follow up will be documented.
4.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity, regulatory acceptability of the study or subject’s safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:

Subjects/subject’s parents/legally acceptable representative(s) [LAR(s)] who, in the 
opinion of the investigator, can and will comply with the requirements of the 
protocol.

Written informed consent obtained from the subject or subject’s parents/LAR(s) 
prior to performing any study specific procedure.

Written informed assent obtained from the subjects below the legal age of consent.

Subjects who received all three doses of the HPV-16/18 vaccine in the HPV-058 
study.

Healthy subjects as established by medical history and clinical examination before 
entering into the study.
4.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity, regulatory acceptability of the study 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:

Use of any investigational or non-registered product (drug or vaccine which may 
have an impact on the study objectives) during the period starting 30 days (Day 29 to 
Day 1) before the study visit.

Concurrently participating in another clinical study, in which the subject has been or 
will be exposed to an investigational or a non-investigational vaccine/product 
(pharmaceutical product or device).

Previous vaccination against HPV outside the HPV-058 study.

Subjects with contraindications related to blood draw such as blood disorders and 
anticoagulants use.
 
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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 GCP, all 
applicable subject privacy requirements and the guiding principles of the Declaration of 
Helsinki. 
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/ subject’s parent(s)/LAR(s) informed consent and subject informed assent, 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 informed consent must be obtained 
from each subject and/or each subject’s parent(s)/LAR(s) and subject informed assent , 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. 
In accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, 
those subjects who can only be enrolled in the study with the consent of the subject’s 
legally acceptable representative (e.g. minors), should be informed about the study to the 
extent compatible with the subject’s understanding and, if capable, the subject should 
sign and personally date a written informed assent form (IAF). It is required that the 
assent be signed by each subject, if capable, in addition to the informed consent that is to 
be signed by her legal representative. It should be assessed whether an assent is required 
depending of the age of the study population and the local requirements.
 
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GSK Biologicals strongly recommends that if the subject reaches the age of consent 
during the study they will be asked to provide consent at the next study visit (if 
applicable). This procedure should be applied according to local laws and regulations.
The investigator has the final responsibility for the final presentation of the ICF and IAF, 
respecting the mandatory requirements of local regulations. The ICF and IAF generated 
by the investigator with the assistance of the sponsor’s representative must be acceptable 
to GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
5.2.
Subject identification and randomisation
5.2.1.
Subject identification
The subject number will be aligned with the subject unique identification numbers of the 
parent study (HPV-058).
5.3.
Method of blinding 
This is an open-label study, and no vaccine will be administered during the study.
The laboratory in charge of the laboratory testing will not 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.
5.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying 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.
 
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5.5.
Outline of study procedures
The list of study procedures is presented in Table 3
Table 3
List of study procedures
Age
17 years and above
Epoch
Epoch 001
Type of contact
Visit 1
Time-point
Day 1
Sampling time-point
Day 1
Informed consent / Informed assent*
●
Check inclusion/exclusion criteria
●
Collect demographic data
●
Medical history including vaccination history
●
Compare the subject information between parent study (HPV-
058) and current study (HPV-093)
O
Subject number allocation
●
Laboratory Assays
Blood sampling for antibody determination (~5 mL)
●
Safety assessments
Record any concomitant medication/vaccination
●
Recording of SAEs related to study procedures or concomitant 
GSK medications/vaccine and events with a fatal outcomes
●
Study conclusion
●
● 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
* Written informed assent will be obtained from the subjects below the legal age of consent.
5.6.
Detailed description of study procedures
5.6.1.
Informed consent and Informed assent
The signed/witnessed/thumb printed informed consent of the subject/subject’s 
parent(s)/LAR(s) must be obtained before study participation. The signed informed 
assent of the subject below the age of consent (i.e. minor) should be obtained in addition 
to the signed informed consent by her parent(s)/LAR(s) according to local rules and 
regulations. Refer to Section 5.1 for the requirements on how to obtain informed consent 
and assent, as appropriate.
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 such as age and race in the subject’s eCRF.
 
