Safety and Protective Effect Study of GSK Biologicals' Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed (GSK580299) in Healthy Female Subjects From the HPV-039 Study
Phase: PHASE4
Conditions: Cervical Intraepithelial Neoplasia
Sponsor: GlaxoSmithKline

CONFIDENTIAL
21-JUN-2018
1
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 (Types 16, 18) Vaccine, Adsorbed
(GSK580299)
eTrack study number and 
Abbreviated Title
205779 (HPV-092 EXT 039)
Date of protocol
Final: 31 March 2017
Date of protocol amendment
Amendment 1 Final: 21 June 2018
Title (Amended: 21 Jun
2018)
Safety and protective effect study of GSK Biologicals’ 
Human Papillomavirus (Types 16, 18) Vaccine,
Adsorbed (GSK580299) in healthy female subjects from 
the HPV-039 study.
Detailed Title (Amended: 21 
Jun 2018)
A phase III/IV open-label, multi-centre study to 
evaluate the safety of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed, 
administered intramuscularly according to a 
0,1,6-month schedule, in healthy Chinese female 
subjects above 26 years of age who received the control 
vaccine in study HPV-039 and to evaluate the 
protective effect of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed, up 
to approximately 10 years after vaccination, in 
reducing HPV-associated cervical infection in subjects 
who participated in the HPV-039 study.
Co-ordinating author
, Scientific Writer
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
1
21-JUN-2018
PPD

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
2
eTrack study number and 
Abbreviated Title
205779 (HPV-092 EXT 039)
Detailed Title (Amended: 21 
Jun 2018)
A phase III/IV open-label, multi-centre study to 
evaluate the safety of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed, 
administered intramuscularly according to a 
0,1,6-month schedule, in healthy Chinese female 
subjects above 26 years of age who received the control 
vaccine in study HPV-039 and to evaluate the 
protective effect of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed, up 
to approximately 10 years after vaccination, in 
reducing HPV-associated cervical infection in subjects 
who participated in the HPV-039 study.
Contributing authors
(Amended: 21 Jun 2018)

, Clinical and 
Epidemiology R&D Project Leads

 
, Clinical Research and Development Leads

, Associate Scientist, Research 
and Development

, Project Statistician

, Lead Statistician

, Study Delivery 
Leads

 
, Clinical Safety representatives

, Study Data Manager

, Oversight Data Manager

, Global Patents representative

, Clinical Trial Supply Manager

, Clinical Read-out Team Leader

, CLS Study Manager

,
Regulatory Affairs representatives

, Local Delivery Lead, China
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
2
21-JUN-2018
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
3
eTrack study number and 
Abbreviated Title
205779 (HPV-092 EXT 039)
Detailed Title (Amended: 21 
Jun 2018)
A phase III/IV open-label, multi-centre study to 
evaluate the safety of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed,
administered intramuscularly according to a 
0,1,6-month schedule, in healthy Chinese female 
subjects above 26 years of age who received the control 
vaccine in study HPV-039 and to evaluate the 
protective effect of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed, up 
to approximately 10 years after vaccination, in 
reducing HPV-associated cervical infection in subjects 
who participated in the HPV-039 study.
Contributing authors 
(continued) (Amended: 21 
Jun 2018)

, Local Medical Lead, China

, Head of Clinical Research and 
Development, China/Hong Kong

, Regulatory Affairs, 
China

, Local Delivery Lead, China
GSK Biologicals’ Protocol DS v 15.0
© [2017-2018] GSK group of companies or its licensor.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
3
21-JUN-2018
PPD
PPD
PPD
PPD

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
4
Protocol Amendment 1 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
205779 (HPV-092 EXT 039)
Date of protocol
Amendment 1 Final: 21 June 2018
Detailed Title (Amended: 21 
Jun 2018)
A phase III/IV open-label, multi-centre study to 
evaluate the safety of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed,
administered intramuscularly according to a 
0,1,6-month schedule, in healthy Chinese female 
subjects above 26 years of age who received the 
control vaccine in study HPV-039 and to evaluate the 
protective effect of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed, up 
to approximately 10 years after vaccination, in 
reducing HPV-associated cervical infection in 
subjects who participated in the HPV-039 study.
Sponsor signatory
Dorota Borys, M.D., 
Director, Clinical and Epidemiology R&D Project 
Lead, HPV, Hepatitis and Pneumococcal vaccines,
GlaxoSmithKline Biologicals SA.
Signature
Date
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
4
21-JUN-2018
- ----------------Checksum----------------!Ver.!Created On -   -
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6 5.0 6/28/2018 3:49:08 PM -   -
---------------------------------------------------------------------------- -
For internal use only

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
5
Protocol Amendment 1 Rationale
Amendment number:
Amendment 1
Rationale/background for changes: The protocol has been amended to support the 
post-licensure commitment to the Center for Drug Evaluation (CDE) of National Drug 
Administration of China (CNDA) with regard to the assessment of long term protective 
effect of GSK Biologicals’ HPV vaccine, Adsorbed in subjects who participated in the 
HPV-039 study. To address this, the following changes have been made:

The study design has been modified to include the HPV-vaccinated subjects from the 
HPV-039 study. The number of subjects for the study has been updated from up to 
3025 to up to 6051.

Assessment of rates of HPV-16/18 incident infection up to approximately 10 years
after vaccination in the study HPV-039 has been added as a secondary objective.
Long term efficacy against virological, cytological, histopathological endpoints will 
be assessed as a tertiary objective.

Procedures namely; gynaecological examination, cervical sampling, follow-up 
colposcopy and biopsy in subjects with abnormal cytology have been added at Visit 
1.

The assay section has been updated to include testing related to cervical samples and 
biopsy.

The statistical section has been updated to describe “Analysis of long term protective
effect” on HPV infection.

Additionally, regulatory approval of Gardasil and Gardasil 9 and approval of 
Cervarix age indication extension up to 45 years in China has been mentioned.

Owing to the extension of age indication of Cervarix up to 45 years, it is specified in 
the protocol that subjects also have the opportunity to receive Cervarix free of charge
outside of the current study, when commercially available.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
5
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
6
Protocol Amendment 1 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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
6
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
7
eTrack study number and 
Abbreviated Title
205779 (HPV-092 EXT 039)
Date of protocol
Amendment 1 Final: 21 June 2018
Detailed Title (Amended: 21 
Jun 2018)
A phase III/IV open-label, multi-centre study to 
evaluate the safety of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed,
administered intramuscularly according to a 
0,1,6-month schedule, in healthy Chinese female 
subjects above 26 years of age who received the 
control vaccine in study HPV-039 and to evaluate the 
protective effect of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed, up 
to approximately 10 years after vaccination, in 
reducing HPV-associated cervical infection in 
subjects who participated in the HPV-039 study.
Investigator name
Signature
Date
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
7
21-JUN-2018
- ----------------Checksum----------------!Ver.!Created On -   -
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6 5.0 6/28/2018 3:49:08 PM -   -
---------------------------------------------------------------------------- -
For internal use only

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
8
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 8.4.2.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
8
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
9
SYNOPSIS
Detailed Title
(Amended: 21 Jun
2018)
A phase III/IV open-label, multi-centre study to evaluate the 
safety of GSK Biologicals’ Human Papillomavirus (Types 16, 
18) Vaccine, Adsorbed, administered intramuscularly according 
to a 0,1,6-month schedule, in healthy Chinese female subjects 
above 26 years of age who received the control vaccine in 
study HPV-039 and to evaluate the protective effect of GSK 
Biologicals’ Human Papillomavirus (Types 16, 18) Vaccine, 
Adsorbed, up to approximately 10 years after vaccination, in 
reducing HPV-associated cervical infection in subjects who 
participated in the HPV-039 study.
Indication
(Amended: 21 Jun
2018)
Cervarix is approved for use in females 9 through 45 years of 
age for the prevention of cervical cancer, cervical intraepithelial 
neoplasia grade 2, grade 3 (CIN 2/3) and adenocarcinoma in 
situ (AIS) and cervical intraepithelial neoplasia grade 1 (CIN1) 
caused by high risk human papillomavirus (HPV) types 16 and 
18.
Rationale for the 
study and study 
design (Amended: 21 
Jun 2018)

Rationale for the study
The burden of cervical cancer in China is most likely 
underestimated. In China, over 61,000 new cases of cervical 
cancer are diagnosed annually, responsible for more than 
29,000 deaths [HPV Information Centre, 2016]. A meta-
analysis of 18 studies on the distribution of HPV types in 
cervical lesions estimated the proportional impact of HPV-16 
and HPV-18 on invasive cervical cancer to be as high as 69.6% 
in Chinese women [Bao, 2007]. A recent assessment in Chinese 
women revealed high-risk (HR)-HPV infection prevalence of 
21.07%, where infection with the HPV-16 sub-type was the 
most common (4.82%) [Wang, 2015]. Prophylactic vaccination 
with a HPV vaccine would efficiently reduce the incidence of 
cervical cancer and may be particularly useful 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 GSK 
Biologicals’ Human Papillomavirus (Types 16, 18) Vaccine, 
Adsorbed were assessed in a total of four clinical trials, 
involving over 8000 Chinese females between 9 and 45 years of 
age, of whom over 4000 subjects received the vaccine [Zhu, 
2011; Cervarix Product Information, 2016]. The results of the 
phase II/III efficacy study (HPV-039) showed high and 
sustained vaccine efficacy against all virological, cytological 
and histopathological efficacy endpoints associated with HPV-
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
9
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
10
16/18. There was no sign of waning efficacy at the end of the 
study (up to Month 72). The Human Papillomavirus (Types 
16, 18) Vaccine, Adsorbed was generally well tolerated in 
Chinese women aged 18-25 years [GlaxoSmithKline 
Biologicals Clinical Report 107638 (HPV-039)].
This study has been designed following ethical considerations, 
to enable all subjects who received placebo in the HPV-039 
study, to also receive GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed. Safety data 
in terms of serious adverse events (SAEs), any adverse events 
(AEs)/SAEs leading to premature discontinuation of the study, 
potential immune mediated diseases (pIMDs) and pregnancies 
(and their outcomes) will be collected during the study period. 
In addition, this study aims to assess the long term protective 
effect of the vaccine, in an exploratory manner, in terms of 
rates of HPV-related (vaccine type) incident cervical infection
(secondary objective), cytological abnormalities and CIN2+ 
lesions (tertiary objective)up to approximately 10 years after 
vaccination in subjects who participated in HPV-039 study, to 
support the post-licensure commitments to the Center for 
Drug Evaluation (CDE) of National Drug Administration of 
China (CNDA).
At the availability of the commercial vaccine for use in 
individuals above 25 years, subjects will be offered the 
opportunity to receive Cervarix free of charge either by 
participating to this study or without participating to this 
study.

Rationale for the study design
This study will be conducted in an open-label and 
non-randomised manner, since the subjects who had 
participated in study HPV-039 already know the treatment 
they received and only those in the control group will receive 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed in 
the current study. Safety data will be collected from Dose 1 
until the end of the study in subjects vaccinated in this study. 
Cervical samples will be collected at Visit 1 from all subjects
to test for HPV incident infection and cytological 
abnormalities. Subjects with abnormal cytology will be called 
back for colposcopy follow-up and biopsy to examine for the 
presence of CIN lesions.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
10
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
11
Limitations: 
In the HPV-039 study, the efficacy of GSK Biologicals’ 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed 
against virological, cytological and histopathological 
endpoints associated with HPV types 16 and 18, was 
demonstrated up to 6 years after vaccination and subjects 
were screened every 6 months. The study was unblinded after 
completion and since the Year 6, 3-4 years have elapsed with 
no regular follow-up of the subjects. As a consequence, at 
Year 10, there might be high subject attrition, leading to a 
potential imbalance in the numbers of subjects from the 
vaccinated versus control group returning for the current 
study. This as well as a lack of regular gynaecological follow-
up between Year 6 and Year 10 may compromise assessments 
of vaccine efficacy in this study. Therefore, vaccine efficacy 
analyses will be exploratory.
Objectives
(Amended: 21 Jun
2018)
Primary objective:

To assess the safety of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed in 
subjects above 26 years of age, who previously received 
placebo in the HPV-039 study, in terms of related SAEs.
Secondary objectives:

To assess the safety of GSK Biologicals Human 
Papillomavirus (Types 16, 18) Vaccine in terms of 
occurrence of unsolicited AEs in subjects above 26 years 
of age, who previously received placebo in the HPV-039 
study.

To assess the protective effect of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed in all 
subjects who participated in the HPV-039 study in terms 
of the rates of HPV 16/18 incident infection up to 
approximately 10 years after vaccination.

To assess the protective effect of GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed in all 
subjects who participated in the HPV-039 study in terms 
of the rates of incident infection associated with any or 
combination of oncogenic HPV types, up to approximately 
10 years after vaccination.
Tertiary objectives:

To assess the long term efficacy of GSK Biologicals’ 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed 
in the prevention of incident infection associated with 
HPV-16 and/or HPV-18 or with any or combination of 
oncogenic HPV types.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
11
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
12

To assess the long term efficacy of GSK Biologicals’ 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed 
in the prevention of cytological abnormalities associated 
with HPV-16 and/or HPV-18.

To assess the long term efficacy of GSK Biologicals’ 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed 
in the prevention of cytological abnormalities associated 
with any or combination of oncogenic HPV types.

To assess the long term efficacy of the GSK Biologicals’ 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed 
in the prevention of histopathologically-confirmed CIN1+ 
associated with HPV-16 and/or HPV-18.

To assess the long term efficacy of the GSK Biologicals’ 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed 
in the prevention of histopathologically-confirmed CIN1+ 
associated with any or combination of oncogenic HPV 
types.

To assess the long term efficacy of the GSK Biologicals’ 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed 
in the prevention of histopathologically-confirmed CIN2+ 
associated with HPV-16 and/or HPV-18.

To assess the long term efficacy of the GSK Biologicals’ 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed 
in the prevention of histopathologically-confirmed CIN2+ 
associated with any or combination of oncogenic HPV 
types.

To assess the long term efficacy of the GSK Biologicals’ 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed 
in the prevention of other histopathologically-confirmed 
endpoints associated with HPV-16 and/or HPV-18 or any 
or combination of oncogenic HPV types.
Study design 
(Amended: 21 Jun
2018)

Experimental design: Phase III/IV, open-label, 
partially-controlled, multi-centric, single-country study 
with two parallel groups.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
12
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
13

Duration of the study:
Subjects who previously received HPV vaccination in 
study HPV-039 (Vacc-HPV-039 group)*:

The study duration is one day (Visit 1) i.e., when a 
subject comes for cervical sample collection.
Subjects who previously received the control vaccine in 
study HPV-039 and will receive HPV vaccination in this 
study (HPV Group)*:

Approximately 12 months per subject (approximately 
6 months for 3-dose vaccination followed by 6-month 
extended safety follow-up after last dose).
o
Epoch 001: starting at Visit 1 (Day 1) and ending 
at Call 2 (Month 12)
*Subjects who have abnormal cytology findings in the 
cervical sample collected at Visit 1 will be called back for 
a follow-up visit for colposcopy examination and biopsy 
(when needed).

Primary completion Date (PCD): Call 2 (Month 12)

End of Study (EoS): Last subject’s last visit/contact (Call 2 
[Month 12]) or last testing results released for samples 
collected at Visit 1 and related call-back visit, whatever 
comes later.

Study groups: Two groups

Vacc-HPV-039 group i.e. subjects who received HPV 
vaccine in HPV-039 study who will undergo cervical 
sample collection only.

HPV group (Ctrl-HPV-039 group) i.e. subjects who 
received control vaccine in HPV-039 study will 
receive HPV vaccine in the current study and 
undergo cervical sample collection before HPV 
vaccination..
Synopsis Table 1
Study groups and epoch foreseen in the study
Study Groups
Number of subjects
Age
Epoch
Epoch 001
Vacc-HPV-039
group
Up to 3026
From 26 years
x
HPV group
Up to 3025
From 26 years
x
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
13
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
14
Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment 
name
Vaccine name
Study Groups
Vacc-HPV-039 group
HPV group
HPV-16/18
Human Papillomavirus (Types 16, 18) 
Vaccine, Adsorbed (HPV16-18 AS04D)
No treatment
x

Control: none for safety objectives; HPV group (Ctrl-HPV-039 
group) for long term protective effect objectives.

Vaccination schedule: Three doses of Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed (20 µg HPV-16, 20 µg 
HPV-18) administered intramuscularly according to a 0, 1, 
6-month schedule.

Treatment allocation: Treatment allocation depends on the 
randomization in the previous study i.e. only the subjects from
the control group of HPV-039 study will receive HPV 
vaccination in the current study. Subjects who previously 
received the Human Papillomavirus (Types 16, 18) Vaccine, 
Adsorbed in HPV-039 study will not receive vaccination in this 
study.

Blinding: open-label
Synopsis Table 3
Blinding of study epoch
Study Epoch
Blinding
Epoch 001
open-label

Sampling schedule: A cervical sample will be taken at Visit 1
before vaccine administration.
For subjects who have abnormal cytology findings in the 
cervical sample collected at Visit 1, there will be a call-back 
follow-up visit for colposcopy examination. A cervical biopsy 
will be taken depending on the results of the colposcopy 
examination.

Type of study: self-contained.

Data collection: Electronic Case Report Form (eCRF).

Safety monitoring:

All subjects: SAEs related to study participation.

HPV group (Ctrl-HPV-039 group):
o
All SAEs, and any AE/SAE leading to premature 
discontinuation of the study will be reported throughout 
the study.
o
pIMDs will be reported throughout the study. 
o
Pregnancies and pregnancy outcomes will be reported 
throughout the study.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
14
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
15
Number of 
subjects 
(Amended: 21 
Jun 2018)
Up to 6051 subjects who participated in the HPV-039 study will be 
invited to participate in this study. 
The study recruitment period is expected to last approximately 6 
months and the recruitment period will be communicated to all 
study investigators. Investigators will make all efforts to invite and 
enrol subjects during this period.
Women who are pregnant during the recruitment period will be 
offered participation in the study or free of charge vaccination 
outside the study using commercial vaccine three months after the 
pregnancy ends.
Hence, the study end may change depending on study progress.
Endpoints 
(Amended: 21 
Jun 2018)
Primary Endpoint:

Safety endpoint

HPV group (Ctrl-HPV-039 group)
o
Occurrence of SAEs related to study vaccine.
Secondary endpoints:

Safety endpoints

HPV group (Ctrl-HPV-039 group)
o
Occurrence of pIMDs throughout the study.
o
Occurrence of pregnancies and pregnancy outcomes 
throughout the study.
o
Any AE/SAE leading to premature discontinuation 
from the study.
o
Occurrence of SAEs.

All subjects
o
Occurrence of SAEs related to study participation.

Virological endpoints

Incident cervical infection associated with HPV-16 and/or 
HPV-18 (by PCR).

Incident cervical infection associated with any oncogenic 
HPV type (e.g. HPV-16, -18, -31, -33, -35, -39, -45, -51, -
52, -56, -58, -59, -66 and -68 or combination of oncogenic 
HPV types; by PCR).
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
15
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
16
Tertiary endpoints

Virological endpoint

Incident infection associated with HPV-16/18, any other 
oncogenic type, irrespective of HPV type.

Cytological endpoints

Any cytological abnormality (i.e., [ASC-US] associated 
with HPV-16 and/or HPV-18 cervical infection (by PCR).

Any cytological abnormality associated with any 
oncogenic HPV type (e.g. HPV-16, -18, -31, -33, -35, -39, 
-45, -51, -52, -56, -58, -59, -66 and -68 or combination of 
oncogenic HPV types; by PCR).

Any cytological abnormality irrespective of the HPV type.

Histopathological endpoints

Histopathologically-confirmed CIN1+ associated with 
HPV-16 and/or HPV-18 (by PCR).

Histopathologically-confirmed CIN2+ associated with 
HPV-16 and/or HPV-18 (by PCR).
CIN2+ is defined as CIN2, CIN3, LCGIN, HCGIN, 
adenocarcinoma in-situ (AIS) or invasive cervical cancer.

Histopathologically-confirmed CIN1+ associated with 
cervical infection with any oncogenic HPV type (e.g. 
HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, 
-66 and -68 or combination of oncogenic HPV types; by 
PCR).

Histopathologically-confirmed CIN2+ associated with 
cervical infection with any oncogenic HPV type (e.g. 
HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, 
-66 and -68 or combination of oncogenic HPV types; by 
PCR).

Histopathologically-confirmed CIN1+ lesions irrespective 
of HPV type

Histopathologically-confirmed CIN2+ lesions irrespective 
of HPV type

Histopathologically-confirmed VIN1+ associated with 
HPV-16 and/or HPV-18 infection (by PCR).

Histopathologically-confirmed VaIN1+ associated with 
HPV-16 and/or HPV-18 infection (by PCR).

Histopathologically-confirmed VIN1+ associated with any 
oncogenic HPV type (e.g. HPV-16, -18, -31, -33, -35, -39, 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
16
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
17
-45, -51, -52, -56, -58, -59, -66 and -68 or combination of 
oncogenic HPV types; by PCR).

Histopathologically-confirmed VaIN1+ associated with 
any oncogenic HPV type (e.g. HPV-16, -18, -31, -33, -35, 
-39, -45, -51, -52, -56, -58, -59, -66 and -68 or 
combination of oncogenic HPV types; by PCR).

Histopathologically-confirmed VIN1+ irrespective of 
HPV type.

Histopathologically-confirmed VaIN1+ irrespective of 
HPV type.
For the above mentioned tertiary endpoints, VIN (Vulvar 
Intraepithelial Neoplasia) is defined as VIN1+ or VIN2+, and 
VaIN (Vaginal Intraepithelial Neoplasia) is defined as VaIN1+ or 
VaIN2+.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
17
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
18
TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................8
SYNOPSIS......................................................................................................................9
LIST OF ABBREVIATIONS (AMENDED: 21 JUN 2018) ...............................................25
GLOSSARY OF TERMS ...............................................................................................26
TRADEMARK................................................................................................................30
1.
INTRODUCTION....................................................................................................31
1.1.
Background (Amended: 21 Jun 2018).........................................................31
1.2.
Rationale for the study and study design ....................................................32
1.2.1.
Rationale for the study (Amended: 21 Jun 2018) .........................32
1.2.2.
Rationale for the study design......................................................33
1.3.
Benefit : Risk Assessment (Amended: 21 Jun 2018) ..................................33
1.3.1.
Risk Assessment .........................................................................34
1.3.2.
Benefit Assessment (Amended: 21 Jun 2018) .............................34
1.3.3.
Overall Benefit : Risk Conclusion.................................................35
2.
OBJECTIVES (AMENDED: 21 JUN 2018) .............................................................35
2.1.
Primary objective ........................................................................................35
2.2.
Secondary objectives..................................................................................35
2.3.
Tertiary objectives.......................................................................................36
3.
STUDY DESIGN OVERVIEW (AMENDED: 21 JUN 2018).....................................37
4.
STUDY COHORT (AMENDED: 21 JUN 2018).......................................................39
4.1.
Number of subjects/centres ........................................................................39
4.2.
Inclusion criteria for enrolment (Amended: 21 Jun 2018) ............................40
4.3.
Exclusion criteria for enrolment...................................................................40
5.
CONDUCT OF THE STUDY ..................................................................................42
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................42
5.2.
Subject identification and randomisation (Amended: 21 Jun 2018) .............43
5.2.1.
Subject identification....................................................................43
5.2.1.1.
Treatment allocation to the subject.............................43
5.3.
Method of blinding (Amended: 21 Jun 2018)...............................................43
5.4.
General study aspects (15 May 2018) ........................................................43
5.4.1.
HPV DNA testing .........................................................................44
5.4.2.
Management of subjects with abnormal cytology.........................44
5.4.2.1.
Cytology and histology report terminology..................45
5.4.2.2.
Cytology and colposcopy management 
algorithms...................................................................46
5.4.2.3.
Unsatisfactory cytological findings and missing 
cytology results...........................................................46
5.5.
Outline of study procedures (Amended: 21 Jun 2018) ................................47
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
18
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
19
5.6.
Detailed description of study procedures (Amended: 21 Jun 2018).............49
5.6.1.
Informed consent.........................................................................49
5.6.2.
Check inclusion and exclusion criteria .........................................49
5.6.3.
Collect demographic data ............................................................49
5.6.4.
Medical history.............................................................................49
5.6.5.
Physical examination ...................................................................49
5.6.6.
Pregnancy test.............................................................................50
5.6.7.
Check contraindications, warnings and precautions to 
vaccination...................................................................................50
5.6.8.
Gynaecological examination and cervical sampling 
(Amended: 21 Jun 2018) .............................................................50
5.6.8.1.
Gynaecological examination.......................................50
5.6.8.1.1.
Requirements for cervical 
specimen collection ................................51
5.6.8.1.2.
Cervical Sampling...................................51
5.6.8.2.
ASC-US or LSIL .........................................................51
5.6.8.3.
AGC ...........................................................................52
5.6.8.4.
ASC-H / greater than or equal to HSIL........................52
5.6.9.
Colposcopic evaluations of abnormal cytologies..........................52
5.6.9.1.
Colposcopic procedures .............................................53
5.6.9.2.
Colposcopy management for low-grade 
cytology......................................................................54
5.6.9.3.
Colposcopy management algorithm for AGC..............56
5.6.9.4.
Colposcopy management algorithm for high-
grade cytology............................................................58
5.6.10.
Sampling (Amended: 21 Jun 2018)..............................................59
5.6.11.
Assess pre-vaccination body temperature ...................................60
5.6.12.
Treatment number allocation .......................................................60
5.6.13.
Study Vaccine administration.......................................................60
5.6.14.
Check and record concomitant medication/vaccination................60
5.6.15.
Recording of AEs, SAEs, pregnancies and its outcome 
and pIMDs ...................................................................................60
5.6.16.
Safety follow-up contact...............................................................60
5.6.17.
Study conclusion..........................................................................61
5.7.
Biological sample handling and analysis (Amended: 21 Jun 2018).............61
5.7.1.
Use of specified study materials ..................................................62
5.7.2.
Biological samples.......................................................................62
5.7.3.
Laboratory assays .......................................................................62
5.7.3.1.
Cervical Cytology .......................................................62
5.7.3.2.
Polymerase chain reaction (PCR) typing of 
HPV DNA from PreservCyt specimens.......................63
5.7.3.3.
Hybrid Capture II testing.............................................63
5.7.3.4.
Histopathology............................................................63
5.7.3.4.1.
Histopathological analysis ......................64
5.7.3.5.
HPV DNA PCR testing in tissue..................................64
6.
STUDY VACCINE AND ADMINISTRATION (AMENDED: 21 JUN 2018) ...............67
6.1.
Description of study vaccine .......................................................................67
6.2.
Storage and handling of study vaccine .......................................................68
6.3.
Dosage and administration of study vaccine...............................................68
6.4.
Replacement of unusable vaccine ..............................................................68
6.5.
Contraindications to subsequent vaccination ..............................................69
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
19
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
20
6.6.
Warnings and precautions ..........................................................................70
6.7.
Concomitant medications/products and concomitant vaccinations..............70
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................70
6.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses............70
7.
HEALTH ECONOMICS ..........................................................................................71
8.
SAFETY (AMENDED: 21 JUN 2018)......................................................................71
8.1.
Safety definitions ........................................................................................71
8.1.1.
Definition of an adverse event......................................................71
8.1.2.
Definition of a serious adverse event ...........................................72
8.1.3.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................73
8.1.4.
Adverse events of specific interest...............................................73
8.1.4.1.
Potential immune-mediated diseases 
(Amended: 21 Jun 2018) ............................................73
8.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events ...........................................................................................76
8.2.1.
Pregnancy ...................................................................................76
8.3.
Detecting and recording adverse events, serious adverse events 
and pregnancies .........................................................................................77
8.3.1.
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies.....................................77
8.3.2.
Post-study adverse events and serious adverse events...............78
8.3.3.
Evaluation of adverse events and serious adverse events...........78
8.3.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................78
8.3.3.2.
Assessment of adverse events...................................79
8.3.3.2.1.
Assessment of intensity..........................79
8.3.3.2.2.
Assessment of causality .........................79
8.3.3.3.
Assessment of outcomes............................................80
8.4.
Reporting of serious adverse events, pregnancies, and other events .........81
8.4.1.
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals............................................81
8.4.2.
Contact information for reporting serious adverse events, 
pregnancies and pIMDs...............................................................81
8.4.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................82
8.4.3.1.
Back-up system in case the electronic 
reporting system does not work..................................82
8.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals ...................................................................................82
8.4.5.
Reporting of pIMDs to GSK Biologicals........................................83
8.4.6.
Updating of SAE, pregnancy, and pIMD information after 
removal of write access to the subject’s eCRF.............................83
8.4.7.
Regulatory reporting requirements for serious adverse 
events..........................................................................................83
8.5.
Follow-up of serious adverse events, and pregnancies...............................84
8.5.1.
Follow-up of adverse events and serious adverse events............84
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
20
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
21
8.5.1.1.
Follow-up during the study..........................................84
8.5.1.2.
Follow-up after the subject is discharged from 
the study.....................................................................84
8.5.2.
Follow-up of pregnancies.............................................................84
8.6.
Treatment of adverse events ......................................................................85
8.7.
Subject card................................................................................................85
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................85
9.1.
Subject completion .....................................................................................85
9.2.
Subject withdrawal......................................................................................85
9.2.1.
Subject withdrawal from the study ...............................................85
9.2.2.
Subject withdrawal from study vaccine ........................................86
10. STATISTICAL METHODS (AMENDED: 21 JUN 2018) ..........................................87
10.1.
Primary endpoint.........................................................................................87
10.2.
Secondary endpoints ..................................................................................87
10.3.
Tertiary endpoints.......................................................................................87
10.4.
Determination of sample size (Amended: 21 Jun 2018)..............................89
10.5.
Cohort for Analyses (Amended: 21 Jun 2018) ............................................89
10.5.1.
Total enrolled set .........................................................................89
10.5.2.
Exposed set HPV-092..................................................................90
10.5.3.
Per-protocol set (PPS-HPV-092) .................................................90
10.6.
Derived and transformed data.....................................................................90
10.7.
Analysis of demographics...........................................................................90
10.8.
Analysis of safety (Amended: 21 Jun 2018)................................................91
10.9.
Analysis of protective effect (Amended: 21 Jun 2018).................................91
10.10. Exploratory analysis of long term efficacy ...................................................91
10.11. Interpretation of analyses............................................................................92
10.12. Conduct of analyses ...................................................................................92
10.12.1. Sequence of analyses..................................................................92
10.12.2. Statistical considerations for interim analyses..............................92
11. ADMINISTRATIVE MATTERS ...............................................................................92
11.1.
Electronic Case Report Form instructions...................................................93
11.2.
Study Monitoring by GSK Biologicals..........................................................93
11.3.
Record retention .........................................................................................94
11.4.
Quality assurance.......................................................................................94
11.5.
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................94
11.6.
Provision of study results to investigators ...................................................95
11.7.
Data Sharing...............................................................................................95
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................95
13. REFERENCES (AMENDED: 21 JUN 2018) ...........................................................96
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
21
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
22
LIST OF TABLES
PAGE
Table 1
Study groups and epoch foreseen in the study.......................................38
Table 2
Study groups and treatment foreseen in the study .................................38
Table 3
Blinding of study epochs ........................................................................39
Table 4
List of study procedures – Vacc-HPV-039 group....................................47
Table 5
List of study procedures – HPV Group (Ctrl-HPV-039 group).................48
Table 6
Intervals between study visits (for the HPV Group) ................................48
Table 7
Laboratory Assays .................................................................................66
Table 8
Study vaccine.........................................................................................67
Table 9
Dosage and administration.....................................................................68
Table 10
List of potential immune-mediated diseases (Amended: 21 Jun 
2018)......................................................................................................74
Table 11
Reporting periods for collecting safety information .................................78
Table 12
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals .................................................81
Table 13
Exact two-sided 95% CI for different sample sizes and the value 
observed for the percentage of subjects reporting at least one 
related SAE............................................................................................89
Table 14
Outsourced laboratories.........................................................................99
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
22
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
23
LIST OF FIGURES
PAGE
Figure 1
Study design diagram ............................................................................37
Figure 2
Cytology Management Algorithm ...........................................................53
Figure 4
Colposcopy Management Algorithm for subjects with ASC-
US/oncogenic HPV positive results or LSIL............................................55
Figure 5
Colposcopy Management Algorithm for subjects with AGC....................57
Figure 6
Coloposcopy Management Algorithm for subjects with ASC-H or 
HSIL.......................................................................................................59
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
23
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
24
LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS (Amended: 21 Jun 2018)................................98
APPENDIX B CLINICAL LABORATORIES (Amended: 21 Jun 2018)...........................99
APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL.........................................................................................100
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
24
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
25
LIST OF ABBREVIATIONS (AMENDED: 21 Jun 2018)
AE:
Adverse Event
AIS:
Adenocarcinoma in situ
CDE:
Center for Drug Evaluation
CICAMS/CFC:
Cancer Institute/Hospital, Chinese Academy of Medical 
Sciences and Cancer Foundation of China
CNDA:
National Drug Administration of China
eCRF:
electronic Case Report Form
EDD:
Estimated Date of Delivery
EGA:
Estimated Gestational Age
EoS:
End of Study
eTDF:
Electronic Temperature Excursion Decision Form
GCP:
Good Clinical Practice
GSK:
GlaxoSmithKline
IB:
Investigator Brochure
ICF:
Informed Consent Form
ICH:
International Conference on Harmonisation
IEC:
Independent Ethics Committee
IRB:
Institutional Review Board
LBC:
Liquid-Based Cytology
LMP:
Last Menstrual Period
LSLV:
Last Subject Last Visit
MedDRA:
Medical Dictionary for Regulatory Activities
PCD:
Primary Completion Date
pIMD:
Potential Immune-Mediated Disease
SAE:
Serious Adverse Event
SBIR:
Randomisation System on Internet
SDV:
Source Document Verification
SPM:
Study Procedures Manual
TVC
Total Vaccinated Cohort
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
25
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
26
GLOSSARY OF TERMS
Adequate contraception:
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example:

abstinence from penile-vaginal intercourse, when this 
is their preferred and usual lifestyle,

Combined estrogen and progesterone oral 
contraceptives,

injectable progestogen,

implants of etenogestrel or levonorgestrel,

Contraceptive vaginal ring,

percutaneous contraceptive patches,

intrauterine device or intrauterine system,

male partner sterilisation prior to the female subject’s 
entry into the study, and this male is the sole partner 
for that subject,
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her medical 
history.

male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository), and/or 
progesterone alone oral contraceptive.
Adequate contraception does not apply to subjects of child 
bearing potential with same sex partners, or for subjects 
who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis, 
when this is their preferred and usual lifestyle.
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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
26
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
27
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 timepoints or a single 
timepoint 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 timepoints
included in an epoch must be sufficient to fulfil the 
purpose of the epoch.
Typical examples of epochs are screening, primary 
vaccinations, boosters, yearly immunogenicity follow-ups, 
and surveillance periods for efficacy or safety.
eTrack:
GSK’s tracking tool for clinical trials.
Investigational vaccine:
(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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
27
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
28
Menarche:
Menarche is the onset of menses for the first time in a 
young female and is preceded by several changes 
associated with puberty including breast development and 
pubic hair growth. Menarche usually occurs within 1-2 
years of breast development, thelarche. However, a young 
female can become pregnant before her first menses. Thus, 
a conservative definition of non-childbearing potential in a 
pre-menarcheal female is a young female who has not yet 
entered puberty as evidenced by lack of breast 
development (palpable glandular breast tissue).
Menopause:
Menopause is the age associated with complete cessation 
of menstrual cycles, menses, and implies the loss of 
reproductive potential by ovarian failure. A practical 
definition accepts menopause after 1 year without menses 
with an appropriate clinical profile at the appropriate age 
e.g. > 45 years.
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.
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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
28
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
29
Study vaccine/product:
Any investigational vaccine/product being tested and/or 
any authorised use of a vaccine/ product/placebo as a 
reference or administered concomitantly, in a clinical trial 
that evaluates the use of an investigational vaccine/product.
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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
29
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
30
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 ™ or ® and in italics.
Trademark of the GSK group of 
companies
Generic description
Cervarix
Human Papillomavirus (Types 16, 18) 
Vaccine, Adsorbed
Trademarks not owned by the GSK 
group of companies
Generic description
GARDASIL (Merck & CO., Inc.)
Quadrivalent human papillomavirus (types 
6, 11, 16, 18) recombinant vaccine
GARDASIL 9 (Merck & CO., Inc.)
Human Papillomavirus 9-valent Vaccine, 
Recombinant
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
30
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
31
1.
INTRODUCTION
1.1.
Background (Amended: 21 Jun 2018)
Cervical cancer is the fourth most common cancer among women worldwide, with nearly 
528,000 new cases and nearly 266,000 deaths each year [International Agency for 
Research on Cancer, 2012]. 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.
GSK Biologicals has therefore developed a prophylactic HPV vaccine, Cervarix, based 
on L1 proteins of HPV-16 and HPV-18 formulated with AS04 (comprising of aluminium 
hydroxide [Al(OH)3] and 3-O-desacyl-4’-monophosphoryl lipid A [MPL]).
Cervarix was first licensed in May 2007 in Australia, for use in 10 to 45 year old females. 
In September 2007, the vaccine was licensed in Europe for use from the age of 9 years
for the prevention of persistent infection, premalignant ano-genital lesions (cervical, 
vulvar, vaginal and anal) and cervical, vulvar, vaginal and anal cancers 
(squamous-cell carcinoma and adenocarcinoma) caused by oncogenic Human 
Papillomaviruses (HPVs). The vaccine has been licensed in over 133 countries and 
regions worldwide. In July 2016, Cervarix (hereafter referred to as the Human 
Papillomavirus [Types 16, 18] Vaccine, Adsorbed) was approved for use as a 3-dose 
schedule at 0, 1, 6 months in females from 9 to 25 years in China. The extension of the 
vaccine indication up to 45 years of age was approved by the Chinese authorities on 
10-May-2018. 
In May 2017, Merck’s recombinant quadrivalent HPV vaccine, Gardasil, also received 
approval in China. In April 2018, Gardasil 9 was granted conditional approval by 
National Drug Administration of China (CNDA)with additional requirements in 
China.
To date, safety and immunogenicity data were evaluated in more than 60,000 
adolescents and adults aged 9 years and above in clinical studies. The vaccine is known 
to be immunogenic and generally well tolerated. Pooled safety analyses of girls and 
women aged 9 years and above have shown that the vaccine was generally well tolerated
in women of all ages [Descamps, 2009; Angelo, 2014].
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
31
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
32
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study (Amended: 21 Jun 2018)
The burden of cervical cancer in China is most likely underestimated. In China, over 
61,000 new cases of cervical cancer are diagnosed annually, responsible for more than 
29,000 deaths [HPV Information Centre, 2016]. A meta-analysis of 18 studies on the 
distribution of HPV types in cervical lesions estimated the proportional impact of HPV-
16 and HPV-18 on invasive cervical cancer to be as high as 69.6% in Chinese women 
[Bao, 2007]. A recent assessment in Chinese women revealed HR-HPV infection 
prevalence of 21.07%, where infection with the HPV-16 sub-type was the most common 
(4.82%) [Wang, 2015]. Prophylactic vaccination with a HPV vaccine would efficiently 
reduce the incidence of cervical cancer and may be particularly useful 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 GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed were assessed in a total of four 
clinical trials conducted in China, involving over 8000 Chinese females between 9 and 
45 years of age, of whom over 4000 subjects received the vaccine [Zhu, 2011; Cervarix
Product Information, 2016]. The results of the phase II/III efficacy study (HPV-039) 
showed high and sustained vaccine efficacy against all virological, cytological and 
histopathological efficacy endpoints associated with HPV-16/18. There was no sign of 
waning efficacy at the end of the study (up to Month 72). The Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed was generally well tolerated in Chinese women aged 
18-25 years [GlaxoSmithKline Biologicals Clinical Report 107638 (HPV-039)].
This study has been designed following ethical considerations, to enable all subjects who 
received placebo in the HPV-039 study, to also receive GSK Biologicals’ Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed. Safety data in terms of serious 
adverse events (SAEs), any adverse events (AEs)/SAEs leading to premature 
discontinuation of the study, potential immune mediated diseases (pIMDs) and 
pregnancies (and their outcomes) will be collected during the study period. In addition, 
this study aims to assess the long term protective effect of the vaccine, in an exploratory 
manner, in terms of rates of HPV related (vaccine type) incident cervical infection
(secondary objective), cytological abnormalities and CIN2+ lesions (tertiary objective) 
up to approximately 10 years after vaccination in subjects who participated in HPV-
039 study, to support the post-licensure commitments to the Center for Drug
Evaluation (CDE) of CNDA.
At the availability of the commercial vaccine for use in individuals above 25 years, 
subjects will be offered the opportunity to receive Cervarix free of charge either by 
participating to this study or without participating to this study.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
32
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
33
1.2.2.
Rationale for the study design
This study will be conducted in an open-label and non-randomised manner since the 
subjects who had participated in study HPV-039 already know the treatment they 
received and only those in the control group will receive Human Papillomavirus (Types 
16, 18) Vaccine, Adsorbed in the current study. Safety data will be collected from Dose 
1 until the end of the study in subjects vaccinated in this study. Cervical samples will be 
collected at Visit 1 from all subjects to test for HPV incident infection and cytological 
abnormalities. Subjects with abnormal cytology will be called back for colposcopy 
follow-up and biopsy to examine for the presence of CIN lesions.
Limitations:
In the HPV-039 study, the efficacy of GSK Biologicals’ Human Papillomavirus (Types 
16, 18) Vaccine, Adsorbed against virological, cytological and histopathological 
endpoints associated with HPV types 16 and 18, was demonstrated up to 6 years after 
vaccination and subjects were screened every 6 months. The study was unblinded after 
completion and since the Year 6, 3-4 years have elapsed with no regular follow-up of 
the subjects. As a consequence, at Year 10, there might be high subject attrition,
leading to a potential imbalance in the numbers of subjects from the vaccinated versus 
control group returning for the current study. This as well as a lack of regular 
gynaecological follow-up between Year 6 and Year 10 may compromise assessment of 
vaccine efficacy in this study. Therefore, vaccine efficacy analyses will be exploratory.
1.3.
Benefit : Risk Assessment (Amended: 21 Jun 2018)
Please refer to the Prescribing Information for information regarding the summary 
potential risks and benefits of Human Papillomavirus (Types 16, 18) Vaccine, 
Adsorbed.
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
33
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
34
1.3.1.
Risk Assessment
Important Potential Risk
Data/Rationale for Risk
Mitigation Strategy
Investigational vaccine
Theoretical potential risk of 
inducing or exacerbating an 
autoimmune disease following 
vaccination.*
Potential concern that Human 
Papillomavirus (Types 16, 18) 
Vaccine, Adsorbed, and 
adjuvanted vaccines in general, 
might be associated with an 
increased risk of new onset of 
autoimmune diseases. Analysis of 
cumulative data so far remains 
inconclusive with respect to any 
potential pathogenic link between 
Human Papillomavirus (Types 16, 
18) Vaccine, Adsorbed and 
autoimmune diseases.
Naturally occurring autoimmune 
diseases are multi-aetiological 
conditions with multiple risk factors, 
including genetic predisposition. Relative 
risks for autoimmune diseases following 
Human Papillomavirus (Types 16, 18) 
Vaccine, Adsorbed administration are 
derived from the most recent pooled 
analysis of clinical trial data, which 
showed no difference between groups. 
The incidence of autoimmune diseases 
is being monitored closely in the ongoing 
clinical trials, post-marketing 
spontaneous reports, literature and 
observational epidemiological studies 
specifically designed to evaluate the risk 
of autoimmune diseases following 
vaccination with Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed.
Study Procedures 
Allergic reactions (including 
anaphylactic and anaphylactoid 
reactions), angioedema, or other 
immediate reactions such as 
syncope or vasovagal response 
following vaccination.
Spontaneous data
Subjects will be observed for at least 30 
minutes after vaccine administration, 
with medical attention available in case 
of anaphylactic reactions.
Colposcopy with targeted 
biopsies may involve rare 
events such as lower abdominal 
pain, vaginal bleeding, fever, 
chills and yellow colored 
vaginal discharge.
Spontaneous data 
In general, the colposcopy and 
biopsy procedures are relatively 
simple and safe
Colposcopy and biopsy will be 
conducted by experts from the 
Cancer Institute/Hospital, Chinese 
Academy of Medical Sciences and 
Cancer Foundation of China
*Only for subjects being vaccinated in this study.
1.3.2.
Benefit Assessment (Amended: 21 Jun 2018)
Cervical cancer is one of the most common cancers in women, and is often fatal. 
Vaccination with Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed is likely to 
prevent the occurrence of HPV infection, premalignant genital lesions and cervical 
cancers associated with HPV types 16 and 18. All study participants who belonged to the 
control group in the HPV-039 study will be invited to receive Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed. In addition, subjects from HPV-039 study will also 
be invited to take part in gynaecological examination and cervical sampling during the 
study. In case of abnormal cytology results of cervical samples, the subjects will be 
called back for a follow-up colposcopy examination. Colposcopy is an important 
routine procedure in the initial evaluation of cervical abnormalities for cancer 
screening in many countries. Colposcopy with targeted biopsies provides accurate 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
34
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
35
identification of cervical diseases when present, as well as reassurance of the absence 
of disease in the subjects. Since cervical screening in this age group is not the standard 
of care in China at present, the study provides an opportunity for the enrolled subjects
to have a cervical cancer screening.
1.3.3.
Overall Benefit : Risk Conclusion
Taking into account the measures taken to minimise risk to subjects participating in this 
study, the potential or identified risks identified in association with Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed or in association with the study 
procedures are justified by the potential benefits (prevention of HPV infection, screening 
of HPV-related diseases) that may be afforded to subjects.
2.
OBJECTIVES (AMENDED: 21 JUN 2018)
2.1.
Primary objective
To assess the safety of GSK Biologicals’ Human Papillomavirus (Types 16, 18) 
Vaccine, Adsorbed in subjects above 26 years of age, who previously received placebo 
in the HPV-039 study, in terms of related SAEs.
Refer to Section 10.1 for the definition of the primary endpoint. 
2.2.
Secondary objectives