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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 at the time of enrolment in the eCRF.
5.6.5.
Compare subject information
The subject information between the parent study (HPV-058) and the current study 
(HPV-093) will be compared in order to avoid collection of any inconsistent information.
5.6.6.
Study group and subject number allocation
Subject number allocation will be performed as described in Section 5.2.1 and aligned 
with the parent study (HPV-058).
5.6.7.
Sampling
Refer to the Module on Biospecimen Management in the Study Procedure Manual (SPM)
for detailed instructions for the collection, handling and processing of the samples.
5.6.7.1.
Blood sampling for antibody determination
Blood samples will be taken during Visit 1 (Day 1) as specified in Section 5.5.

A volume of at least approximately 5 mL of whole blood (to provide at least 1.8
mL of serum) should be drawn from all subjects for analysis of humoral immune 
response at Visit 1 (Day 1). After centrifugation, serum samples should be kept 
at –20°C/ –4°F or below until shipment. Refer to the SPM for more details on 
sample storage conditions.
5.6.8.
Check and record concomitant medication/vaccination
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.1.
5.6.9.
Recording of SAEs
Refer to Section 8.2 for procedures for the investigator to record SAEs. Refer to Section 
8.3 for guidelines and how to report SAE reports to GSK Biologicals.
5.6.10.
Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness

complete the Study Conclusion screen in the eCRF.
 
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5.7.
Biological sample handling and analysis
Please refer to the SPM for 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, 
all subjects 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 China 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/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.
 
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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 per-protocol 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.
5.7.2.
Biological samples
The type and quantity of biological samples that will be collected for analysis has been 
provided in Table 4.
Table 4
Biological samples
Sample type
Quantity
Unit
Time-point
Blood
At least 5
mL
Visit 1 (Day 1)
5.7.3.
Laboratory assays
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the address of the clinical laboratories used for 
sample analysis.
One aliquot will be prepared for all serological samples, which will then be shipped to the 
National Institutes for Food and Drug Control (NIFDC) in China. The NIFDC will 
perform all serological assays.
Table 5 presents the laboratory assays for humoral immunity (antibody determination).
Table 5
Humoral Immunity (Antibody determination)
System
Component
Method
Kit / 
Manufacturer
Unit*
Cut-off*
Laboratory
Serum
Human Papilloma Virus 
Genotype 16.Virus Like 
Particle Ab.IgG
ELI**
NA
EU/ml
19
NIFDC***
Human Papilloma Virus 
Genotype 18.Virus Like 
Particle Ab.IgG
18
*Assay cut-off and unit might be subject to change during the course of the study (e.g. in case of requalification, 
revalidation or standardisation). In this case, this will be documented in the clinical report.
**ELI: GSK validated Enzyme Linked Immuno Sorbent Assay (ELISA).
***NIFDC: National Institutes for Food and Drug Control, China.
 
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Additional exploratory testing on the vaccine and/or on the disease under study may be 
performed within the framework of the study if deemed necessary for accurate 
interpretation of the data or should such assay(s) become available at GSK. These assays 
may not be represented in the objectives/endpoints of the study protocol.
5.7.4.
Biological samples evaluation
5.7.4.1.
Immunological read-outs
The immunological read-outs are presented in Table 6.
Table 6
Immunological read-outs
Blood sampling time-point
No. subjects
Component
Components
priority rank
Type of contact and time-
point
Sampling time-
point
Visit 1 (Day 1)
Day 1
All
anti-HPV-16
1
anti-HPV-18
2
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analysed according to priority ranking provided in Table 6.
5.7.5.
Immunological correlates of protection
There are currently no correlates of protection defined for the HPV-16 and HPV-18 
antigens used as part of the HPV-16/18 vaccine.
6.
STUDY VACCINE AND ADMINISTRATION
No vaccine will be administered in this extension study. The HPV-16/18 vaccine was 
administered as a three dose schedule in the primary vaccination study HPV-058.
Please refer to the HPV-058 study protocol for a detailed description of the study vaccine 
and administration.
6.1.
Concomitant medications/products and concomitant 
vaccinations
At each study visit, the investigator or delegate should question the subject and/or the 
subject’s parent(s)/LAR(s) about any medications/products taken and vaccinations
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6.1.1.
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 during the period starting 30 days before the study visit.

Any concomitant vaccination administered in the period starting 30 days before the 
study visit.

Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature 37.0°C regardless the location of measurement per local guidance]. 
The preferred location for measuring temperature in this study will be the axilla.