To assess the safety of GSK Biologicals Human Papillomavirus (Types 16, 18) 
Vaccine in terms of occurrence of unsolicited AEs in subjects above 26 years of 
age, who previously received placebo in the HPV-039 study.

To assess the protective effect of GSK Biologicals’ Human Papillomavirus (Types 
16, 18) Vaccine, Adsorbed in all subjects who participated in the HPV-039 study in 
terms of the rates of HPV 16/18 incident infection up to approximately 10 years 
after vaccination.

To assess the protective effect of GSK Biologicals’ Human Papillomavirus (Types 
16, 18) Vaccine, Adsorbed in all subjects who participated in the HPV-039 study in 
terms of the rates of incident infection associated with any or combination of 
oncogenic HPV types, up to approximately 10 years after vaccination.
Refer to Section 10.2 for the definition of the secondary endpoints.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
35
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
36
2.3.
Tertiary objectives

To assess the long term efficacy of GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of incident infection associated 
with HPV-16 and/or HPV-18 or with any or combination of oncogenic HPV types.

To assess the long term efficacy of GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of cytological abnormalities 
associated with HPV-16 and/or HPV-18.

To assess the long term efficacy of GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of cytological abnormalities 
associated with any or combination of oncogenic HPV types.

To assess the long term efficacy of the GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of 
histopathologically-confirmed CIN1+ associated with HPV-16 and/or HPV-18.

To assess the long term efficacy of the GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of 
histopathologically-confirmed CIN1+ associated with any or combination of 
oncogenic HPV types.

To assess the long term efficacy of the GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of 
histopathologically-confirmed CIN2+ associated with HPV-16 and/or HPV-18.

To assess the long term efficacy of the GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of 
histopathologically-confirmed CIN2+ associated with any or combination of 
oncogenic HPV types.

To assess the long term efficacy of the GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of other 
histopathologically-confirmed endpoints associated with HPV-16 and/or HPV-18 
or any or combination of oncogenic HPV types.
Refer to Section 10.3 for the definition of the tertiary endpoint(s) and to section 10.12.1
for the reporting of tertiary endpoint results.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
36
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
37
3.
STUDY DESIGN OVERVIEW (AMENDED: 21 JUN 2018)
Figure 1
Study design diagram
N: Number of subjects
1 Sampling from the subjects of Ctrl-HPV-039 group will be done before vaccination.
2 Subjects can choose to consent to both cervical sampling and vaccination procedures or one of the two 
procedures during the informed consent process.
3 Call back visit for colposcopy and follow-up of subjects with abnormal cytology. Medical care of subjects 
with abnormal cervical lesions will be outside of the study, according to the local medical practice.
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/IV, open-label, partially-controlled, multi-centric, 
single-country study with two parallel groups.

Duration of the study:
Subjects who previously received HPV vaccination in study HPV-039 (Vacc-HPV-
039 group)*:

The study duration is one day (Visit 1) i.e., when a subject comes for cervical 
sample collection.
Subjects who previously received the control vaccine in study HPV-039 and will 
receive HPV vaccination in this study (HPV Group)*:

Approximately 12 months per subject (approximately 6 months for 3-dose 
vaccination followed by 6-month extended safety follow-up after last dose)
o
Epoch 001: starting at Visit 1 (Day 1) and ending at Call 2 (Month 12)
*Subjects who have abnormal cytology findings in the cervical sample collected at 
Visit 1 will be called back for a follow-up visit for colposcopy examination and 
biopsy (when needed).
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
37
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
38

Primary completion Date (PCD): Call 2 (Month 12)
Refer to glossary of terms for the definition of PCD.

End of Study (EoS): Last subject’s last visit/contact (Call 2 [Month 12]) or last 
testing results released for samples collected at Visit 1 and related call back visits, 
whatever comes later.
Refer to glossary of terms for the definition of EoS.

Study groups: Two groups:

Vacc-HPV-039 group i.e. subjects who received HPV vaccine in HPV-039 
study who will undergo cervical sample collection only.

HPV group (Ctrl-HPV-039 group) i.e. subjects who received control vaccine 
in HPV-039 study will receive HPV vaccine in the current study and undergo 
cervical sample collection before HPV vaccination.
Table 1
Study groups and epoch foreseen in the study
Study Groups
Number of subjects
Age
Epoch
Epoch 001
Vacc-HPV-039
group
up to 3026
From 26 years
x
HPV group
up to 3025
From 26 years
x
Table 2
Study groups and treatment foreseen in the study
Treatment 
name
Vaccine name
Study Groups
Vacc-HPV-039
group
HPV group
HPV-16/18
Human Papillomavirus (Types 16, 18) 
Vaccine, Adsorbed (HPV16-18 AS04D)
No treatment
x

Control: none for safety objectives; HPV group (Ctrl-HPV-039 group) for long 
term protective effect objectives.

Vaccination schedule: Three doses of Human Papillomavirus (Types 16, 18) 
Vaccine, Adsorbed (20 µg HPV-16, 20 µg HPV-18) administered intramuscularly 
according to a 0, 1, 6-month schedule.

Treatment allocation: Treatment allocation depends on the randomization in the 
previous study i.e. only the subjects from the control group of HPV-039 study will 
receive HPV vaccination in the current study. Subjects who previously received the 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed in HPV-039 will not 
receive vaccination in this study.

Blinding: open-label
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
38
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
39
Table 3
Blinding of study epochs
Study Epoch
Blinding
Epoch 001
open-label

Sampling schedule: A cervical sample will be taken at Visit 1 before vaccine 
administration.
For subjects who have abnormal cytology findings in the cervical sample collected 
at Visit 1, there will be a call-back follow-up visit for colposcopy examination. A
cervical biopsy will be taken depending on the results of the colposcopy 
examination.

Type of study: self-contained.

Data collection: Electronic Case Report Form (eCRF).

Safety monitoring:

All subjects:
o
SAEs related to study participation.

HPV group (Ctrl-HPV-039 group):
o
All SAEs, and any AE/SAE leading to premature discontinuation of the 
study will be reported throughout the study.
o
pIMDs will be reported throughout the study.
o
Pregnancies and pregnancy outcomes will be reported throughout the study.
4.
STUDY COHORT (AMENDED: 21 JUN 2018)
4.1.
Number of subjects/centres
Overview of the recruitment plan 
Up to 6051 subjects who participated in the HPV-039 study will be invited to participate 
in this study.
The study recruitment period is expected to last approximately 6 months and the 
recruitment period will be communicated to all study investigators. Investigators will 
make all efforts to invite and enrol subjects during this period.
Women who are pregnant during the recruitment period will be offered participation in 
the study or free of charge vaccination outside the study using commercial vaccine
three months after the pregnancy ends.
Hence, the study end may change depending on study progress.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
39
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
40
4.2.
Inclusion criteria for enrolment (Amended: 21 Jun 2018)
Deviations from inclusion 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.
All subjects must satisfy ALL the following criteria at study entry:

Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. return for study visits, available for follow-up 
telephone contacts).

Written informed consent obtained from the subject prior to performing any study 
specific procedure.

Subjects previously enrolled in the HPV-039 study.

Subjects with negative pregnancy test at Visit 1.
Additional inclusion criteria for subjects of HPV group undergoing vaccination
ONLY:

Healthy subjects as established by medical history and clinical examination before 
entering into the study.

Female subjects of non-childbearing potential may be enrolled in the study. 

Non-childbearing potential is defined as pre-menarche, current bilateral tubal 
ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause.
Please refer to the glossary of terms for the definition of menarche and menopause.

Female subjects of childbearing potential may be enrolled in the study, if the subject:

has practiced adequate contraception for 30 days prior to vaccination, and

has a negative pregnancy test on the day of vaccination, and

has agreed to continue adequate contraception during the entire treatment period 
and for 2 months after completion of the vaccination series.
Please refer to the glossary of terms for the definition of adequate contraception.
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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
40
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
41
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:

Concurrently participating in another clinical study, at any time during the study 
period, 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 of study HPV-039.
Additional exclusion criteria for subjects of HPV group undergoing vaccination
ONLY:

Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine during the period starting 30 days before the first dose of study 
vaccine (Day -29 to Day 1), or planned use during the study period.

Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe.

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting six 
months prior to the first vaccine dose. For corticosteroids, this will mean prednisone 
(20 mg/day, or equivalent). Inhaled and topical steroids are allowed.

Planned administration/administration of a vaccine/product not foreseen by the study 
protocol in the period starting 30 days before and after each dose of vaccine 
administration, with the exception of administration of routine vaccines e.g. 
meningococcal, hepatitis B, hepatitis A, inactivated influenza up to eight days before 
and after each dose of study vaccine. Enrolment will be deferred until the subject is 
outside of the specified window.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine.

Previous administration of MPL or AS04 adjuvant.

Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality, as determined by physical examination or laboratory 
screening tests.

Cancer or autoimmune disease under treatment.

Hypersensitivity to latex.

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature ≥37.0°C. The preferred location for measuring 
temperature in this study will be the axilla.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may, be enrolled at the discretion of the investigator.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
41
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
42

Pregnant or breastfeeding. Subjects must be at least three months post-pregnancy 
and not breastfeeding to enter the study. For pregnant or lactating women, also 
please refer to Section 4.1.

Females planning to become pregnant or planning to discontinue contraceptive 
precautions during the vaccination phase of the study, i.e. up to two months after the 
last vaccine dose.
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 informed consent.

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, 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 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
42
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
43
5.2.
Subject identification and randomisation (Amended: 21 Jun
2018)
5.2.1.
Subject identification
Subjects will be allocated the same identification numbers as in study HPV-039.
5.2.1.1.
Treatment allocation to the subject
The treatment numbers will be allocated by dose.
A sequential list of treatment numbers will be generated by MATerial EXcellence 
(MATEX). The Randomisation and Treatment Allocation System on Internet (SBIR) 
will be used to allocate treatment numbers to the subjects.
After obtaining the signed and dated ICF from the subject and having checked the 
eligibility of the subject, the site staff in charge of the vaccine administration will access 
SBIR. Upon providing the subject identification number, the system will provide the 
treatment number to be used for the first dose.
When SBIR is not available, please refer to the SBIR user guide for specific instructions.
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
5.3.
Method of blinding (Amended: 21 Jun 2018)
Not applicable since this is an open-label study. However 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.
The laboratory testing mentioned above refers to the cytology, histopathology and PCR 
and HPV DNA testing described in Table 7.
5.4.
General study aspects (15 May 2018)
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying study procedure 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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
43
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
44
5.4.1.
HPV DNA testing
All assessments of cervical samples for this study will be done by the Cancer 
Institute/Hospital, Chinese Academy of Medical Sciences and Cancer Foundation of 
China (CICAMS/CFC).
“Reflex” testing by the US FDA and China FDA-approved hybridization assay (Hybrid 
Capture® 2 test [HCII]) will be used to guide a subject’s management in case of 
atypical squamous cells of undetermined significance (ASC-US, see Section 5.6.8.2). 
CICAMS/CFC will automatically perform HPV DNA Hybrid Capture II (HCII) testing 
on the liquid-based cytology specimen. Study personnel do not need to request the 
HCII testing.
Currently available data do not support the use of HPV DNA PCR testing in the 
routine management of subjects diagnosed with abnormal cervical cytology. The HPV 
DNA PCR testing, which will be used in this study, has been developed for 
investigational use only. For this reason, clinical management will not be driven by the 
results of this testing. A number of procedures will be followed to ensure that HPV 
DNA PCR test results do not bias either the conduct of the trial, or the clinical 
management of the study subjects.
These procedures include:
1.
Study sites and study personnel will be blinded to HPV DNA PCR test results 
throughout the study to ensure that these results do not bias either the conduct of 
the trial, or the clinical management of study subjects. This includes bias that 
might result from deviations from regular study interval visits for cervical 
cytological follow-up and/or colposcopic procedures.
2.
HPV DNA PCR test results will NOT be provided to the investigators or study 
subjects until the end of the study. A summary report on results will be distributed 
to the investigators after study completion. It will be the responsibility of the 
investigators to inform study subjects of their results. The clinical management of 
subjects should follow the recommended guidelines outlined below and should be 
based solely on cervical cytology or biopsy results and HCII testing (not HPV DNA 
PCR test results). 
5.4.2.
Management of subjects with abnormal cytology
Cervical cytology specimens will be collected using the sampling device provided. 
Cytological examination will be performed using the ThinPrep® PapTest (Cytyc 
Corporation, Boxborough, MA, USA). HPV DNA PCR testing will be performed on the 
cervical cytology specimens collected on Day 1 (Visit 1). In case of abnormal cytology 
results, the subjects will be called back for a follow-up visit for colposcopy 
examination. The following algorithms (see Figure 2, Figure 3, Figure 4 and Figure 5) 
describe clinical management guidelines to be followed by the investigator (and/or 
designee). Treatment of subjects with abnormal findings is not within the scope of this 
study; however, the subjects will be referred to local healthcare centres to follow local 
medical practices. The algorithms are based on the guidelines of the American Society 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
44
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
45
for Colposcopy and Cervical Pathology and European guidelines, and are designed to 
provide a consistent method of detection, clinical management and reporting for 
cervical lesions. The clinical management algorithms cannot define every clinical 
situation and, therefore, it is the investigator’s (or designee’s) responsibility to exercise 
appropriate clinical judgment in the medical management of exceptional cases. 
Compliance with the algorithm will be monitored.
5.4.2.1.
Cytology and histology report terminology
Each cytopathology specimen will be reported according to the Bethesda 2001 
Classification of cytological findings. The terminology will include a statement as to 
whether a specimen is satisfactory or unsatisfactory. In addition, specimens that are 
satisfactory but show no endocervical component will be identified for quality control 
of cytological sampling.
For the purposes of the trial, management is specified for the categories:

Unsatisfactory

Negative for intraepithelial lesion or malignancy (negative)

Atypical squamous cells of undetermined significance (ASC-US):

ASC-US / Hybrid Capture II negative (ASC-US/oncogenic HPV negative)

ASC-US / Hybrid Capture II positive (ASC-US/oncogenic HPV positive)

ASC-US / Hybrid Capture II quantity not sufficient (ASC-US/QNS)

Atypical squamous cells-cannot exclude HSIL (ASC-H)

Low-grade squamous intraepithelial lesion (LSIL)

High-grade squamous intraepithelial lesion (HSIL)

Atypical glandular cells (AGC)

Invasive malignancy
Specimens will be reported as “Quantity Not Sufficient” when there is an inadequate 
amount of cells for HCII testing. In case of ASC-US/QNS or missing HCII test results, 
subjects will be informed and encouraged to follow regular gynaecological 
examination according to local practice.
Histopathological reports on biopsy and excision specimens will classify the findings 
as:

Negative

Condyloma

Cervical intraepithelial neoplasia grade 1 [CIN1]
Vaginal intraepithelial neoplasia grade 1 [VaIN1]
Vulvar intraepithelial neoplasia grade 1 [VIN1])
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
45
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
46

Cervical intraepithelial neoplasia grade 2 [CIN2]
Vaginal intraepithelial neoplasia grade 2 [VaIN2]
Vulvar intraepithelial neoplasia grade 2 [VIN2])

Cervical intraepithelial neoplasia grade 3 [CIN3]
Vaginal intraepithelial neoplasia grade 3 [VaIN3]
Vulvar intraepithelial neoplasia grade 3 [VIN3])

Low grade cervical glandular intraepithelial neoplasia (LCGIN)

High grade cervical glandular intraepithelial neoplasia (HCGIN) 

Adenocarcinoma in-situ (AIS)

Invasive malignancy
5.4.2.2.
Cytology and colposcopy management algorithms
The algorithm in Figure 2 describes the clinical management of all cytology results 
obtained at Day 1 (Visit 1). Subjects with cytology reported as negative or as ASC-US/ 
oncogenic HPV negative will not be called back for a follow-up biopsy sample. Subjects 
with abnormal cytological findings (except ASC-US/oncogenic HPV negative) should 
be managed according to the recommendations for follow-up in Figure 2 and the 
colposcopy algorithms in Figure 3, Figure 4 and Figure 5. The results of the cytology 
will be communicated to the investigator (or designee) by CICAMS/CFC. The 
investigator (or designee) will notify the subject of the test result and, when 
appropriate, the subject should receive colposcopy within approximately 30 days after 
cytology results have been communicated by CICAMS/CFC.
5.4.2.3.
Unsatisfactory cytological findings and missing cytology results
When the laboratory results deem a cervical liquid-based cytology (cervical-LBC)
specimen unsatisfactory, study personnel are required to repeat the cervical-LBC 
specimen as soon as possible after cytology results have been communicated. Only 
satisfactory results of a repeat cytology result will count as the final cytology result.
Likewise, HPV DNA PCR testing will not be performed on unsatisfactory cytology 
specimens.
In addition, cytological specimens reported as “satisfactory for evaluation-
endocervical/ transformation zone component absent” should be managed according to 
the given cytological diagnosis. These smears should not be repeated but the 
information will be used for quality control monitoring. Abnormal cytology should be 
managed according to the appropriate protocol-specified algorithm. Missing cytology 
results will be recorded as missing results (in the case of lost damaged sample).
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
46
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
47
5.5.
Outline of study procedures (Amended: 21 Jun 2018)
Table 4
List of study procedures – Vacc-HPV-039 group
Epoch
Epoch 001
Type of contact
Visit 1
Time points
Day 1
Informed consent 
●
Check inclusion/exclusion criteria 
●
Collect demographic data 
●
Medical and vaccination history†
●
Physical examination 
●
Pregnancy test 
●
Gynaecological Examination 
●
Cervical sampling
●
Referral for colposcopy (if applicable)**
O
Report colposcopy results (if applicable)**
●
Safety assessments
Record any concomitant medications/vaccinations*
●
Recording of SAEs (related to study participation)
●
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.
† Medical history since the last visit in study HPV- 039 will be recorded. The subjects should also provide their 
history of any HPV related infection/disease with all available information.
*Including only medications/vaccinations which may lead to elimination from per-protocol analysis
** Subjects with abnormal cervical cytology will be evaluated according to the cytology and colposcopy 
clinical management algorithms (see Section 5.4.2 and Section 5.6.9) at unscheduled visits following Visit 1.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
47
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
48
Table 5
List of study procedures – HPV Group (Ctrl-HPV-039 group)
Epoch
Epoch 001
Type of contact
Visit 1
Visit 2
Visit 3
Call 1
Call 2
Time points
Day 1
Month 1
Month 6
Month 7
Month 12
Informed consent 
●
Check inclusion/exclusion criteria 
●
Collect demographic data 
●
Medical and vaccination history †
●
Physical examination 
●
Pregnancy test 
●
●
●
Check contraindications and warnings and precautions 
to vaccination 
●
●
●
Gynaecological Examination 
●
Cervical sampling 
●
Referral for colposcopy (if applicable)**
O
Report colposcopy results (if applicable)**
●
Pre-vaccination body temperature 
●
●
●
Vaccine
Treatment number allocation 
O
Treatment number allocation for subsequent doses 
O
O
Recording of administered treatment number 
●
●
●
Vaccine administration 
●
●
●
Safety assessments
Record any concomitant medications/vaccinations 
●
●
●
●
●
Recording of pregnancies and outcomes 
●
●
●
●
●
Recording of SAEs 
●
●
●
●
●
Recording of AEs/SAEs leading to premature 
withdrawal from the study 
●
●
●
●
●
Recording of pIMDs 
●
●
●
●
●
Safety follow-up contact 
●
●
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.
† Medical history since the last visit in study HPV- 039 must be recorded. The subjects should also provide 
their history of any HPV related infection/disease with all available information.
** Subjects with abnormal cervical cytology will be evaluated according to the cytology and colposcopy 
clinical management algorithms (see Section 5.4.2 and Section 5.6.9) at unscheduled visits following Visit 1.
Whenever possible, the investigator should arrange study visits within the interval 
described in Table 6.
Table 6
Intervals between study visits (for the HPV Group)
Interval
Length of interval 
Optimal length of interval
Visit 1 Visit 2
21 - 62 days
30 days
Visit 1 Visit 3
161 - 216 days
180 days
Visit 3 Call 1
21 - 62 days 
30 days
Visit 3 Call 2
150 - 210 days
180 days
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
48
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
49
5.6.
Detailed description of study procedures (Amended: 21 Jun
2018)
Note: Each study procedure is detailed in subsequent subsections only once, even if 
some of them need to be performed during more than one visit.
5.6.1.
Informed consent
The signed/witnessed/thumb printed informed consent of the subject must be obtained 
before study participation. Refer to Section 5.1 for the requirements on how to obtain 
informed consent, as appropriate.
Subjects in the HPV group (Ctrl-HPV-039 group) will be given the choice to consent to 
either sampling or vaccination or both procedures during the informed consent
process.
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.
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 cervical sample collection or the first study vaccination in the eCRF.
The subjects should also provide their history of any HPV related infection/disease 
with all available information since their last visit in study HPV-039.
5.6.5.
Physical examination
Perform a physical examination of the subject, including assessment of axillary body 
temperature and resting vital signs: systolic/diastolic blood pressure, heart rate and 
respiratory rate after at least 10 minutes of rest. Collected information needs to be 
recorded in the eCRF. 
Physical examination at each study visit subsequent to the first vaccination visit will be 
performed only if the subject indicates during questioning that there might be some 
underlying pathology(ies) or if deemed necessary by the Investigator or delegate.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
49
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
50
If the investigator determines that the subject’s health on the day of vaccination 
temporarily precludes vaccination, the visit will be rescheduled.
For subjects in the Vacc-HPV-039 group, the investigator must use her medical 
judgement to decide if a subject can undergo cervical sampling procedure. Subjects 
may be rescheduled or excluded from the study on the basis of medical history.
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.
Pregnancy test
Female subjects of childbearing potential are to have a negative urine pregnancy test 
prior to any gynaecological examination, cervical sample collection or vaccine 
administration. 
Note: Pregnancy test must be performed even if the subject is menstruating at the time of 
the study visit.
In case of a positive urine pregnancy test result, the subjects would not be allowed to 
receive vaccination or undergo cervical sampling until 3 months after the end of 
pregnancy.
5.6.7.
Check contraindications, warnings and precautions to 
vaccination
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of each vaccination visit. Refer to Sections 6.5 and 6.6 for more details. 
5.6.8.
Gynaecological examination and cervical sampling (Amended: 21 
Jun 2018)
5.6.8.1.
Gynaecological examination
Gynaecological examination will be performed on Day 1 (Visit 1). At gynaecological 
examination, according to local medical practice, the vagina and vulva will be 
inspected using the unaided eye or the colposcope or a magnifying glass. If needed, 
acetic acid may be applied.
Any vaginal or vulvar lesions possibly associated with HPV (other than condylomas) 
will be biopsied and excised according to local medical practice. This may include 
referral to the study colposcopists. All tissues will be shipped to CICAMS/CFC. After 
completion of the gynaecological examination, women should be encouraged to 
continue follow-up in the context of local medical practice.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
50
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
51
5.6.8.1.1.
Requirements for cervical specimen collection
Sexual intercourse must be avoided for the 24 hours before collection of a cervical 
specimen. Cervical specimen collection must be performed a minimum of one day after 
menstrual flow has ceased. Female subjects who are menstruating during planned 
visits will be invited to reschedule cervical specimen collection according to the medical 
judgement of the investigator. 
Pelvic examinations for collection of cervical specimens will be suspended in female 
subjects known to be pregnant until 3 months after delivery.
5.6.8.1.2.
Cervical Sampling
All subjects should undergo pelvic examination during which a cervical-LBC sample 
will be collected for HPV DNA testing by PCR and cytological examination (refer to 
Sections 5.4.2 and 5.6.9 for details on gynaecological examination and follow-up 
algorithms [colposcopy and biopsy procedures]).
5.6.8.2.
ASC-US or LSIL
An observation of ASC-US will result in reflex testing by CICAMS/CFC for high-risk 
HPV types (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) using HCII. 
Results will be communicated to the investigator (or designee) as “ASC-US/oncogenic 
HPV negative” or “ASC-US/oncogenic HPV positive”.
Subjects with ASC-US/oncogenic HPV negative results will not be called back for a 
follow-up biopsy procedure; however, will be encouraged to continue follow-up in the 
context of local medical practice.
Subjects with ASC-US/oncogenic HPV positive results or LSIL will be referred for 
colposcopic evaluation (see Figure 3 for the low-grade colposcopy management 
algorithm).
Specimens will be reported as “Quantity Not Sufficient” (QNS) when there is an 
inadequate amount of cells for HCII testing. In case of ASC-US/QNS or missing HCII 
test results, subjects will be informed and encouraged to follow regular gynaecological 
examination according to local practice.
To ensure active follow-up with subjects missing a follow-up visit or a colposcopy visit, 
study personnel will contact the subject by using established local communication 
methods. The site will make at least three attempts to contact the subject. If contact 
cannot be achieved after three attempts, a certified/registered letter will be sent by the 
site.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
51
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
52
5.6.8.3.
AGC
Observation of AGC will result in an immediate referral for colposcopic evaluation (see 
Figure 4 for the AGC colposcopy management algorithm).
5.6.8.4.
ASC-H / greater than or equal to HSIL
Observation of ASC-H or ≥HSIL will result in an immediate referral for colposcopic 
evaluation (see Figure 5 for the high-grade colposcopy management algorithm).
5.6.9.
Colposcopic evaluations of abnormal cytologies
Colposcopy provides the link between cytology and biopsy. Colposcopy will be 
performed by a trained and experienced colposcopist. Colposcopy will be performed on 
subjects with abnormal cytological findings (except ASC-US/oncogenic HPV negative, 
see Figure 2).
Given that the expertise of the clinical site teams varies in the field of cervical disease 
management and colposcopy, the qualifications and experience of the participating 
colposcopists will be reviewed.
All colposcopies will be recorded in the eCRF and every attempt will be made to 
document colposcopy performed outside the study in the specific section on the eCRF.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
52
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
53
Figure 2
Cytology Management Algorithm
* If a cervical liquid-based cytology (LBC) specimen is deemed “unsatisfactory” by the laboratory, the subject 
must be informed to arrange for another cervical sampling visit.
** Oncogenic HPV positive means that the cytology specimen is positive for an oncogenic HPV type by Hybrid 
Capture II (HCII) testing. This test will automatically be performed on specimens with an ASC-US result 
(reflex testing). Specimens will be reported as “Quantity Not Sufficient” (QNS) when there is an 
inadequate amount of cells for HCII testing. In case of ASC-US/QNS or missing HCII test results, subjects 
will be informed and encouraged to follow regular gynaecological examination according to local 
practice.
5.6.9.1.
Colposcopic procedures
If the transformation zone is not fully visualized, the colposcopy is to be considered as 
not satisfactory. In these cases, an endocervical specimen by endocervical curettage 
will have to be collected during the colposcopy and the vagina carefully inspected.

A normal colposcopy impression may result in taking an endocervical 
specimen by endocervical curettage according to the appropriate algorithm 
and local medical practices. 

A colposcopy impression of LSIL or equivocal will result in biopsy. A 
colposcopy impression of HSIL will also result in a biopsy. 
If the biopsy result/endocervical specimen is negative or ≤CIN1, no further action is 
required; however, the subjects can continue with protocol-specified procedures if 
applicable and will be encouraged to have a follow-up according to local medical 
practice. If the biopsy result or the endocervical specimen is CIN2 or AIS, the subject 
will be referred for treatment according to local medical practice.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
53
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
54
A biopsy specimen that cannot be adequately evaluated by the histopathologist will be 
reported as non-diagnostic. If the biopsy is reported as non-diagnostic, the subjects will 
be offered a repeat colposcopy as soon as possible and a further biopsy would be taken 
from any abnormal or equivocal area.
Any cervical lesions will be biopsied according to colposcopy management algorithms. 
In addition, the vagina and vulva will be inspected with each colposcopy and any 
vaginal or vulvar lesions possibly associated with HPV (other than condylomas) will be 
biopsied or excised according to local medical practice.
All tissues will be shipped to CICAMS/CFC. All tissues will be examined in 
CICAMS/CFC and the report from CICAMS/CFC will be used for clinical 
management.
Every effort should be made to encourage subjects to have the colposcopic examination 
within this study. Should a subject have a colposcopy performed outside of the study, 
she will be asked to consent to allow study staff to access her medical records and to 
obtain slides and tissue for evaluation if possible. 
5.6.9.2.
Colposcopy management for low-grade cytology
The management algorithm shown in Figure 3 should be used for any subject who has 
cytological abnormalities graded as ASC-US/oncogenic HPV positive or LSIL. 
An unsatisfactory colposcopy indicates that the transformation zone is unable to be 
fully visualized. In these cases, an endocervical specimen must be taken by 
endocervical curettage and the vagina carefully inspected. If any abnormality is seen, 
this should be managed according to the algorithm.
If it is a normal colposcopy impression no further action is required and the subjects 
can continue with protocol-specified procedures, if applicable and will be encouraged 
to continue follow-up in the context of local medical practice.
A colposcopy impression of LSIL will result in biopsy - collection of an endocervical 
specimen by endocervical curettage is optional. If the biopsy result is negative or 
CIN1, no further action is required and the subjects can continue with protocol-
specified procedures, if applicable and is encouraged to be followed up according to the 
local medical practice. If biopsy or endocervical curettage show CIN2 or AIS, subjects 
will be referred for treatment according to local medical practice.
For colposcopic impression of HSIL, a biopsy will be performed. If the biopsy result is 
CIN2 or AIS, the subject will be referred for treatment according to local medical 
practice. Subjects with HSIL may also be referred to treatment without biopsy.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
54
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
55
Figure 3
Colposcopy Management Algorithm for subjects with ASC-
US/oncogenic HPV positive results or LSIL
Note: Specimens will be reported as “Quantity Not Sufficient” (QNS) when there is an inadequate amount of 
cells for HCII testing. In case of ASC-US/QNS or missing HCII test results, subjects will be informed and 
encouraged to follow regular gynaecological examination according to local practice
** An unsatisfactory colposcopy indicates that the transformation zone is unable to be fully visualized. In 
these cases an endocervical specimen must be taken and the vagina inspected.
***If invasive cancer is suspected, management should be according to accepted standard medical practice. 
Subjects who do not have a biopsy in the study will be asked to consent to allow study staff to obtain 
their tissue for evaluation if possible.
†Collection of endocervical specimen will depend on local practice and clinical judgement. 
‡ subjects will be encouraged to have gynaecological follow-up as per local practice.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
55
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
56
5.6.9.3.
Colposcopy management algorithm for AGC
This management algorithm (Figure 4) should be used for any subject who has a 
single cytological abnormality graded as AGC.
An unsatisfactory colposcopy indicates that the transformation zone is unable to be 
fully visualized. In these cases, an endocervical specimen must be taken and the vagina 
carefully inspected. If any abnormality is seen, this should be managed according to 
the algorithm.
If the colposcopic impression is normal, an endocervical specimen by endocervical 
curettage will be collected, cytology will be reviewed and the vagina should also be 
carefully inspected. If endocervical and cytological review results are negative or 
LSIL orCIN1 or negative, no further action is required and the subjects can 
continue with protocol-specified procedures, if applicable and will be encouraged to 
continue follow-up in the context of local medical practice. If cytology result (except 
ASC-US/oncogenic HPV negative) or colposcopy is abnormal, please refer to 
appropriate colposcopy management algorithm. 
If endocervical and cytological review results are HSIL, AGC or AIS, the subjects will 
be referred for treatment as per local medical practice.
If the colposcopic impression is LSIL or equivocal, a biopsy should be performed 
depending on the colposcopic impression and local medical practice. An endocervical 
specimen by endocervical curettage may be collected. If a biopsy confirms CIN2 or 
AIS, the subjects will be referred for treatment as per local medical practice. If the 
biopsy result is negative or CIN1, no further action is required and the subjects can 
continue with protocol-specified procedures, if applicable and will be encouraged to 
continue follow-up in the context of local medical practice. If cytology result (except 
ASC-US/oncogenic HPV negative) or colposcopy is abnormal, please refer to 
appropriate colposcopy management algorithm.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
56
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
57
Figure 4
Colposcopy Management Algorithm for subjects with AGC 
* An unsatisfactory colposcopy indicates that the transformation zone is unable to be fully visualized. In these 
cases, an endocervical specimen must be taken and the vagina inspected.
†Collection of endocervical specimen and cytological review will depend on local practice and clinical 
judgement of discrepancy between findings. A high grade AGC should lead to excision biopsy.
ᶲIf invasive cancer is suspected, management should be according to accepted standard medical practice.
‡ subjects will be encouraged to have gynaecological follow-up as per local practice
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
57
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
58
5.6.9.4.
Colposcopy management algorithm for high-grade cytology
This management algorithm (Figure 5) should be used for any subject who has a 
single cytological abnormality graded as ASC-H or ≥HSIL.
An unsatisfactory colposcopy indicates that the transformation zone is unable to be 
fully visualized. In these cases, an endocervical specimen must be taken and the vagina 
carefully inspected. If any abnormality is seen, this should be managed according to 
the algorithm.
If the colposcopic impression is normal, an endocervical specimen by endocervical 
curettage will be collected, cytology will be reviewed and the vagina should also be 
carefully inspected. If the endocervical sampling and cytological review results are 
negative or ≤LSIL, ≤CIN1 no further action is required and the subjects can continue 
with protocol-specified procedures, if applicable. If cytological review or endocervical 
sampling confirms HSIL, ASC-H, AGC or AIS, the subjects will be referred for 
treatment as per local medical practice.
If the colposcopic impression is LSIL or equivocal, a biopsy should be performed. An 
endocervical specimen by endocervical curettage may be collected and cytology 
reviewed depending on local medical practice. If the biopsy result is negative or ≤CIN1, 
no further action is required and the subjects can continue with protocol-specified 
procedures, if applicable. If the biopsy result is CIN2 or AIS, the subjects will be 
referred for treatment as per local medical practice.
For colposcopic impression of HSIL, a biopsy will be performed. If the biopsy result is 
negative or CIN1, no further action is required and the subjects can continue with 
protocol-specified procedures, if applicable. If the biopsy result is CIN2 or AIS, the 
subjects will be referred for treatment as per local medical practice.
For any colposcopy/biopsy/endocervical specimen results ≤LSIL or ≤CIN1, subjects 
will be encouraged to continue follow-up in the context of local medical practice.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
58
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
59
Figure 5
Coloposcopy Management Algorithm for subjects with ASC-H or 
HSIL
* An unsatisfactory colposcopy indicates that the transformation zone is unable to be fully visualized. In these 
cases, an endocervical specimen must be taken and the vagina inspected.
** If invasive cancer is suspected, management should be according to accepted standard medical practice.
†Collection of endocervical specimen will depend on local practice and clinical judgement.
‡ subjects will be encouraged to have gynaecological follow-up as per local practice.
5.6.10.
Sampling (Amended: 21 Jun 2018)
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples. Refer to section 5.6.8 for 
cervical sample collection.
The procedures listed in sections 5.6.11 to 5.6.13 are only applicable for subjects 
undergoing vaccination in this study.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
59
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
60
5.6.11.
Assess pre-vaccination body temperature
The axillary temperature of each subject needs to be measured prior to any study vaccine
administration. If the subject has fever [fever is defined as temperature 37.0°C 
regardless the location of measurement] on the day of vaccination, the vaccination visit 
will be rescheduled within the allowed interval for this visit (see Table 7).
5.6.12.
Treatment number allocation
Treatment number allocation will be performed as described in Section 5.2.1.1. The 
number of each administered treatment must be recorded in the eCRF.
5.6.13.
Study Vaccine administration

After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered intramuscularly (IM) in the deltoid of the non-dominant 
arm (refer to Section 6.3 for detailed description of the vaccine administration 
procedure). If the investigator or delegate determines that the subject’s health on the 
day of administration temporarily precludes vaccine administration, the visit will be 
rescheduled within the allowed interval for this visit (refer to Table 7).

The subjects 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.
5.6.14.
Check and record concomitant medication/vaccination
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.7.
5.6.15.
Recording of AEs, SAEs, pregnancies and its outcome and 
pIMDs

Refer to Section 8.3 for procedures for the investigator to record SAEs, pregnancies 
and pIMDs. Refer to Section 8.4 for guidelines and how to report SAE, pregnancy 
and pIMD reports to GSK Biologicals.
5.6.16.
Safety follow-up contact

The investigator or his/her designee will contact the subjects who have been 
vaccinated, by telephone approximately one and six months after the third vaccine 
dose to obtain information on the occurrence of any of the safety endpoints.

The procedures to be performed during the follow-up telephone contact such as 
recording of any concomitant medication/vaccination or medical treatment and 
recording of SAEs, pregnancies and its outcome (as applicable) and pIMDs are also 
performed during this phone contact and are described in Section 5.6.14 and 
Section 5.6.15, respectively.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
60
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
61
5.6.17.
Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness

complete the Study Conclusion screen in the eCRF.
5.7.
Biological sample handling and analysis (Amended: 21 Jun
2018)
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.