Any concomitant medications/products/vaccines relevant to a SAE to be reported as 
per protocol or administered for the treatment of a SAE. In addition, concomitant 
medications relevant to SAEs need to be recorded on the expedited Adverse Event 
report.
6.1.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol 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 
per-protocol analysis.

Drug and/or alcohol abuse.
7.
HEALTH ECONOMICS
Not applicable.
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 SAE as 
provided in this protocol. 
Each subject/subject’s parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should they/the subject manifest any signs or symptoms they perceive as 
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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:

Significant or unexpected worsening or exacerbation of the condition/indication 
under study.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study vaccine administration even 
though they may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
vaccine or a concurrent medication (overdose per se should not be reported as an 
AE/SAE).

Signs, symptoms temporally associated with study vaccine(s) 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).
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. 

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
study vaccination. These events will be recorded in the medical history section of the 
eCRF.
 
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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.
 
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8.1.3.
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 (e.g. ECGs, X-rays, vital signs, 
etc) that are judged by the investigator to be clinically significant will be recorded as AE 
or SAE 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.
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.
8.2.
Detecting and recording serious adverse events
8.2.1.
Time period for detecting and recording serious adverse events
The time period for collecting and recording SAEs will begin and end at Visit 1 (Day1) 
for each subject. See Section 8.3 for instructions on reporting of 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 is discharged from the study.
An overview of the protocol-required reporting periods for SAEs is given in Table 7.
Table 7
Reporting periods for collecting safety information
Event
V1
D1
SAEs related to study participation or 
concurrent GSK medication/vaccine and 
events with a fatal outcome
V1: Visit 1, D1: Day 1.
8.2.2.
Post-Study serious adverse events
A post-study SAE is defined as any event that occurs outside of the SAE reporting period 
defined in Table 7. Investigators are not obligated to actively seek SAEs 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 she considers the event reasonably related to the 
study vaccine, the investigator will promptly notify the Study Contact for Reporting 
SAEs.
 
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8.2.3.
Evaluation of serious adverse events
When a SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding a SAE 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 SAE and not the individual signs/symptoms.
8.2.3.1.
Assessment of outcomes
The investigator will assess the outcome of all SAEs recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
8.3.
Reporting of serious adverse events
8.3.1.
Prompt reporting of serious adverse events
SAEs that occur in the time period defined in Section 8.2, and considered related to study 
participation or concurrent GSK medication/vaccine, will be reported promptly to GSK 
within the timeframes described in Table 8, once the investigator determines that the 
event meets the protocol definition of a SAE.
Table 8
Timeframes for submitting serious adverse events
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
* Timeframe allowed after receipt or awareness of the information.
‡ The investigator will be required to confirm 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.
 
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8.3.2.
Contact information for reporting serious adverse events
Study Contact for Reporting SAEs
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Outside US & Canada sites:
Fax: +
 or +
Email address: 
8.3.3.
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.
8.3.3.1.
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. 
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8.3.4.
Updating of SAE information after removal of write access to the 
subject’s eCRF
When additional SAE 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 8.
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 8.3.1. 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 study 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 serious adverse events
8.4.1.
Follow-up of serious adverse events 
8.4.1.1.
Follow-up during the study
After the initial SAE 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 SAEs; refer to Table 8).
8.4.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:

with SAEs, until the event has resolved, 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, 
he/she will provide this information to GSK Biologicals using a electronic Expedited 
Adverse Events Report.
 
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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 SAE. 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 serious adverse events
Treatment of any SAE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of a SAE should 
be recorded in Expedited Adverse Event Report of the subject’s eCRF (refer to Section 
6.1).
9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject completion
A subject who 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 
signs the consent form but refuses blood sampling and hence withdraws from the study. 
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 herself, 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.

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 she/the subject’s 
parent(s)/LAR(s) has 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.
 