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.
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. 
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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
61
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
62
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 10.5 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
Cervical samples will be collected at Visit 1 from all the subjects to check for HPV 
infection. Subjects who have abnormal cytology findings in the cervical sample 
collected at Visit 1 will be called back for a follow-up colposcopy visit. A cervical biopsy 
may be taken depending on the colposcopy findings. No blood samples will be taken 
during the study.
5.7.3.
Laboratory assays
The assays to be performed are summarized in Table 7.
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.
5.7.3.1.
Cervical Cytology
All original cervical samples collected will be prepared by trained laboratory personnel 
using the ThinPrep® 2000 Processor to transfer and fix the cells onto glass slides. All 
cytology specimens will be processed and then evaluated according to the Bethesda 
2001 classification system for reporting cervical cytology diagnoses.
Cervical cytology will be performed using the ThinPrep® PapTest. (Cytyc Corporation, 
Boxborough, MA, USA). Cervical cells for ThinPrep® cytology will be collected using 
the sampling device provided rinsed into a collection vial containing PreservCyt® 
medium. Specimens will be stored according to the CICAMS/CFC procedure until 
shipment to CICAMS/CFC. Cytological specimens must be shipped at ambient 
temperature within one month of collection.
From the PreservCyt® specimen (original sample), one 1 mL aliquot will be prepared 
and withdrawn prior to ThinPrep® slide preparation (to avoid possible specimen-to-
specimen contamination) for HPV DNA testing. The remaining sample will be used for 
cytological analysis at CICAMS/CFC. 
In case a commercialized test/equipment is not available, an equivalent test/equipment 
may be used after approval by GSK.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
62
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
63
5.7.3.2.
Polymerase chain reaction (PCR) typing of HPV DNA from PreservCyt 
specimens
To test for HPV DNA, SPF10 primers which amplify a 65 nucleotide region of the 
HPV L1 gene for most of the known HPV isolates are used; the generic amplification 
products are detected by hybridization on a microtitre plate (DEIA). HPV-positive 
specimens will be typed by reverse hybridization line probe assay (LiPA), using 25
HPV-specific hybridization probes enabling detection of 14 oncogenic HPV types 
[HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68] and 11 non-
oncogenic HPV types [HPV-6, -11, -34, -40, -42, -43, -44, -53, -54, -70 and -74]. All 
HPV positive samples will also be tested by HPV-16 specific PCR and HPV-18 specific 
PCR. Redundant testing using generic SPF10 PCR with LiPA, followed by HPV-16/18 
type-specific PCR (TS-PCR) affords maximum test sensitivity. The results of this 
testing algorithm will be considered definitive for all HPV-16, -18, -31, -33, -35, -39, -
45, -51, -52, -56, -58, -59, -66 and -68 and HPV-6, -11, -34, -40, -42, -43, -44, -53, -54, -
70 and -74 related study endpoints using HPV DNA testing from PreservCyt® 
specimens.
5.7.3.3.
Hybrid Capture II testing
Clinical management will be guided by Hybrid Capture II testing (see Section 5.4.2). 
After ThinPrep® cytology slides have been prepared, residual PreservCyt® specimens 
on slides read as ASC-US will be tested for HPV DNA. Testing will be done by 
CICAMS/CFC using the HCII test (Digene Corp., Gaithersburg, MD, USA). Probe B 
will be used and is designed to detect infections with 13 oncogenic HPV types (HPV 
types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) [Vernick, 2003]. This test is 
fast, reliable and accurate, but does not provide type-specific data. Therefore, 
additional HPV DNA testing by PCR will be required to define trial endpoints, as 
discussed above. 
Vaginal and vulvar biopsies will be handled according to the same procedures as 
cervical biopsies.
5.7.3.4.
Histopathology
Biopsy specimens obtained during the trial will be fixed in buffered formalin (provided 
by the sponsor) and shipped to CICAMS/CFC for histopathological evaluation and 
PCR examination.
Vaginal and vulvar biopsies will be handled according to the same procedures as 
cervical biopsies.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
63
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
64
5.7.3.4.1.
Histopathological analysis
Histopathological analysis will be performed by CICAMS/CFC. All biopsies will be 
reported independently by two designated, expert pathologists. In case of disagreement 
in diagnosis between the two pathologists, a third expert panel member will examine 
the specimen and a consensus diagnosis will be reached. These diagnoses will be 
placed in the results reporting system and made available electronically at each site 
within a designated timeframe (e.g. 7 days) of receipt at CICAMS/CFC. These results 
will be used for patient management. CICAMS/CFC will expedite reports on specimens 
marked urgent, engage in telephone consultation with clinicians and send slides to 
sites for review by local pathologists on request. Tissue blocks will be retained by 
CICAMS/CFC and, at the discretion of the sponsor, may be evaluated by additional 
techniques to assess the presence of HPV, expression of HPV genes, host responses 
elicited by HPV or other mechanisms involved in cervical carcinogenesis.
Specimens from subjects having biopsies performed outside the study (e.g. very urgent 
clinical need such as suspected invasive cancer) can be examined and entered into the 
study.
5.7.3.5.
HPV DNA PCR testing in tissue
The formalin fixed and paraffin embedded tissue blocks used for histopathological 
analysis will be sectioned for PCR examination at CICAMS/CFC using an appropriate 
clean technique. Sections will be tested for HPV DNA using PCR methodology. 
Samples of lesions will be selected for further analysis using micro-dissection as 
appropriate. To test for HPV DNA, SPF10 primers which amplify a 65 nucleotide 
region of the HPV L1 gene for most of the known HPV isolates are used; the generic 
amplification products are detected by hybridization on a microtitre plate (DEIA). 
HPV-positive specimens will be typed by reverse hybridization line probe assay (LiPA), 
using 25 type-specific hybridization probes. This typing process enables detection of 14 
oncogenic HPV types [HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 
and -68] and 11 non-oncogenic HPV types [HPV-6, -11, -34, -40, -42, -43, -44, -53, -54, 
-70 and -74]. All HPV positive samples will also be tested by HPV-16 specific PCR and 
HPV-18 specific PCR. Redundant testing using generic SPF10 PCR with LiPA, 
followed by HPV-16/18 type-specific PCR (TS-PCR) affords maximum test sensitivity. 
The results of this testing algorithm will be considered definitive for all HPV-16, -18, -
31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68 and HPV-6, -11, -34, -40, -42, -
43, -44, -53, -54, -70 and -74 related study endpoints using HPV DNA testing from 
histopathology. 
Any remaining histopathological sample may be used to further characterize HPV 
infections and associated molecular changes. Histopathological samples may also be 
used for the purpose of validating HPV assays.
Because the proper role of HPV DNA PCR testing in clinical management is 
undefined, the results of this testing will be released to investigators and subjects only 
at the end of the study.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
64
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
65
In cases where multiple HPV types are detected in the samples, additional exploratory 
assays, such as laser microdissection may be performed to investigate the causal role of 
individual HPV types.
Please refer to APPENDIX A for more details on the laboratory assays. Any remaining 
cytological sample may be used to further characterize HPV infections and associated 
molecular changes. This may include sequencing, determination of viral load using 
quantitative HPV PCR or subtyping of HPV detected.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
65
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
66
Table 7
Laboratory Assays
Assay type
Marker
Assay method
Test kit/ 
Manufacturer
Assay unit
Assay
cut-off
Laboratory
Qualitative 
cervical 
cytology
Bethesda 2001 
System for 
reporting 
cervical 
cytology 
diagnoses
MICRLI
(Microscopy 
of cervical 
cytology)
ThinPrep® 
PapTest™
No unit
N/A
CICAMS/CFC
Qualitative 
Histopathology
CIN 
classification
MICRLI
(Microscopy 
of tissue 
sections)
Not applicable Qualitative Qualitative
CICAMS/CFC
Qualitative 
("generic") PCR 
for HPV DNA
(using SPF10 
primers) + LiPA 
on cervical swab
HPV-16, 18, 
31, 33, 35, 39, 
45, 51, 52, 56, 
58, 59, 66, 68, 
6, 11, 34, 40, 
42, 43, 44, 53, 
54, 70 and 74
PCR
HPV SPF10 
PCR DEIA
No unit
N/A
CICAMS/CFC
nucleic acid 
hybridization
HPV SPF10 
PCR LIPA
No unit
N/A
CICAMS/CFC
Qualitative 
("generic") PCR 
for HPV DNA
(using SPF10 
primers) + LiPA 
on cervical 
tissue
HPV-16, 18, 
31, 33, 35, 39, 
45, 51, 52, 56, 
58, 59, 66, 68, 
6, 11, 34, 40, 
42, 43, 44, 53, 
54, 70 and 74
PCR
HPV SPF10 
PCR DEIA
No unit
Qualitative
N/A
Qualitative
CICAMS/CFC
nucleic acid 
hybridization
HPV SPF10 
PCR LIPA
No unit
N/A
CICAMS/CFC
Qualitative 
("type-specific") 
PCR for HPV 
DNA on cervical 
swab
HPV-16
PCR
HPV TS16 
PCR/DEIA
No unit
N/A
CICAMS/CFC
HPV-18
PCR
HPV TS18 
PCR/DEIA
No unit
N/A
CICAMS/CFC
Qualitative 
("type-specific") 
PCR for HPV 
DNA on cervical 
tissue
HPV-16
PCR
HPV TS16 
PCR/DEIA
No unit
N/A
CICAMS/CFC
HPV-18
PCR
HPV TS18 
PCR/DEIA
No unit
N/A
CICAMS/CFC
Qualitative
HPV-16, 18, 
31, 33, 35, 39, 
45, 51, 52, 56, 
58, 59 and 68 
(Oncogenic 
probe 
[cocktail B])
NAH (Nucleic 
acid 
hybridization)
Hybrid 
Capture® 2 
HPV DNA 
Test/Digene 
Corporation
No unit
Qualitative
N/A
Qualitative
CICAMS/CFC
CICAMS/CFC: Cancer Institute/Hospital Chinese Academy Medical Sciences and Cancer Foundation of China; 
DEIA: DNA enzyme immunoassay; PCR: Polymerase Chain Reaction
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
66
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
67
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.
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.
6.
STUDY VACCINE AND ADMINISTRATION (AMENDED: 
21 JUN 2018)
6.1.
Description of study vaccine
The Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed has been developed and 
manufactured by GSK Biologicals. 
The Quality Control Standards and Requirements for 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 is labelled and packed according to applicable regulatory requirements.
Table 8
Study vaccine
Treatment 
name
Vaccine name
Formulation
Presentation
Volume to be 
administered*
Number of 
doses
HPV-16/18
Human 
Papillomavirus 
(Types 16, 18) 
Vaccine, 
Adsorbed
(HPV16-18 
AS04D)
Each 0.5 mL dose 
contains:
HPV16 L1 VLP=20µg; 
HPV18 L1 VLP=20µg; 
Al(OH)₃=325/175µg 
Al3+; MPL=50µg
Liquid in pre-
filled syringes
0.5 ml
3
MPL = 3-O-desacyl-4’-monophosphoryl lipid A; Al(OH)3 = aluminium hydroxide; L1 = structural protein of HPV; VLP = 
Virus-like Particle; mL = millilitre; g = microgram; mg=milligram
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
67
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
68
6.2.
Storage and handling of study vaccine
The study vaccine 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 authorised 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.
Temperature excursions must be reported in degree 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 temperature excursion application. 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 the temperature excursion application, 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.
6.3.
Dosage and administration of study vaccine
Table 9
Dosage and administration
Type of contact 
and time point
Study groups
Treatment 
name
Volume to be 
administered
Route1
Site
Location
Laterality2
Visit 1 (Day 1)
HPV group
HPV-16/18
0.5 ml
IM
Deltoid
Non-dominant
Visit 2 (Month 1)
0.5 ml
IM
Deltoid
Non-dominant
Visit 3 (Month 6)
0.5 ml
IM
Deltoid
Non-dominant
1Intramuscular (IM)
2The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the non-
dominant arm, an injection in the dominant arm may be performed.
6.4.
Replacement of unusable vaccine
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomisation when applicable), at least 10% additional vaccine doses will be 
supplied to replace those that are unusable. 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
68
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
69
6.5.
Contraindications to subsequent vaccination
The following events constitute absolute contraindications to further administration of the 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed. 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 (see Section 8.5). 

Anaphylaxis following the administration of vaccine.

Pregnancy (see Section 8.2.1).

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including HIV infection.

Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe.

Hypersensitivity to the active substances or to any of the excipients.

Any SAE judged by Investigator to be related to the study vaccine.

Administration of another HPV vaccine during the study other than that foreseen by 
protocol.

Any acute or newly acquired chronic condition at the time of scheduled vaccination, 
which in the opinion of the investigator precludes further administration of the study 
vaccine.

Other significant reactions which in the opinion of the investigator (or designate) 
preclude further administration of the study vaccine (may include severe pain, severe 
swelling, severe limitation of motion, persistent high fever, severe headache or other 
systemic or local reactions).

Occurrence of a new pIMD or the exacerbation of an existing pIMD that, in the 
opinion of the investigator, expose the subject to unacceptable risk from subsequent 
vaccination. In such cases, the investigator should use his/her clinical judgement 
prior to administering the next dose of the vaccine. Refer to Section 8.1.4.1 for the 
definition of pIMDs.
The following events constitute contraindications to administration of the Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed 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 (see Section 5.5), or the 
subject may be withdrawn at the discretion of the investigator (see Section 8.5). 

Acute disease and/or fever at the time of vaccination. 

Fever is defined as temperature 37.0°C. The preferred location for measuring 
temperature in this study will be the axilla.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered the Human Papillomavirus (Types 
16, 18) Vaccine, Adsorbed.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
69
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
70
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 or delegate should question the subject 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 during the period starting 30 days before and following each dose of 
study vaccine (Day 1 to Day 31).

Any concomitant vaccination administered in the period starting 30 days before the 
first dose of study vaccine and last contact for each subject.

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]. The preferred location 
for measuring temperature in this study will be the axilla.

Any concomitant medications/products/vaccines listed in Section 6.7.2.

Any concomitant medications/products/vaccines relevant to a SAE/pIMD to be 
reported as per protocol or administered at any time during the study period for the 
treatment of a SAE /pIMD. In addition, concomitant medications relevant to SAEs 
and pIMD need to be recorded on the expedited Adverse Event report.
6.7.2.
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. See Section 10.5 for cohorts to be analysed.

Previous vaccination against HPV outside of study HPV-039.

History of long-acting immune-modifying drugs administered at any time (e.g. 
infliximab).

Drug and/or alcohol abuse.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
70
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
71
7.
HEALTH ECONOMICS
Not applicable.
8.
SAFETY (AMENDED: 21 JUN 2018)
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an AE or SAE as provided in 
this protocol.
Each subject will be instructed to contact the investigator immediately should they 
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:

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 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).
Collection of solicited AEs is not planned in this study. All other AEs will be recorded 
as UNSOLICITED AEs.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
71
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
72
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 
first study 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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
72
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
73
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.
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.
8.1.4.
Adverse events of specific interest
8.1.4.1.
Potential immune-mediated diseases (Amended: 21 Jun 2018)
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 10.
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other diseases have an autoimmune origin (i.e. pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
73
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
74
Table 10
List of potential immune-mediated diseases (Amended: 21 Jun 2018)
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve neuropathy, 
including paralysis and 
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.

Demyelinating peripheral 
neuropathies including:
-
Chronic inflammatory 
demyelinating 
polyneuropathy, 
-
Multifocal motor 
neuropathy 
-
Polyneuropathies 
associated with 
monoclonal 
gammopathy.

Narcolepsy.

Systemic lupus 
erythematosus and 
associated conditions

Systemic scleroderma 
(Systemic sclerosis), 
including:
-
Diffuse Scleroderma
-
CREST syndrome

Idiopathic inflammatory 
myopathies, including:
-
Dermatomyositis 
-
Polymyositis 

Anti-synthetase syndrome.

Rheumatoid Arthritis and 
associated conditions 
including: 
-
Juvenile Idiopathic 
Arthritis
-
Still’s disease.

Polymyalgia rheumatica.

Spondyloarthropathies, 
including: 
-
Ankylosing 
Spondylitis, 
-
Reactive Arthritis 
(Reiter's Syndrome),
-
Undifferentiated 
Spondyloarthritis,
-
Psoriatic Arthritis,
-
Enteropathic arthritis.

Relapsing Polychondritis.

Mixed Connective Tissue 
disorder.

Gout

Psoriasis.

Vitiligo.

Erythema nodosum.

Autoimmune bullous skin 
diseases (including pemphigus, 
pemphigoid and dermatitis 
herpetiformis).

Lichen planus.

Sweet’s syndrome.

Localised Scleroderma 
(Morphoea).
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
74
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
75
Vasculitis
Blood disorders
Others

Large vessels vasculitis 
including: 
-
Giant Cell Arteritis 
(Temporal Arteritis),
-
Takayasu's Arteritis. 

Medium sized and/or small 
vessels vasculitis 
including: 
-
Polyarteritis nodosa,
-
Kawasaki's disease, 
-
Microscopic 
Polyangiitis, 
-
Wegener's 
Granulomatosis 
(granulomatosis with 
polyangiitis), 
-
Churg–Strauss 
syndrome (allergic 
granulomatous 
angiitis or 
eosinophilic 
granulomatosis with 
polyangiitis), 
-
Buerger’s disease 
(thromboangiitis 
obliterans), 
-
Necrotizing vasculitis 
(cutaneous or 
systemic), 
-
anti-neutrophil 
cytoplasmic antibody 
(ANCA) positive 
vasculitis (type 
unspecified),
-
Henoch-Schonlein 
purpura (IgA 
vasculitis), 
-
Behcet's syndrome,
-
Leukocytoclastic 
vasculitis.

Autoimmune hemolytic 
anemia.

Autoimmune 
thrombocytopenia.

Antiphospholipid syndrome.

Pernicious anemia.

Autoimmune aplastic 
anemia.

Autoimmune neutropenia.

Autoimmune pancytopenia.

Autoimmune glomerulonephritis 
including:
-
IgA nephropathy, 
-
Glomerulonephritis rapidly 
progressive, 
-
Membranous 
glomerulonephritis, 
-
Membranoproliferative 
glomerulonephritis, 
-
Mesangioproliferative 
glomerulonephritis. 
-
Tubulointerstitial nephritis 
and uveitis syndrome.

Ocular autoimmune diseases 
including:
-
Autoimmune uveitis 
-
Autoimmune retinitis.

Autoimmune myocarditis.

Sarcoidosis.

Stevens-Johnson syndrome.

Sjögren’s syndrome.

Alopecia areata.

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 
(Hashimoto thyroiditis).

Grave's or Basedow’s disease.

Diabetes mellitus type I.

Addison’s disease.

Polyglandular autoimmune 
syndrome.

Autoimmune hypophysitis.
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD. 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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
75
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
76
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.
8.2.
Events or outcomes not qualifying as adverse events or 
serious adverse events
8.2.1.
Pregnancy
Subjects from HPV group (Ctrl-HPV-039 group) who are pregnant or lactating at the 
time of vaccination must not receive additional doses of study vaccine but may continue 
other study procedures at the discretion of the investigator.
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or a SAE.
Note: The pregnancy itself should always be recorded on an electronic pregnancy report.
The following should always be considered as SAE and will be reported as described in 
Sections 8.4.1 and 8.4.3:

Spontaneous pregnancy loss, including:

spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation)

ectopic and molar pregnancy

stillbirth (intrauterine death of foetus after 22 weeks of gestation).
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognised that national 
regulations might be different.

Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life).

Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the foetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion.
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the study vaccine will be reported to GSK 
Biologicals as described in Section 8.4.3. While the investigator is not obligated to 
actively seek this information from former study participants, he/she may learn of a 
pregnancy through spontaneous reporting.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
76
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
77
8.3.
Detecting and recording adverse events, serious adverse 
events and pregnancies
8.3.1.
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine (Day 1) and will end six months following administration of the last dose of 
study vaccine (Call 2 [Month 12]) for each vaccinated subject. See Section 8.4 for 
instructions on reporting of SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccine.
SAEs that are related to the study vaccine will be collected and recorded from the time of 
the first receipt of study vaccine until the subject is discharged from the study.
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 for all subjects and 
recorded from the time the subject consents to participate in the study until she is 
discharged from the study.
The time period for collecting and recording pregnancies will begin at the first receipt of 
study vaccine (Day 1) and will end six months following administration of the last dose 
of study vaccine (Call 2 [Month 12]). See Section 8.4 for instructions on reporting of 
pregnancies.
The time period for collecting and recording of pIMDs will begin at the first receipt of 
study vaccine and will end six months following administration of the last dose of study 
vaccine (Call 2 [Month 12]). See Section 8.4 for instructions on reporting of pIMDs.
An overview of the protocol-required reporting periods for SAEs, pIMDs, and 
pregnancies is given in Table 11.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
77
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
78
Table 11
Reporting periods for collecting safety information
Event
V1
V2
V3
Call 1
Call 2
D1
M1
M6
M7
M12
Vacc-HPV-039
Reporting of SAEs related to study participation or 
concurrent GSK medication/vaccine*
HPV Group (Ctrl-HPV-039 group)
Reporting of SAEs 
Reporting of AEs/SAEs leading to withdrawal from the 
study
Reporting of SAEs related to the study vaccine
Reporting of SAEs related to study participation or 
concurrent GSK medication/vaccine
Reporting of pregnancies and pregnancy outcomes
Reporting of pIMDs
V: vaccination; D: Day, M: Month
* Serious adverse events will be collected up to end of call back visit (if applicable).
Note: Pregnancy outcomes of subjects who are pregnant at the time of study conclusion will be recorded and reported 
to GSK Biologicals’ Safety department.
8.3.2.
Post-study adverse events and serious adverse events
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 11. Investigators are not obligated to actively seek AEs 
or 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 he/she considers the 
event reasonably related to the study vaccine, the investigator will promptly notify the 
Study Contact for Reporting SAEs.
8.3.3.
Evaluation of adverse events and serious adverse events
8.3.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject should be asked a non-leading 
question such as:
‘Have you felt different in any way since receiving the vaccine or since the previous 
visit?’
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
78
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
79
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in the 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/SAE and not the individual signs/symptoms.
8.3.3.2.
Assessment of adverse events
8.3.3.2.1.
Assessment of intensity
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 adults, such an AE would, for example, prevent attendance at 
work and would necessitate the administration of corrective 
therapy.
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.
8.3.3.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between study vaccine and the 
occurrence of each AE/SAE using clinical judgement. In case of concomitant 
administration of multiple vaccines/products, if possible, the investigator should specify 
if the AE could be causally related to a specific vaccine/product administered (i.e 
investigational, control/placebo or co-administered vaccine). When causal relationship to 
a specific vaccine(s)/product(s) cannot be determined the investigator should indicate the 
AE to be related to all products.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
79
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
80
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 
study vaccine will be considered and investigated. The investigator will also consult the 
IB 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.
Causality of 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 study vaccine?
YES
:
There is a reasonable possibility that the study vaccine contributed to the AE. 
NO
:
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine. There are other, more likely causes and 
administration of the study vaccine is not suspected to have contributed to the 
AE.
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, if applicable.

Erroneous administration.

Other cause (specify).
8.3.3.3.
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.

Fatal (SAEs only).
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
80
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
81
8.4.
Reporting of serious adverse events, pregnancies, and 
other events
8.4.1.
Prompt reporting of serious adverse events, pregnancies, and 
other events to GSK Biologicals
SAEs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 12, once the investigator determines that 
the event meets the protocol definition of a SAE.
Pregnancies that occur in the time period defined in Section 8.3 will be reported promptly 
to GSK within the timeframes described in Table 12, once the investigator becomes 
aware of the pregnancy. 
pIMDs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 12, once the investigator determines that 
the event meets the protocol definition of a pIMD.
Table 12
Timeframes for submitting serious adverse event, pregnancy and 
other events 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
Pregnancies 
2 weeks*
electronic pregnancy report
2 weeks*
electronic pregnancy 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.
8.4.2.
Contact information for reporting serious adverse events,
pregnancies and pIMDs
Study Contact for Reporting SAEs, pIMDs and pregnancies 
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs, pIMDs and pregnancies 
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Fax: 
Email address: 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
81
21-JUN-2018
PPD
PPD

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
82
8.4.3.
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.
8.4.3.1.
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.
8.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS.
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
82
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
83
8.4.5.
Reporting of pIMDs to GSK Biologicals
Once a pIMD is diagnosed (serious or non-serious) in a study subject, 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 8.4.3.1 for back-up system in case the electronic reporting system does 
not work.
8.4.6.
Updating of SAE, pregnancy, and pIMD information after removal 
of write access to the subject’s eCRF
When additional SAE, pregnancy, 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 12.
8.4.7.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.4.1. 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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
83
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
84
8.5.
Follow-up of serious adverse events, and pregnancies
8.5.1.
Follow-up of adverse events and serious adverse events 
8.5.1.1.
Follow-up during the study
After the initial AE/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 12).
All SAEs and pIMDs (serious or non-serious) 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 last visit of the subject.
8.5.1.2.
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, 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 paper/ electronic 
Expedited Adverse Events Report and/or pregnancy report as applicable.
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.
8.5.2.
Follow-up of pregnancies
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using the electronic pregnancy report and 
the Expedited Adverse Events Report if applicable. Generally, the follow-up period 
doesn’t need to be longer than six to eight weeks after the estimated date of delivery.
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
84
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
85
8.6.
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 a SAE / pIMDs 
should be recorded in Expedited Adverse Event Report of the subject’s eCRF (refer to 
Section 6.7).
8.7.
Subject card
Study subjects 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. 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 must be instructed to keep subject cards in their possession at all times during 
the study duration.
9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject completion
A subject who is available for the concluding visit/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 
was not available for the concluding visit/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. 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
85
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
86
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, or by the investigator, as well as which of the following possible 
reasons was responsible for withdrawal:

Serious adverse event.

Unsolicited 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 she has withdrawn consent, the 
investigator will document the reason for withdrawal of consent, if specified by the 
subject, in the eCRF.
Subjects who are withdrawn from the study because of SAEs/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 a SAE/AE until resolution 
of the event (see Section 8.5.1.2).
9.2.2.
Subject withdrawal from study vaccine
A ‘withdrawal’ from the study 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 study 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 study vaccine will be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination/treatment was made by 
the subject herself, or by the investigator, as well as which of the following possible 
reasons was responsible for withdrawal:

Serious adverse event.

Unsolicited non-serious adverse event.

Not willing to be vaccinated

Other (specify).
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
86
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
87
10.
STATISTICAL METHODS (AMENDED: 21 JUN 2018)
10.1.
Primary endpoint

Safety endpoint

HPV group (Ctrl-HPV-039 group)
o
Occurrence of SAEs related to study vaccine.
10.2.
Secondary endpoints

Safety endpoints

HPV group (Ctrl-HPV-039 group)
o
Occurrence of pIMDs throughout the study.
o
Occurrence of pregnancies and pregnancy outcomes throughout the study.
o
Occurrence of SAEs.
o
Any AE/SAE leading to premature discontinuation from the study.

All subjects
o
Occurrence of SAEs related to study participation.

Virological endpoints

Incident cervical infection associated with HPV-16 and/or HPV-18 (by PCR).

Incident cervical infection associated with any oncogenic HPV type (e.g. 
HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68 or 
combination of oncogenic HPV types; by PCR).
10.3.
Tertiary endpoints

Virological endpoint

Incident infection associated with HPV-16/18, any other oncogenic type, 
irrespective of HPV type.

Cytological endpoints

Any cytological abnormality (i.e., [ASC-US] associated with HPV-16 and/or 
HPV-18 cervical infection (by PCR).

Any cytological abnormality associated with any oncogenic HPV type (e.g. 
HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68 or 
combination of oncogenic HPV types; by PCR).

Any cytological abnormality irrespective of the HPV type.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
87
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
88

Histopathological endpoints.

Histopathologically-confirmed CIN1+ associated with HPV-16 and/or HPV-
18 (by PCR).

Histopathologically-confirmed CIN2+ associated with HPV-16 and/or HPV-
18 (by PCR).
CIN2+ is defined as CIN2, CIN3, LCGIN, HCGIN, adenocarcinoma in-situ 
(AIS) or invasive cervical cancer.

Histopathologically-confirmed CIN1+ associated with cervical infection with 
any oncogenic HPV type (e.g. HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -
56, -58, -59, -66 and -68 or combination of oncogenic HPV types; by PCR).

Histopathologically-confirmed CIN2+ associated with cervical infection with 
any oncogenic HPV type (e.g. HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -
56, -58, -59, -66 and -68 or combination of oncogenic HPV types; by PCR).

Histopathologically-confirmed CIN1+ lesions irrespective of HPV type.

Histopathologically-confirmed CIN2+ lesions irrespective of HPV type.

Histopathologically-confirmed VIN1+ associated with HPV-16 and/or HPV-
18 infection (by PCR).

Histopathologically-confirmed VaIN1+ associated with HPV-16 and/or HPV-
18 infection (by PCR).

Histopathologically-confirmed VIN1+ associated with any oncogenic HPV 
type (e.g. HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -
68 or combination of oncogenic HPV types; by PCR).

Histopathologically-confirmed VaIN1+ associated with any oncogenic HPV 
type (e.g. HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -
68 or combination of oncogenic HPV types; by PCR).

Histopathologically-confirmed VIN1+ irrespective of HPV type.

Histopathologically-confirmed VaIN1+ irrespective of HPV type.
For the above mentioned tertiary endpoints, VIN (Vulvar Intraepithelial Neoplasia) is 
defined as VIN1+ or VIN2+, and VaIN (Vaginal Intraepithelial Neoplasia) is defined 
as VaIN1+ or VaIN2+.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
88
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
89
10.4.
Determination of sample size (Amended: 21 Jun 2018)
Since the objectives of the study are descriptive, the sample size for this study is not 
estimated using any power based computations.
Sample size for this study depends on the recruitment of the subjects who previously 
participated in study HPV-039. Up to 6051 subjects who participated in the HPV-039 
study will be invited to participate in this study, of which 3025 subjects did not receive 
the HPV vaccine and are therefore eligible to receive the HPV vaccine in this study.
It is estimated that approximately 1500 to 3000 subjects from the control group in 
HPV-039 will effectively participate in this study and will receive at least one dose of 
HPV vaccine and will be available for the evaluation of the primary objective of the 
study.
The exact 95% confidence interval (CI) for different sample sizes and the value 
observed for the percentage of subjects reporting at least one related SAE is presented 
in the table below.
Table 13
Exact two-sided 95% CI for different sample sizes and the value 
observed for the percentage of subjects reporting at least one 
related SAE
No. of evaluable subjects to be expected (N)
Subjects who reported related SAEs post vaccination
n
%
Exact 95% CI
LL
UL
3000
1
0.0
0.0
0.2
3
0.1
0.0
0.3
5
0.2
0.1
0.4
15
0.5
0.3
0.8
30
1.0
0.7
1.4
1500
1
0.1
0.0
0.4
3
0.2
0.0
0.6
5
0.3
0.1
0.8
8
0.5
0.2
1.0
10
1.0
0.6
1.6
n = Number of subjects who reported related SAEs.
% = (n/N) *100; LL = Lower limit; UL = Upper limit
Reference: HPV-039 (107638): At least one SAE throughout the study period (72 Months) in HPV Group = 1.9% 
[95% CI: 1.4; 2.4]. At least one related SAE was reported by one subject in control group.
10.5.
Cohort for Analyses (Amended: 21 Jun 2018)
10.5.1.
Total enrolled set
The total enrolled set includes all subjects enrolled in study HPV-092 EXT 039.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
89
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
90
10.5.2.
Exposed set HPV-092
The Exposed Set (ES) includes all vaccinated subjects in HPV-092 EXT 039 for whom 
data were available.
10.5.3.
Per-protocol set (PPS-HPV-092)
The Per-Protocol Set (PPS) will include all evaluable subjects, i.e.,

Who meet all eligibility criteria.

Who do not meet any of the criteria for elimination from an PPS analysis during 
the study (see Section 6.7.2).

For whom data concerning endpoint measures are available.

Who belong to the ATP cohort for efficacy of the study HPV-039.
Total Vaccinated Cohort (TVC) and the ATP cohort for the analysis of efficacy in 
study HPV-039 will be used for the analysis of protective effect.
10.6.
Derived and transformed data
The follow-up time for each subject starts:

at the day after first vaccination (Month 0 study HPV-039) if analyses were 
done on the TVC of HPV-039, or

at the day after third vaccination (Month 6 study HPV-039) if analyses were 
done on the ATP cohort of efficacy of HPV-039.
The follow-up time for each subject ends:

at the time of the event (e.g. the start of incident infection or the time of the 
histopathological endpoint),

at Visit 1 in HPV-092 study (Month 120 EXT-039) for subjects who returned 
for HPV-092 but did not have an event, or 

last available timepoint for subjects who do not have an event and do not 
return for study HPV-092 EXT 039.
10.7.
Analysis of demographics
Demographic characteristics (age) at first visit in study HPV-092 EXT 039 and HPV 
vaccination history in study HPV-039 will be summarised overall and by group using 
descriptive statistics. In addition, baseline characteristics (HPV DNA and serostatus) in 
study HPV-039 will be summarised overall and by group for subjects enrolled in study 
HPV-092 EXT 039.
The mean age (plus range and standard deviation) of the enrolled subjects at Dose 1 in 
study HPV-039 as a whole, and per group, will be calculated.
The distribution of subjects enrolled among the study sites were tabulated as a whole 
and per group.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
90
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
91
10.8.
Analysis of safety (Amended: 21 Jun 2018)
Analysis of safety events reported after vaccination in HPV-092 will be performed on 
the Exposed set HPV-092. 
Related SAEs, any AEs/SAEs leading to premature discontinuation of the study, 
pregnancies and pIMDs up to the end of the study (Month 12) will be described in 
detail.
Analysis of SAEs related to study participation will be performed on the total enrolled 
set.
10.9.
Analysis of protective effect (Amended: 21 Jun 2018)
The analysis of protective effect will be performed on the ATP cohort for efficacy and 
TVC of study HPV-039, considering the data from the entire follow-up period of 
studies HPV-039 and HPV-092 combined, i.e., pooled analyses (from Month 0 in study 
HPV-039 up to Month 120 in study HPV-092).

Number and percentage of subjects with incident cervical infection associated 
with HPV-16 and HPV-18 will be summarized by group. 

Number and percentage of subjects with incident cervical infection associated 
with any oncogenic HPV type (e.g. HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, 
-56, -58, -59, -66 and -68 or combination of oncogenic HPV types; by PCR) will 
be summarized by group.
10.10.
Exploratory analysis of long term efficacy
Analysis of long term efficacy will be exploratory. Vaccine efficacy with a 95% CI will 
be calculated using the conditional exact method.
Efficacy analysis of histopathological, virological and cytological endpoints associated 
with HPV-16/18 will be performed and stratified by HPV-16/18 serostatus (by ELISA) 
at baseline in the study HPV-039 with the primary analysis performed on subjects who 
were seronegative (by ELISA) prior to vaccination in study HPV-039 for the 
corresponding HPV type considered in the analysis. 
Additional efficacy analyses will be performed irrespective of baseline HPV DNA, 
cytology and serostatus.
The vaccine efficacy for all endpoints will be calculated using a conditional exact 
method. This method computes an exact CI around the rate ratio (ratio of the 
incidence rates in the HPV group versus the Control group) and takes into account the 
follow-up time of the subjects within each group. Vaccine efficacy is then defined as 
1 minus the rate ratio. In addition, p-values will be calculated using the Fisher’s exact 
test. 
Kaplan-Meier curves for both groups will be generated.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
91
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
92
The analysis of long term vaccine efficacy will be performed on the ATP cohort for 
efficacy and TVC of study HPV-039, considering the data from the entire follow-up 
period of studies HPV-039 and HPV-092 combined, i.e., pooled analyses (from Month 
0 in study HPV-039 up to Month 120 in study HPV-092).
Number and percentage of subjects with referrals to treatment according to local 
medical practice will be summarized by group.
Analyses will be further described in detail in the Statistical Analysis Plan (SAP).
10.11.
Interpretation of analyses
All analyses will be descriptive with the aim to characterise the observed outcomes. 
These descriptive analyses should be interpreted with caution. Refer to limitations of the 
study in the rationale for study design section.
10.12.
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.
10.12.1.
Sequence of analyses

Interim analyses of available safety and protective effect data, may be performed if 
deemed necessary for regulatory or reporting obligations.

A final analysis of all data collected up to Call 2 (Month 12) will be conducted for 
all subjects.
An integrated clinical study report containing all data will be written and made available 
to the investigators.
10.12.2.
Statistical considerations for interim analyses
All analyses in the study will be descriptive. Hence, no statistical considerations for 
interim analysis will be done.
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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
92
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
93
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.
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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
93
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
94
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.
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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
94
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
95
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.
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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
95
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
96
13.
REFERENCES (AMENDED: 21 JUN 2018)
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.
Bao YP, Li N, Wang H et al. Study on the distribution of human papillomavirus types in 
cervix among Chinese women: A meta-analysis. Chin J Epidemiol. 2007; 28 (10): 941-
946. (PubMed link to English abstract: http://www.ncbi.nlm.nih.gov/pubmed/18399135)
Centers for Disease Control and Prevention Metropolitan Atlanta Congenital Defects 
Program (CDC MACDP) guidelines. Birth defects and genetic diseases branch 6-digit 
code for reportable congenital anomalies; 
http://www.cdc.gov/ncbddd/birthdefects/documents/MACDPcode0807.pdf. Accessed on:
15 May 2018.
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.
EMA Guideline on the exposure to medicinal products during pregnancy: need for post-
authorization data (Doc. Ref. EMEA/CHMP/313666/2005 ) ‘adopted at Community level 
in May 2006);
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g
uideline/2009/11/WC500011303.pdf. Accessed on: 15 May 2018.
GlaxoSmithKline Biologicals Clinical Report 107638 (HPV-039). A phase II/III, double-
blind, randomised, controlled study to evaluate the efficacy, immunogenicity and safety 
of GlaxoSmithKline Biologicals’ HPV-16/18 L1 VLP AS04 vaccine administered 
intramuscularly according to a 0, 1, 6-month schedule in healthy Chinese female subjects 
aged 18-25 years. GSK Biologicals’ data on file. 
HPV Information Centre, China: Human Papillomavirus and Related Cancers, Fact Sheet 
2016. Available at: www.hpvcentre.net/statistics/reports/CHN_FS.pdf. Accessed on: 15 
May 2018.
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: 15 May
2018.
Vernick JP, Steigman CK. The HPV DNA virus hybrid capture assay: What is it – and 
where do we go from here? MLO Med Lab Obs. 2003;35:8-13.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
96
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
97
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.
Wang R, Guo XL, Wisman GB, et al. Nationwide prevalence of human papillomavirus 
infection and viral genotype distribution in 37 cities in China. BMC Infect Dis. 2015 Jul 
4;15:257.
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.
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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
97
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
98
APPENDIX A LABORATORY ASSAYS (Amended: 21 Jun 2018)
Polymerase chain reaction (PCR) for HPV DNA detection
To test for HPV DNA, SPF10 primers which amplify a 65 nucleotide region of the HPV 
L1 gene for most of the known HPV isolates are used; the generic amplification 
products are detected by hybridization on a microtiter plate (DEIA). HPV-positive 
specimens will be typed by reverse hybridization line probe assays (LiPA), using 25
type-specific hybridization probes. This typing process enables detection of 14 
oncogenic HPV types [HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 
and -68] and 11 non-oncogenic HPV types [HPV-6, -11, -34, -40, -42, -43, -44, -53, -54, 
-70 and -74.
All HPV positive samples will also be tested by HPV-16 specific PCR and HPV-18 
specific PCR. Redundant testing using generic SPF10 PCR with LiPA, followed by 
HPV-16/18 type-specific PCR (TS-PCR) affords maximum test sensitivity. The results 
of this testing algorithm will be considered definitive for all HPV-16, -18, -31, -33, -35, 
-39, -45, -51, -52, -56, -58, -59, -66 and -68 and HPV-6, -11, -34, -40, -42, -43, -44, -53, 
-54, -70 and -74 related study endpoints using HPV DNA testing from PreservCyt® 
specimens. 
The aliquots and tissue samples may be used to further characterize HPV cervical 
infections (if appropriate, determination of viral load using quantitative HPV PCR, 
sequencing and/or subtyping of HPV types, other type-specific PCR and other PCR 
typing methods). 
Cytology
All original cervical samples collected will be prepared by trained laboratory personnel 
using the ThinPrep® 2000 Processor to transfer and fix the cells onto glass slides. All 
cytology specimens will be processed and then evaluated according to the Bethesda 
2001 classification system for reporting cervical cytology diagnoses.
Cervical cytology will be performed using the ThinPrep® PapTest. (Cytyc Corporation, 
Boxborough, MA, USA). Cervical cells for ThinPrep® cytology will be collected using 
the sampling device provided rinsed into a collection vial containing PreservCyt® 
medium. Specimens will be stored according to the CICAMS/CFC manual until 
shipment to CICAMS/CFC. Cytological specimens must be shipped at ambient 
temperature within one month of collection.
From the PreservCyt® specimen (original sample), one 1 mL aliquot will be prepared 
and withdrawn prior to ThinPrep® slide preparation (to avoid possible specimen-to-
specimen contamination) for HPV DNA testing. The remaining sample will be used for 
cytological analysis at CICAMS/CFC. 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
98
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
99
APPENDIX B
CLINICAL LABORATORIES (Amended: 21 Jun
2018)
Table 14
Outsourced laboratories
Laboratory
Address
Cancer Institute/Hospital, Chinese Academy 
of Medical Sciences and Cancer Foundation 
of China (CICAMS/CFC)
17# Pan Jia Yuan Nan Li, Chaoyang District, Beijing, China
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
99
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
100
APPENDIX C
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 1
eTrack study number and 
Abbreviated Title
205779 (HPV-092 EXT 039)
Amendment number:
Amendment 1
Amendment date:
21 June 2018
Co-ordinating author:
Rationale/background for changes: The protocol has been amended to support the 
post-licensure commitment to the Center for Drug Evaluation (CDE) of National Drug 
Administration of China (CNDA) with regard to the assessment of long term protective 
effect of GSK Biologicals’ HPV vaccine, Adsorbed in subjects who participated in the 
HPV-039 study. To address this, the following changes have been made:

The study design has been modified to include the HPV-vaccinated subjects from the 
HPV-039 study. The number of subjects for the study has been updated from up to 
3025 to up to 6051.

Assessment of rates of HPV-16/18 incident infection up to approximately 10 year 
after vaccination in the study HPV-039 has been added as a secondary objective. 
Long term efficacy against virological, cytological, histopathological endpoints will 
be assessed as a tertiary objective.

Procedures namely; gynaecological examination, cervical sampling, follow-up 
colposcopy and biopsy in subjects with abnormal cytology have been added at Visit 
1.

The assay section has been updated to include testing related to cervical samples and 
biopsy.

The statistical section has been updated to describe “Analysis of long term protective 
effect ” on HPV infection.

Additionally, regulatory approval of Gardasil and Gardasil 9 and approval of 
Cervarix age indication extension up to 45 years in China has been mentioned.