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Subjects who are withdrawn from the study because of SAEs 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 a SAE until resolution of 
the event (see Section 8.4.1.2).
10.
STATISTICAL METHODS
10.1.
Primary endpoint

Anti-HPV-16/18 seropositivity rates and antibody concentrations assessed by ELISA 
at Visit 1 (Day 1).
10.2.
Secondary endpoint

Anti-HPV-16/18 seropositivity rates and antibody concentrations assessed by ELISA 
at Visit 1 (Day 1) compared with anti-HPV-16/18 seropositivity rates and antibody 
concentrations at Year 6 in subjects from the immunogenicity subset in study HPV-
039.
10.3.
Determination of sample size
No sample size is calculated for this study. Up to 369 healthy Chinese female subjects of 
age 17 years and above at the time of enrolment are expected to participate in this 
extension study. Subjects from HPV-058 study who completed the vaccination schedule 
(0, 1 and 6 months) will be eligible to take part in this study.
10.4.
Cohorts for Analyses
10.4.1.
Exposed Set

The Exposed Set (ES) will include all subjects who participate in this study, and

Analysis of immunogenicity on this cohort will include subjects for whom serology 
results are available.
10.4.2.
Per-protocol cohort for analysis of immunogenicity
The Per-Protocol Set (PPS) for analysis of immunogenicity will include all evaluable 
subjects who were included in the according to protocol (ATP) immunogenicity analysis 
in the primary vaccination study (HPV-058), met all eligibility criteria, complied with the 
procedures defined in the protocol, with no elimination criteria during the study, and with
serology results available at this blood sampling time-point.
 
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10.5.
Derived and transformed data

The cut-off value of anti-HPV-16/18 antibodies is defined by the laboratory before 
the analysis.

A seronegative subject is a subject whose antibody concentration is below the cut-off 
value.

A seropositive subject is a subject whose antibody concentration is greater than or 
equal to the cut-off value.

The Geometric Mean Concentration (GMC) calculations are performed by taking the 
anti-log of the mean of the log concentration transformations. Antibody 
concentrations below the cut-off of the assay will be given an arbitrary value of half 
the cut-off for the purpose of GMC calculation.

For a given subject and a given immunogenicity measurement, missing or non-
evaluable measurements will not be replaced. Therefore, an analysis will exclude 
subjects with missing or non-evaluable measurements
10.6.
Analysis of demographics

Demographic characteristics (age and race) of each study cohort will be tabulated.

The mean age (plus range and standard deviation) of the enrolled subjects, will be 
calculated.
10.7.
Analysis of immunogenicity
The primary analysis will be based on the PPS for analysis of immunogenicity.

For all subjects, for whom blood sample results are available:

Seropositivity rates with exact 95% confidence interval (CI) will be calculated 
for anti-HPV-16 and anti-HPV-18 antibodies.

GMCs (with 95% CI and range) will be tabulated for anti-HPV-16 and anti-
HPV-18 antibodies.

The distribution of antibody concentrations for anti-HPV-16 and anti-HPV-18 will 
be displayed using reverse cumulative curves.

An analysis of the anti-HPV-16 and anti-HPV-18 seropositivity rates and antibody
concentrations at Year 6 in subjects from the HPV-039 study and blood sampling 
time-point of this study will be presented.
10.8.
Interpretation of analyses
All analyses will be descriptive with the aim to assess the persistence of anti-HPV-16/18 
antibodies.
 
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10.9.
Conduct of analyses
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.
10.9.1.
Sequence of analyses
The analysis of all immunogenicity data collected in the study will be conducted. 
An integrated clinical study report containing all data will be written and made available 
to the investigators.
10.9.2.
Statistical considerations for interim analyses
All analyses will be conducted on final data and therefore no statistical adjustment for 
interim analyses is required.
11.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality, public disclosure requirements 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.
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 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.
 
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11.2.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst other items, 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 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 eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the investigator’s study file. Any data item for which 
the eCRF will serve as the source must be identified, agreed and documented in the 
source documentation agreement form. 
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 
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.
 
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GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by ICH GCP, any 
institutional requirements, applicable laws or regulations, or GSK standards/procedures, 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report.
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
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations.
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in compliance 
with the current regulations. The minimal requirement is to have primary endpoint 
summary results disclosed at latest 12 months post primary completion date (PCD) and to 
have secondary endpoint disclosed at latest 12 months after the last subject last visit 
(LSLV) as described in the protocol.
GSK also aims to publish the results of these studies in searchable, peer reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors.
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.
 