Owing to the extension of age indication of Cervarix up to 45 years, it is specified in 
the protocol that subjects also have the opportunity to receive Cervarix free of charge 
outside of the current study, when commercially available.
The changes with regard to CDE feedback in the main sections of the protocol are 
described here.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
100
21-JUN-2018
PPD

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
101
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Throughout this protocol amendment, the name of the vaccine has been updated from 
“human papillomavirus (HPV) vaccine containing HPV-16/18 L1 virus-like particles 
(VLPs) and AS04 adjuvant” to “Human Papillomavirus (Types 16, 18) Vaccine, 
Adsorbed” as this is the name which appears in the Chinese license.
Title
Safety and protective effect study of GSK Biologicals’ human papillomavirus vaccine 
Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed (GSK580299) in healthy 
female subjects from the HPV-039 study.
Detailed Title
A phase IIIb/IV open-label, multi-centre immunisation study to evaluate the safety of
GSK Biologicals’ Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed, 
administered intramuscularly according to a 0,1,6-month schedule, in healthy Chinese 
female subjects above 26 years of age who received the placebo control vaccine in study
HPV-039 study and to evaluate the safety protective effect of GSK Biologicals’ HPV-
Human Papillomavirus (Types 16/, 18 L1 VLP AS04 vaccine ) Vaccine, Adsorbed, up 
to approximately 10 years after vaccination, in reducing HPV-associated cervical 
infection in subjects who participated in the HPV-039 study.
Indication
The GDS indication was deleted from the synopsis and only indication specific to China 
was retained.
From the age of nine years for the prevention of premalignant ano-genital lesions 
(cervical, vulvar, vaginal and anal) and cervical and anal cancers causally related to 
certain oncogenic Human Papillomavirus (HPV) types. In China, Cervarix is approved 
for use in females 9 through 4525 years of age for the prevention of cervical cancer, 
cervical intraepithelial neoplasia grade 2, grade 3 (CIN 2/3) and adenocarcinoma in situ 
(AIS) and cervical intraepithelial neoplasia grade 1 (CIN1) caused by high risk human 
papillomavirus (HPV) types 16 and 18.
Introduction
The following changes were made in this section.
Cervarix was first licensed in May 2007 in Australia, for use in 10 to 45 year old females. 
In September 2007, the vaccine was licensed in Europe for use from the age of 9 years
for the prevention of persistent infection, premalignant ano-genital lesions (cervical, 
vulvar, vaginal and anal) and cervical, vulvar, vaginal and anal cancers (squamous-
cell carcinoma and adenocarcinoma) caused by oncogenic Human Papillomaviruses 
(HPVs). The vaccine has been licensed in over 133 countries and regions worldwide. In 
July 2016, Cervarix (hereafter referred to as the Human Papillomavirus [Types 16, 18] 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
101
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
102
Vaccine, Adsorbed) was approved for use as a 3-dose schedule at 0, 1, 6 months in 
females from 9 to 25 years in China. The extension of the vaccine indication up to 45 
years of age was approved by the Chinese authorities on 10-May-2018.
In May 2017, Merck’s recombinant quadrivalent HPV vaccine, Gardasil, also received 
approval in China. In April 2018, Gardasil 9 was granted conditional approval by 
National Drug Administration of China (CNDA) with additional requirements in 
China.
To date, safety and immunogenicity data were evaluated in more than 60,000 
adolescents and adults aged 9 years and above have received at least one dose of the HPV 
vaccine in clinical studies. The vaccine is known to be immunogenic and generally well 
tolerated. Pooled safety analyses of girls and women aged 9 years and above have shown 
that the vaccine was generally well tolerated in women of all ages [Descamps, 2009; 
Angelo, 2014].
Section 1.1: Background
The number of countries where Cervarix has been licensed since then was changed from 
136 to 133 countries.
Rationale for the study
In China, the HPV-16/18 L1 VLP AS04 vaccine is not indicated for women over 26 
years, and therefore approximately 3025 subjects from the control group in the HPV-039 
study are currently unable to receive the HPV-16/18 L1 VLP AS04 vaccine. This study is 
being conducted has been designed following ethical considerations, to enable all 
subjects who received placebo in the HPV-039 study, to also receive the GSK 
Biologicals’ Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed. Subjects in the 
control group of HPV-058 study may also be invited to participate in this study if they are 
26 years of age or above at the time when cross-over vaccination is offered to HPV-058 
participants. Safety data in terms of serious adverse events (SAEs), any adverse events 
(AEs)/SAEs leading to premature discontinuation of the study, potential immune 
mediated diseases (pIMDs) and pregnancies (and their outcomes) will be collected during 
the study period. In addition, this study also aims to assess the long term protective 
effect of the vaccine, in an exploratory manner, in terms of rates of HPV-related 
(vaccine type) incident cervical infection (secondary objective), cytological 
abnormalities and CIN2+ lesions (tertiary objective) up to approximately 10 years after 
vaccination in subjects who participated in HPV-039 study, to support the post-
licensure commitment from the Center for Drug Evaluation (CDE) of CNDA. At the 
availability of the commercial vaccine for use in individuals above 25 years, subjects 
will be offered the opportunity to receive Cervarix free of charge either by participating 
to this study or without participating to this study.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
102
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
103
Rationale for the study design
Since all subjects will receive three doses of the HPV-16/18 L1 VLP AS04 vaccine, this 
This study will be conducted in an open-label and non-randomised manner, since the 
subjects who had participated in study HPV-039 already know the treatment they 
received and only those of the control group in study HPV-039 will receive Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed in the current study. Safety data will 
be collected from Dose 1 until the end of the study in subjects vaccinated in this study. 
No blood or other biological samples Cervical samples will be collected in this study at 
Visit 1 from all subjects to test for HPV incident infection and cytological 
abnormalities. Subjects with abnormal cytology will be called back for colposcopy 
follow-up and biopsy to examine for the presence of CIN lesions.
Limitations:
In the HPV-039 study, the efficacy of GSK Biologicals’ Human Papillomavirus (Types 
16, 18) Vaccine, Adsorbed against virological, cytological and histopathological 
endpoints associated with HPV types 16 and 18, was demonstrated up to 6 years after 
vaccination and subjects were screened every 6 months. The study was unblinded after 
completion and since the Year 6, 3-4 years have elapsed with no regular follow-up of 
the subjects. As a consequence, at Year 10, there might be high subject attrition, 
leading to a potential imbalance in the numbers of subjects from the vaccinated versus 
control group returning for the current study. This as well as a lack of regular 
gynaecological follow-up between Year 6 and Year 10 may compromise assessment of 
vaccine efficacy in this study. Therefore, vaccine efficacy analyses will be exploratory.
Section 1.3.1: Risk assessment
Angioedema was added as a risk associated with study procedure of vaccination.
Additionally, risks and benefits associated with colposcopy were added and overall 
benefit risk assessment was updated as follows.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
103
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
104
Risk assessment table was updated as follows:
Important Potential Risk
Data/Rationale for Risk
Mitigation Strategy
Investigational vaccine
Theoretical potential risk of 
inducing or exacerbating an 
autoimmune disease following 
vaccination.*
Potential concern that Human 
Papillomavirus (Types 16, 18) 
Vaccine, Adsorbed, and 
adjuvanted vaccines in general, 
might be associated with an 
increased risk of new onset of 
autoimmune diseases. Analysis of 
cumulative data so far remains 
inconclusive with respect to any 
potential pathogenic link between 
Human Papillomavirus (Types 16, 
18) Vaccine, Adsorbed and 
autoimmune diseases.
Naturally occurring autoimmune 
diseases are multi-aetiological 
conditions with multiple risk factors, 
including genetic predisposition. Relative 
risks for autoimmune diseases following 
Human Papillomavirus (Types 16, 18) 
Vaccine, Adsorbed administration are 
derived from the most recent pooled 
analysis of clinical trial data, which 
showed no difference between groups. 
The incidence of autoimmune diseases 
is being monitored closely in the ongoing 
clinical trials, post-marketing 
spontaneous reports, literature and 
observational epidemiological studies 
specifically designed to evaluate the risk 
of autoimmune diseases following 
vaccination with Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed.
Study Procedures 
Allergic reactions (including 
anaphylactic and anaphylactoid 
reactions), angioedema, or other 
immediate reactions such as 
syncope or vasovagal response 
following vaccination.
Spontaneous data
Subjects will be observed for at least 30 
minutes after vaccine administration, 
with medical attention available in case 
of anaphylactic reactions.
Colposcopy with targeted 
biopsies may involve rare 
events such as lower abdominal 
pain, vaginal bleeding, fever, 
chills and yellow colored 
vaginal discharge.
Spontaneous data 
In general, the colposcopy and 
biopsy procedures are relatively 
simple and safe
Colposcopy and biopsy will be 
conducted by experts from the 
Cancer Institute/Hospital, Chinese 
Academy of Medical Sciences and 
Cancer Foundation of China
*Only for subjects being vaccinated in this study.
Section 1.3.2: Benefit Assessment was updated as follows:
Cervical cancer is one of the most common cancers in women, and is often fatal. 
Vaccination with Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed is likely to 
prevent the occurrence of HPV infection, premalignant genital lesions and cervical 
cancers associated with HPV types 16 and 18. All study participants who belonged to the 
control group in the HPV-039 study will be invited to receive Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed. In addition, subjects from HPV-039 study will also 
be invited to take part in gynaecological examination and cervical sampling during the 
study. In case of abnormal cytology results of cervical samples, the subjects will be 
called back for a follow-up colposcopy examination. Colposcopy is an important 
routine procedure in the initial evaluation of cervical abnormalities for cancer 
screening in many countries. Colposcopy with targeted biopsies provides accurate 
identification of cervical diseases when present, as well as reassurance of the absence 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
104
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
105
of disease in the subjects. Since cervical screening in this age group is not the standard 
of care in China at present, the study provides an opportunity for the enrolled subjects 
to have a cervical cancer screening.
Section 1.3.3: Overall Benefit : Risk Conclusion was updated as follows:
Taking into account the measures taken to minimise risk to subjects participating in this 
study, the potential or identified risks identified in association with Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed or in association with the study 
procedures are justified by the potential benefits (prevention of HPV infection, screening 
of HPV-related diseases) that may be afforded to subjects. receiving Human 
Papillomavirus (Types 16, 18) Vaccine, Adsorbed.
Section 2: Objectives
Objectives were updated to add vaccine efficacy-related objectives in addition to the 
safety objective of the study.
Primary objective:
To assess the safety of the HPV-GSK Biologicals’ Human Papillomavirus (Types 16/, 
18L1 VLP AS04 vaccine) Vaccine, Adsorbed throughout the study period in subjects 
above 26 years of age who previously received placebo in the HPV-039 study in terms 
of related SAEs.
Secondary objectives:

To assess the safety of GSK Biologicals Human Papillomavirus (Types 16, 18) 
Vaccine in terms of occurrence of unsolicited AEs in subjects above 26 years of 
age, who previously received placebo in the HPV-039 study.

To assess the protective effect of GSK Biologicals’ Human Papillomavirus (Types 
16, 18) Vaccine, Adsorbed in all subjects who participated in the HPV-039 study in 
terms of the rates of HPV 16/18 incident infection up to approximately 10 years 
after vaccination.

To assess the protective effect of GSK Biologicals’ Human Papillomavirus (Types 
16, 18) Vaccine, Adsorbed in all subjects who participated in the HPV-039 study in 
terms of the rates of incident infection associated with any or combination of 
oncogenic HPV types, up to approximately 10 years after vaccination.
Tertiary objectives

To assess the long term efficacy of GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of incident infection associated 
with HPV-16 and or HPV-18 or with any or combination of oncogenic HPV types.

To assess the long term efficacy of GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of cytological abnormalities 
associated with HPV-16 and/or HPV-18.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
105
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
106

To assess the long term efficacy of GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of cytological abnormalities 
associated with any or combination of oncogenic HPV types.

To assess the long term efficacy of the GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of histopathologically-
confirmed CIN1+ associated with HPV-16 and/or HPV-18.

To assess the long term efficacy of the GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of histopathologically-
confirmed CIN1+ associated with any or combination of oncogenic HPV types.

To assess the long term efficacy of GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of histopathologically-
confirmed CIN2+ associated with HPV-16 and/or HPV-18.

To assess long term efficacy of the GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of histopathologically-
confirmed CIN2+ associated with any or combination of oncogenic HPV types.

To assess the long term efficacy of the GSK Biologicals’ Human Papillomavirus 
(Types 16, 18) Vaccine, Adsorbed in the prevention of other 
histopathologically-confirmed endpoints associated with HPV-16 and/or HPV-18 
or any or combination of oncogenic HPV types.
Section 3: Study design

The study design was updated to add a group with HPV vaccinated subjects from 
HPV-039. Consequently, the study design was updated to have two study groups, as 
follows:

Vacc-HPV-039 group i.e. subjects who received HPV vaccine in HPV-039 
study who will undergo cervical sample collection only.

HPV group (Ctrl-HPV-039 group) i.e. subjects who received control vaccine 
in HPV-039 study will receive HPV vaccine in the current study and undergo 
cervical sample collection before HPV vaccination.

The study design figure was also updated:
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
106
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
107
N: Number of subjects
1 Sampling from the subjects of Ctrl-HPV-039 group will be done before vaccination.
2 Subjects can choose to consent to both cervical sampling and vaccination procedures or one of the two 
procedures during the informed consent process.
3Call back visit for colposcopy and follow-up of subjects with abnormal cytology. Medical care of subjects 
with abnormal cervical lesions will be outside of the study, according to the local medical practice.

Throughout the protocol amendment, the tables and text was updated to reflect two
study groups (where applicable). Consequently, duration of study for different groups 
were updated as one day (Visit 1) for HPV vaccinated subjects from HPV-039 study
(Vacc-HPV-039 Group) and Month 12 for control group subjects from HPV-039 
study (HPV Group). Individual changes have not been tracked in bold and italics.

End of Study (EoS): Last subject’s last visit/contact (Call 2 [Month 12]) or last 
testing results released for samples collected at Visit 1 and related call back visits, 
whatever comes later.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
107
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
108

Treatment allocation: sequential allocation of treatment to subjects by 
randomisation system on internet (SBIR). Treatment allocation depends on the 
randomization in the previous study i.e. only the subjects from the control group of 
HPV-039 study will receive HPV vaccination in the current study. Subjects who 
previously received the Human Papillomavirus (Types 16, 18) Vaccine, Adsorbed in 
HPV-039 will not receive vaccination in this study.
As the study now involves collection of cervical samples, sampling schedule was added 
as follows:

Sampling schedule: A cervical sample will be taken at Visit 1 before vaccine 
administration.
For subjects who have abnormal cytology findings in the cervical sample collected 
at Visit 1, there will be a call-back follow-up visit for colposcopy examination. A 
cervical biopsy will be taken depending on the results of the colposcopy 
examination.

Data collection: Standardised Electronic Case Report Form (eCRF).

Safety monitoring:

All subjects: 
o
SAEs related to study participation.

HPV Group (Ctrl-HPV-039 group):
o
All SAEs, and any AE/SAE leading to premature discontinuation of the 
study will be reported throughout the study.
o
pIMDs will be reported for all subjects throughout the study.
o
Pregnancies and pregnancy outcomes will be reported for all subjects
throughout the study.
Section 4.1: Number of subjects/centres
Overview of recruitment plan
Approximately 3025Up to 6051 subjects who participated received placebo in the 
HPV-039 study and above 26 years of age at the time of entry in this study will be invited 
to participate in this study. cross-over vaccination study with GSK Biologicals’ HPV-
16/18 L1 VLP AS04 vaccine. Subjects Subjects in the control group of HPV-058 study 
may also be invited to participate in this study if they are above 26 years of age at the 
time when cross-over vaccination will be offered to HPV-058 participants.
The study recruitment period is expected to last approximately 6 months and the 
recruitment period will be communicated to all study investigators. Investigators will 
make all efforts to invite and enrol subjects during this period.
Women who are pregnant during the recruitment period will be offered participation in 
the study or free of charge vaccination outside the study using commercial vaccine
three months after the pregnancy ends.
Hence, the study end may change depending on study progress.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
108
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
109
Section 4.2: Inclusion criteria for enrolment
The inclusion criteria were updated to organize the criterion as per the study procedure.
All subjects must satisfy ALL the following criteria at study entry:

Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. return for study visits, available for follow-up 
telephone contacts).

Written informed consent obtained from the subject prior to performing any study 
specific procedure.

A Subjects previously enrolled in the HPV-039 study., who received the control 
vaccine, and who is above 26 years of age at the time of entry in this study. Subjects 
in the control group of HPV-058 study may also be invited to participate in this study 
if they are above 26 years of age at the time when cross-over vaccination is offered 
to HPV-058 participants.

Subjects with negative pregnancy test at Visit 1.
Additional inclusion criteria for subjects of HPV group undergoing vaccination 
ONLY:

Healthy subjects as established by medical history and clinical examination before 
entering into the study.

Female subjects of non-childbearing potential may be enrolled in the study.

Non-childbearing potential is defined as pre-menarche, current bilateral tubal 
ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause.
Please refer to the glossary of terms for the definition of menarche and menopause.

Female subjects of childbearing potential may be enrolled in the study, if the subject:

has practiced adequate contraception for 30 days prior to vaccination, and

has a negative pregnancy test on the day of vaccination, and

has agreed to continue adequate contraception during the entire treatment period 
and for 2 months after completion of the vaccination series.
Please refer to the glossary of terms for the definition of adequate contraception.
Section 4.3: Exclusion criteria for enrolment
The exclusion criteria were updated to organize the criterion as per study procedure.
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:

Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device).
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
109
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
110

Previous vaccination against HPV outside of study HPV-039. or planned 
administration of another HPV vaccine during the study other than that foreseen in 
the protocol.
Additional exclusion criteria for subjects of HPV group undergoing vaccination 
ONLY:

Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine during the period starting 30 days before the first dose of study 
vaccine (Day -29 to Day 1), or planned use during the study period.

Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe.

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting six 
months prior to the first vaccine dose. For corticosteroids, this will mean prednisone 
(20 mg/day, or equivalent. Inhaled and topical steroids are allowed.

Planned administration/administration of a vaccine/product not foreseen by the study 
protocol in the period starting 30 days before and after each dose of vaccine 
administration, with the exception of administration of routine meningococcal, 
hepatitis B, hepatitis A, inactivated influenza and/or rabies vaccine up to eight days 
before and after each dose of study vaccine. Enrolment will be deferred until the 
subject is outside of the specified window.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine. 

Previous administration of MPL or AS04 adjuvant.

Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality, as determined by physical examination or laboratory 
screening tests.

Cancer or autoimmune disease under treatment.

Hypersensitivity to latex.

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature 37.0°C. The preferred location for measuring 
temperature in this study will be the axilla.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may, be enrolled at the discretion of the investigator.

Pregnant or lactating female breastfeeding. Subjects must be at least three months 
post-pregnancy and not breastfeeding to enter the study. For pregnant or lactating 
women, also please refer to Section 4.1
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
110
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
111

Female planning to become pregnant or planning to discontinue contraceptive 
precautions during the vaccination phase of the study, i.e. up to two months after the 
last vaccine dose.
Section 5.2: Subject identification and randomisation
Section 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.
Subjects will be allocated the same identification numbers as in study HPV-039.
Section 5.2.1.2: Treatment allocation to the subject was re-organized for clear flow of 
information and to minimize the redundant information as follows:
The treatment numbers will be allocated by dose. 
A sequential list of treatment numbers will be generated by MATerial EXcellence 
(MATEX). The Randomisation and Treatment Allocation System on Internet (SBIR) 
will be used to allocate treatment numbers to the subjects.
After obtaining the signed and dated ICF from the subject and having checked the 
eligibility of the subject, the site staff in charge of the vaccine administration will access 
SBIR. Upon providing the subject identification number, the randomisation system will 
provide the treatment number to be used for the first dose.
When SBIR is not available, please refer to the SBIR user guide for specific instructions.
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
Section 5.3: Method of blinding
This is an open-label study since all subjects who received placebo in the HPV-039 study 
will receive GSK Biologicals’ HPV-16/18 L1 VLP AS04 vaccine. Not applicable since 
this is an open-label study. However the laboratory in charge of the laboratory testing: 
personnel 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.
The laboratory testing mentioned above refers to cytology and PCR testing.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
111
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
112
Section 5.4: General study aspects was updated to include procedures of HPV DNA 
testing and cytology testing as follows:
Section 5.4.1: HPV DNA testing
All the assessment of cervical samples for this study will be done by the Cancer 
Institute/Hospital, Chinese Academy of Medical Sciences and Cancer Foundation of 
China (CICAMS/CFC).
“Reflex” testing by the US FDA and China FDA-approved hybridization assay (Hybrid 
Capture® 2 test [HCII]) will be used to guide a subject’s management in case of 
atypical squamous cells of undetermined significance (ASC-US, see Section 5.6.8.2). 
CICAMS/CFC will automatically perform HPV DNA Hybrid Capture II (HCII) testing 
on the liquid-based cytology specimen. Study personnel do not need to request the 
HCII testing.
Currently available data do not support the use of HPV DNA PCR testing in the 
routine management of subjects diagnosed with abnormal cervical cytology. The HPV 
DNA PCR testing, which will be used in this study, has been developed for 
investigational use only. For this reason, clinical management will not be driven by the 
results of this testing. A number of procedures will be followed to ensure that HPV 
DNA PCR test results do not bias either the conduct of the trial, or the clinical 
management of the study subjects.
These procedures include:
1.
Study sites and study personnel will be blinded to HPV DNA PCR test results 
throughout the study to ensure that these results do not bias either the conduct of 
the trial, or the clinical management of study subjects. This includes bias that 
might result from deviations from regular study interval visits for cervical 
cytological follow-up and/or colposcopic procedures.
2.
HPV DNA PCR test results will NOT be provided to the investigators or study 
subjects until the end of the study. A summary report on results will be distributed 
to the investigators after study completion. It will be the responsibility of the 
investigators to inform study subjects of their results. The clinical management of 
subjects should follow the recommended guidelines outlined below and should be 
based solely on cervical cytology or biopsy results and HCII testing (not HPV DNA 
PCR test results). 
Section 5.4.2: Management of subjects with abnormal cytology
Cervical cytology specimens will be collected using the sampling device provided. 
Cytological examination will be performed using the ThinPrep® PapTest (Cytyc 
Corporation, Boxborough, MA, USA). HPV DNA PCR testing will be performed on the 
cervical cytology specimens collected on Day 1 (Visit 1). In case of abnormal cytology 
results, the subjects will be called back for a follow-up visit for colposcopy 
examination. The following algorithms (see Figure 2, Figure 3, Figure 4 and Figure 5) 
describe clinical management guidelines to be followed by the investigator (and/or 
designee). Treatment of subjects with abnormal findings is not within the scope of this 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
112
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
113
study; however, the subjects will be referred to local healthcare centres to follow local 
medical practices. The algorithms are based on the guidelines of the American Society 
for Colposcopy and Cervical Pathology and European guidelines, and are designed to 
provide a consistent method of detection, clinical management and reporting for 
cervical lesions. The clinical management algorithms cannot define every clinical 
situation and, therefore, it is the investigator’s (or designee’s) responsibility to exercise 
appropriate clinical judgment in the medical management of exceptional cases. 
Compliance with the algorithm will be monitored.
Section 5.4.2.1: Cytology and histology report terminology
Each cytopathology specimen will be reported according to the Bethesda 2001 
Classification of cytological findings. The terminology will include a statement as to 
whether a specimen is satisfactory or unsatisfactory. In addition, specimens that are 
satisfactory but show no endocervical component will be identified for quality control 
of cytological sampling.
For the purposes of the trial, management is specified for the categories:

Unsatisfactory

Negative for intraepithelial lesion or malignancy (negative)

Atypical squamous cells of undetermined significance (ASC-US):

ASC-US / Hybrid Capture II negative (ASC-US/oncogenic HPV negative)