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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.
11.7.
Data Sharing
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non- GSK studies, to investigate further about the study product(s) and other 
product(s), and /or the disease/condition under investigation and related diseases and 
conditions.
12.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
 
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13.
REFERENCES
Angelo MG, David MP, Zima J et al. Pooled analysis of large and long term safety data 
from the human papillomavirus-16/18-AS04-adjuvanted vaccine clinical trial 
programme. Pharmacoepidemiol Drug Saf. 2014; 23(5):466-79.
De Martel Catherine, Martyn Plummer, Jerome Vignat, Silvia Franceschi. Worldwide 
burden of  cancer attributable to HPV by site, country and HPV type. International 
Journal of Cancer, April 2017. 10.1002/ijc.30716
Cervarix Product Information, China. July, 2016.
de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution 
in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet 
Oncol. 2010;11:1048-56.
Descamps D, Hardt K, Spiessens B, et al. Safety of human papillomavirus (HPV)-16/18 
AS04-adjuvanted vaccine for cervical cancer prevention: A pooled analysis of 11 clinical 
trials. Hum Vaccin. 2009; 5: 332-340.
HPV Information Centre, China: Human Papillomavirus and Related Cancers, Fact Sheet 
2016. Available at: www.hpvcentre.net/statistics/reports/CHN_FS.pdf. Accessed on: 19 
May 2017 .
International Agency for Research on Cancer (IARC) Cervical Cancer: Estimated 
Incidence, Mortality and Prevalence Worldwide in 2012. Available at: 
http://globocan.iarc.fr/old/FactSheets/cancers/cervix-new.asp. Accessed on: 19 May 
2017.
Shi JF, Canfell K, Lew JB et al. The burden of cervical cancer in China: synthesis of the 
evidence. Int J Cancer.2012; 130: 641-52.
Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary 
cause of invasive cervical cancer worldwide. J Pathol. 1999; 189:12-19.
Yang L HX, Zhang SW. Changes of mortality rate for cervical cancer during 1970s and 
1990s periods in China. Acta Acad Med Sin. 2003; 25: 386-90.
Zhao F, Zhu F, Chen W, et al. Baseline prevelance and type distribution of human 
papillomavirus in healthy Chinese women aged 18-25 years enrolled in a clinical trial. Int 
J Cancer. 2014; 135, 2604-11.
Zhu FC, Li CG, Bi D, et al. Safety and immunogenicity of human papillomavirus-16/18 
AS04-adjuvanted vaccine in healthy Chinese females aged 15 to 45 years: a phase I trial. 
Chin J Cancer. 2011; 30(8): 559-64.
Zhu F, Li J, Hu Y et al. Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted 
vaccine in healthy Chinese girls and women aged 9 to 45 years: Results from 2 
randomised controlled trials. Hum Vaccin Immunother. 2014(a);10 (7), 1795-1806.
 
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Zhu FC, Chen W, Hu YM et al. Efficacy, immunogenicity and safety of the HPV-16/18 
AS04-adjuvanted vaccine in healthy Chinese women aged 18-25 years: Results from a 
randomised controlled trial. Int J Cancer. 2014(b); 135(11), 2612-22.
 
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APPENDIX A
LABORATORY ASSAYS
Anti-HPV-16 and anti-HPV-18 enzyme-linked immunosorbent assay (ELISA)
Antibody responses against HPV-16 and HPV-18 VLPs will be quantified by ELISA. 
These immunoassays are based on the direct test principle. Purified VLPs from Cervarix
are coated onto a 96-well microtitration plate. After a washing and saturation step, serial 
dilutions of sera, control sera and standards are distributed and incubated in the coated 
wells to allow the specific antibody present in the sample to react with the corresponding 
antigen. Non-specific reactants are removed by washing, and a peroxidase-conjugated 
anti human IgG polyclonal antibody is added to react with the specific antibody. Excess 
conjugate is removed by washing. Enzyme substrate and chromogen are added and the 
colour is allowed to develop. After adding the Stop Reagent, the resultant colour change 
is quantified and expressed in EU/mL. The intensity of the resultant yellow colour is 
directly proportional to the concentration of anti-VLP antibodies present in the sample.
Titres are calculated by reference to a standard serum using the 4-parameters equation for 
each serum dilution, and the final titre of a serum is the average of all titres falling in the 
proportional part of the reference curve. The cut-off of the assay for HPV-16 is 19 ELISA 
units per millilitre (EU/mL) and for HPV-18 is 18 EU/mL.
 
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APPENDIX B
CLINICAL LABORATORIES
Table 9
Outsourced laboratories
Laboratory
Address
National Institute for Food and Drug 
Control (NIFDC), China.
No 2 Tiantan Xili,
Beijing, 100050,
China.
 
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PPD