ASC-US / Hybrid Capture II positive (ASC-US/oncogenic HPV positive)

ASC-US / Hybrid Capture II quantity not sufficient (ASC-US/QNS)

Atypical squamous cells-cannot exclude HSIL (ASC-H)

Low-grade squamous intraepithelial lesion (LSIL)

High-grade squamous intraepithelial lesion (HSIL)

Atypical glandular cells (AGC)

Invasive malignancy
Specimens will be reported as “Quantity Not Sufficient” when there is an inadequate 
amount of cells for HCII testing. In case of ASC-US/QNS or missing HCII test results, 
subjects will be informed and encouraged to follow regular gynaecological 
examination according to local practice.
Histopathological reports on biopsy and excision specimens will classify the findings 
as:

Negative

Condyloma
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
113
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
114

Cervical intraepithelial neoplasia grade 1 [CIN1]
Vaginal intraepithelial neoplasia grade 1 [VaIN1]
Vulvar intraepithelial neoplasia grade 1 [VIN1])

Cervical intraepithelial neoplasia grade 2 [CIN2]
Vaginal intraepithelial neoplasia grade 2 [VaIN2]
Vulvar intraepithelial neoplasia grade 2 [VIN2])

Cervical intraepithelial neoplasia grade 3 [CIN3]
Vaginal intraepithelial neoplasia grade 3 [VaIN3]
Vulvar intraepithelial neoplasia grade 3 [VIN3])

Low grade cervical glandular intraepithelial neoplasia (LCGIN)

High grade cervical glandular intraepithelial neoplasia (HCGIN) 

Adenocarcinoma in-situ (AIS)

Invasive malignancy
Section 5.4.2.2: Cytology and colposcopy management algorithms
The algorithm in Figure 2 describes the clinical management of all cytology results 
obtained at Day 1 (Visit 1). Subjects with cytology reported as negative or as ASC-US/ 
oncogenic HPV negative will not be called back for a follow-up biopsy sample. Subjects 
with abnormal cytological findings (except ASC-US/oncogenic HPV negative) should 
be managed according to the recommendations for follow-up in Figure 2 and the 
colposcopy algorithms in Figure 3, Figure 4 and Figure 5. The results of the cytology 
will be communicated to the investigator (or designee) by CICAMS/CFC. The 
investigator (or designee) will notify the subject of the test result and, when 
appropriate, the subject should receive colposcopy within approximately 30 days after 
cytology results have been communicated by CICAMS/CFC.
Section 5.4.2.3: Unsatisfactory cytological findings and missing cytology results
When the laboratory results deem a cervical liquid-based cytology (cervical-LBC) 
specimen unsatisfactory, study personnel are required to repeat the cervical-LBC 
specimen as soon as possible after cytology results have been communicated. Only 
satisfactory results of a repeat cytology result will count as the final cytology result. 
Likewise, HPV DNA PCR testing will not be performed on unsatisfactory cytology 
specimens.
In addition, cytological specimens reported as “satisfactory for evaluation-
endocervical/ transformation zone component absent” should be managed according to 
the given cytological diagnosis. These smears should not be repeated but the 
information will be used for quality control monitoring. Abnormal cytology should be 
managed according to the appropriate protocol-specified algorithm. Missing cytology 
results will be recorded as missing results (in the case of lost damaged sample).
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
114
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
115
Section 5.5: Outline to study procedures
Three different tables on list of study procedures, one for each group and sub-group, were 
added, as follows:
Table 4
List of study procedures – Vacc-HPV-039 group
Epoch
Epoch 001
Type of contact
Visit 1 
Time points
Day 1
Informed consent
● 
Check inclusion/exclusion criteria
● 
Collect demographic data
● 
Medical history†
● 
Physical examination
● 
Pregnancy test
● 
Gynaecological examination
●
Cervical sampling
●
Referral for colposcopy (if applicable)**
○
Report colposcopy results (if applicable)**
●
Safety assessments
Record any concomitant medication/vaccination*
●
Recording of SAEs related to study participation
●
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.
† Medical history since the last visit in study HPV- 039 will be recorded. The subjects should also provide their 
history of any HPV related infection/disease with all available information.
*Including only HPV vaccination and others which may lead to elimination from per-protocol analysis.
** Subjects with abnormal cervical cytology will be evaluated according to the cytology and colposcopy 
clinical management algorithms (see Section 5.4.2 and Section 5.6.9) at unscheduled visits following Visit 1.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
115
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
116
Table 5
List of study procedures – HPV Group (Ctrl-HPV-039 group)
Epoch
Epoch 001
Type of contact
Visit 1 
Visit 2
Visit 3
Call 1
Call 2
Time points
Day 1
Month 1
Month 6
Month 7
Month 12 
Informed consent
● 
Check inclusion/exclusion criteria
● 
Collect demographic data
● 
Medical and vaccination history†
● 
Physical examination
● 
Pregnancy test
● 
● 
● 
Check contraindications and warnings and precautions 
to vaccination
● 
● 
● 
Gynaecological examination
●
Cervical sampling
●
Referral for colposcopy (if applicable)**
○
Report colposcopy results (if applicable)**
●
Pre-vaccination body temperature
● 
● 
● 
Vaccine
Treatment number allocation
O 
Treatment number allocation for subsequent doses
O 
O 
Recording of administered treatment number
● 
● 
● 
Vaccine administration
● 
● 
● 
Safety assessments
Record any concomitant medications/vaccinations
● 
● 
● 
● 
● 
Recording of pregnancies and outcomes 
● 
● 
● 
● 
● 
Recording of SAEs
● 
● 
● 
● 
● 
Recording of AEs/SAEs leading to premature 
withdrawal from the study 
● 
● 
● 
● 
● 
Recording of pIMDs 
● 
● 
● 
● 
● 
Safety follow-up contact 
● 
● 
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.
† Medical history since the last visit in study HPV- 039 must be recorded. The subjects should also provide 
their history of any HPV related infection/disease with all available information.
** Subjects with abnormal cervical cytology will be evaluated according to the cytology and colposcopy 
clinical management algorithms (see Section 5.4.2 and Section 5.6.9) at unscheduled visits following Visit 1.
The title of the table for intervals between study visits was updated as follows:
“Intervals between study visits (for the HPV Group)”
Section 5.6: Detailed description of study procedures
Note: Each study procedure is detailed in subsequent subsections only once, even if 
some of them need to be performed during more than one visit.
Section 5.6.1: Informed consent
The following text was added:
Subjects in the HPV group (Ctrl-HPV-039 group) will be given the choice to consent to 
either sampling or vaccination or both procedures during the informed consent
process.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
116
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
117
Section 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 cervical sample collection or the first study vaccination in the eCRF.
The subjects should also provide their history of any HPV related infection/disease 
with all available information since their last visit in study HPV-039.
Section 5.6.5: Physical examination:
The following text was added:
For subjects in the Vacc-HPV-039 group, the investigator must use her medical 
judgement to decide if a subject can undergo cervical sampling procedure; Subjects 
may be rescheduled or excluded from the study on the basis of medical history.
Section 5.6.6: Pregnancy test
Female subjects of childbearing potential are to have a negative urine pregnancy test 
prior to any study gynaecological examination, cervical sample collection or vaccine 
administration. The study vaccine may only be administered if the pregnancy test is 
negative.
In case of a positive urine pregnancy test result, the subjects would not be allowed to 
receive vaccination or undergo cervical sampling until 3 months after the end of 
pregnancy.
Sections on gynaecological examination and cervical sampling were added.
Section 5.6.8: Gynaecological examination and cervical sampling
Section 5.6.8.1: Gynaecological examination
Gynaecological examination will be performed on Day 1 (Visit 1). At gynaecological 
examination, according to local medical practice, the vagina and vulva will be 
inspected using the unaided eye or the colposcope or a magnifying glass. If needed, 
acetic acid may be applied.
Any vaginal or vulvar lesions possibly associated with HPV (other than condylomas) 
will be biopsied and excised according to local medical practice. This may include 
referral to the study colposcopists. All tissues will be shipped to CICAMS/CFC. After 
completion of the gynaecological examination, women should be encouraged to 
continue follow-up in the context of local medical practice.
Section 5.6.8.1.1: Requirements for cervical specimen collection
Sexual intercourse must be avoided for the 24 hours before collection of a cervical 
specimen. Cervical specimen collection must be performed a minimum of one day after 
menstrual flow has ceased. Female subjects who are menstruating during planned 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
117
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
118
visits will be invited to reschedule cervical specimen collection according to the medical 
judgement of the investigator. 
Pelvic examinations for collection of cervical specimens will be suspended in female 
subjects known to be pregnant until 3 months after delivery.
Section 5.6.8.1.2: Cervical Sampling
All subjects should undergo pelvic examination during which a cervical liquid-based 
cytology (LBC) sample will be collected for HPV DNA testing by PCR and cytological 
examination (refer to Sections 5.4.2 and 5.6.9 for details on gynaecological 
examination and follow-up algorithms (colposcopy and biopsy procedures).
Section 5.6.8.2: ASC-US or LSIL
An observation of ASC-US will result in reflex testing by CICAMS/CFC for high-risk 
HPV types (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) using HCII. 
Results will be communicated to the investigator (or designee) as “ASC-US/oncogenic 
HPV negative” or “ASC-US/oncogenic HPV positive”.
Subjects with ASC-US/oncogenic HPV negative results will not be called back for a 
follow-up biopsy procedure; however, will be encouraged to continue follow-up in the 
context of local medical practice.
Subjects with ASC-US/oncogenic HPV positive results or LSIL will be referred for 
colposcopic evaluation (see Figure 3 for the low-grade colposcopy management 
algorithm).
Specimens will be reported as “Quantity Not Sufficient” (QNS) when there is an 
inadequate amount of cells for HCII testing. In case of ASC-US/QNS or missing HCII 
test results, subjects will be informed and encouraged to follow regular gynaecological 
examination according to local practice.
To ensure active follow-up with subjects missing a follow-up visit or a colposcopy visit, 
study personnel will contact the subject by using established local communication 
methods. The site will make at least three attempts to contact the subject. If contact 
cannot be achieved after three attempts, a certified/registered letter will be sent by the 
site.
Section 5.6.8.3: AGC
Observation of AGC will result in an immediate referral for colposcopic evaluation (see 
Figure 4 for the AGC colposcopy management algorithm).
Section 5.6.8.4: ASC-H / greater than or equal to HSIL
Observation of ASC-H or ≥HSIL will result in an immediate referral for colposcopic 
evaluation (see Figure 5 for the high-grade colposcopy management algorithm).
Section 5.6.9: Colposcopic evaluations of abnormal cytologies
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
118
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
119
Colposcopy provides the link between cytology and biopsy. Colposcopy will be 
performed by a trained and experienced colposcopist. Colposcopy will be performed on 
subjects with abnormal cytological findings (except ASC-US/oncogenic HPV negative, 
see Figure 2).
Given that the expertise of the clinical site teams varies in the field of cervical disease 
management and colposcopy, the qualifications and experience of the participating 
colposcopists will be reviewed.
All colposcopies will be recorded in the eCRF and every attempt will be made to 
document colposcopy performed outside the study in the specific section on the eCRF.
Figure 2
Cytology Management Algorithm
* If a cervical liquid-based cytology (LBC) specimen is deemed “unsatisfactory” by the laboratory, the subject 
must be informed to arrange for another cervical sampling visit.
** Oncogenic HPV positive means that the cytology specimen is positive for an oncogenic HPV type by Hybrid 
Capture II (HCII) testing. This test will automatically be performed on specimens with an ASC-US result (reflex 
testing). Specimens will be reported as “Quantity Not Sufficient” (QNS) when there is an inadequate amount of 
cells for HCII testing. In case of ASC-US/QNS or missing HCII test results, subjects will be informed and 
encouraged to follow regular gynaecological examination according to local practice.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
119
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
120
Section 5.6.9.1: Colposcopic procedures
If the transformation zone is not fully visualized, the colposcopy is to be considered as 
not satisfactory. In these cases, an endocervical specimen by endocervical curettage 
will have to be collected during the colposcopy and the vagina carefully inspected.

A normal colposcopy impression may result in taking an endocervical 
specimen by endocervical curettage according to the appropriate algorithm and 
local medical practices. 

A colposcopy impression of LSIL or equivocal will result in biopsy. A 
colposcopy impression of HSIL will also result in a biopsy. 
If the biopsy result/endocervical specimen is negative or ≤CIN1, no further action is 
required; however, the subjects can continue with protocol-specified procedures if 
applicable and will be encouraged to have a follow-up according to local medical 
practice. If the biopsy result or the endocervical specimen is CIN2 or AIS, the subject 
will be referred for treatment according to local medical practice.
A biopsy specimen that cannot be adequately evaluated by the histopathologist will be 
reported as non-diagnostic. If the biopsy is reported as non-diagnostic, the subjects will 
be offered a repeat colposcopy as soon as possible and a further biopsy would be taken 
from any abnormal or equivocal area.
Any cervical lesions will be biopsied according to colposcopy management algorithms. 
In addition, the vagina and vulva will be inspected with each colposcopy and any 
vaginal or vulvar lesions possibly associated with HPV (other than condylomas) will be 
biopsied or excised according to local medical practice.
All tissues will be shipped to CICAMS/CFC. All tissues will be examined in 
CICAMS/CFC and the report from CICAMS/CFC will be used for clinical 
management.
Every effort should be made to encourage subjects to have the colposcopic examination 
within this study. Should a subject have a colposcopy performed outside of the study, 
she will be asked to consent to allow study staff to access her medical records and to 
obtain slides and tissue for evaluation if possible. 
Section 5.6.9.2: Colposcopy management for low-grade cytology
The management algorithm shown in Figure 3 should be used for any subject who has 
cytological abnormalities graded as ASC-US/oncogenic HPV positive or LSIL. 
An unsatisfactory colposcopy indicates that the transformation zone is unable to be 
fully visualized. In these cases, an endocervical specimen must be taken by 
endocervical curettage and the vagina carefully inspected. If any abnormality is seen, 
this should be managed according to the algorithm.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
120
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
121
If it is a normal colposcopy impression no further action is required and the subjects 
can continue with protocol-specified procedures, if applicable and will be encouraged 
to continue follow-up in the context of local medical practice.
A colposcopy impression of LSIL will result in biopsy - collection of an endocervical 
specimen by endocervical curettage is optional. If the biopsy result is negative or 
CIN1, no further action is required and the subjects can continue with protocol-
specified procedures, if applicable and is encouraged to be followed up according to the 
local medical practice. If biopsy or endocervical curettage show CIN2 or AIS, subjects 
will be referred for treatment according to local medical practice.
For colposcopic impression of HSIL, a biopsy will be performed. If the biopsy result is 
CIN2 or AIS, the subject will be referred for treatment according to local medical 
practice. Subjects with HSIL may also be referred to treatment without biopsy.
Figure 3
Colposcopy Management Algorithm for subjects with ASC-US/oncogenic 
HPV positive results or LSIL
Note: Specimens will be reported as “Quantity Not Sufficient” (QNS) when there is an inadequate amount of 
cells for HCII testing. In case of ASC-US/QNS or missing HCII test results, subjects will be informed and 
encouraged to follow regular gynaecological examination according to local practice
** An unsatisfactory colposcopy indicates that the transformation zone is unable to be fully visualized. In 
these cases an endocervical specimen must be taken and the vagina inspected.
***If invasive cancer is suspected, management should be according to accepted standard medical practice. 
Subjects who do not have a biopsy in the study will be asked to consent to allow study staff to obtain their 
tissue for evaluation if possible.
†Collection of endocervical specimen will depend on local practice and clinical judgement. 
‡ subjects will be encouraged to have gynaecological follow-up as per local practice.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
121
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
122
Section 5.6.9.3: Colposcopy management algorithm for AGC
This management algorithm (Figure 4) should be used for any subject who has a 
single cytological abnormality graded as AGC.
An unsatisfactory colposcopy indicates that the transformation zone is unable to be 
fully visualized. In these cases, an endocervical specimen must be taken and the vagina 
carefully inspected. If any abnormality is seen, this should be managed according to 
the algorithm.
If the colposcopic impression is normal, an endocervical specimen by endocervical 
curettage will be collected, cytology will be reviewed and the vagina should also be 
carefully inspected. If endocervical and cytological review results are negative or 
LSIL orCIN1 or negative, no further action is required and the subjects can 
continue with protocol-specified procedures, if applicable and will be encouraged to 
continue follow-up in the context of local medical practice. If cytology result (except 
ASC-US/oncogenic HPV negative) or colposcopy is abnormal, please refer to 
appropriate colposcopy management algorithm. 
If endocervical and cytological review results are HSIL, AGC or AIS, the subjects will 
be referred for treatment as per local medical practice.
If the colposcopic impression is LSIL or equivocal, a biopsy should be performed 
depending on the colposcopic impression and local medical practice. An endocervical 
specimen by endocervical curettage may be collected. If a biopsy confirms CIN2 or 
AIS, the subjects will be referred for treatment as per local medical practice. If the 
biopsy result is negative or CIN1, no further action is required and the subjects can 
continue with protocol-specified procedures, if applicable and will be encouraged to 
continue follow-up in the context of local medical practice. If cytology result (except 
ASC-US/oncogenic HPV negative) or colposcopy is abnormal, please refer to 
appropriate colposcopy management algorithm.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
122
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
123
Figure 4
Colposcopy Management Algorithm for subjects with AGC 
* An unsatisfactory colposcopy indicates that the transformation zone is unable to be fully visualized. In these 
cases, an endocervical specimen must be taken and the vagina inspected.
†Collection of endocervical specimen and cytological review will depend on local practice and clinical 
judgement of discrepancy between findings. A high grade AGC should lead to excision biopsy.
ᶲIf invasive cancer is suspected, management should be according to accepted standard medical practice.
‡ subjects will be encouraged to have gynaecological follow-up as per local practice
Section 5.6.9.4: Colposcopy management algorithm for high-grade cytology
This management algorithm (Figure 5) should be used for any subject who has a 
single cytological abnormality graded as ASC-H or ≥HSIL.
An unsatisfactory colposcopy indicates that the transformation zone is unable to be 
fully visualized. In these cases, an endocervical specimen must be taken and the vagina 
carefully inspected. If any abnormality is seen, this should be managed according to 
the algorithm.
If the colposcopic impression is normal, an endocervical specimen by endocervical 
curettage will be collected, cytology will be reviewed and the vagina should also be 
carefully inspected. If the endocervical sampling and cytological review results are 
negative or ≤LSIL, ≤CIN1 no further action is required and the subjects can continue 
with protocol-specified procedures, if applicable. If cytological review or endocervical
sampling confirms HSIL, ASC-H, AGC or AIS, the subjects will be referred for 
treatment as per local medical practice.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
123
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
124
If the colposcopic impression is LSIL or equivocal, a biopsy should be performed. An 
endocervical specimen by endocervical curettage may be collected and cytology 
reviewed depending on local medical practice. If the biopsy result is negative or ≤CIN1, 
no further action is required and the subjects can continue with protocol-specified 
procedures, if applicable. If the biopsy result is CIN2 or AIS, the subjects will be 
referred for treatment as per local medical practice.
For colposcopic impression of HSIL, a biopsy will be performed. If the biopsy result is 
negative or CIN1, no further action is required and the subjects can continue with 
protocol-specified procedures, if applicable. If the biopsy result is CIN2 or AIS, the 
subjects will be referred for treatment as per local medical practice.
For any colposcopy/biopsy/endocervical specimen results ≤LSIL or ≤CIN1, subjects 
will be encouraged to continue follow-up in the context of local medical practice.
Figure 5
Coloposcopy Management Algorithm for subjects with ASC-H or HSIL
* An unsatisfactory colposcopy indicates that the transformation zone is unable to be fully visualized. In these 
cases,an endocervical specimen must be taken and the vagina inspected.
** If invasive cancer is suspected, management should be according to accepted standard medical practice.
†Collection of endocervical specimen will depend on local practice and clinical judgement.
‡ subjects will be encouraged to have gynaecological follow-up as per local practice.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
124
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
125
Section 5.6.10: Sampling
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples. Refer to section 5.6.8 for 
cervical sample collection.
The procedures listed in sections 5.6.11 to 5.6.13 are only applicable for subjects 
undergoing vaccination in this study.
Section 5.6.11: Assess pre-vaccination body temperature
The location of body temperature measurement was changed from “oral” to “axilla”.
Section 5.6.16: Safety follow-up contact

The investigator or his/her designee will contact the subjects who have been 
vaccinated, by telephone approximately one and six months after the third vaccine 
dose to obtain information on the occurrence of any of the safety endpoints.

The procedures to be performed during the follow-up telephone contact such as 
recording of any concomitant medication/vaccination or medical treatment and 
recording of SAEs, pregnancies and its outcome (as applicable) and pIMDs are also 
performed during this phone contact and are described in Section 5.6.14 and Section
5.6.15, respectively.
Section 5.7: Biological sample handling and analysis
As the study now involves collection of a cervical sample from the subjects from 
HPV-039 study, a section on biological sample handling and analysis was added.
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.

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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
125
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
126
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.
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. 
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.
Section 5.7.1: Use of specified study materials
Not applicable, as no clinical samples will be collected in this study.
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 10.5 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.
Section 5.7.2: Biological samples
Cervical samples will be collected at Visit 1 from all the subjects to check for HPV 
infection. Subjects who have abnormal cytology findings in the cervical sample 
collected at Visit 1 will be called back for a follow-up colposcopy visit. A cervical biopsy 
may be taken depending on the colposcopy findings. No blood samples will be taken 
during the study.
Section 5.7.3: Laboratory assays
The assays to be performed are summarized in Table 7.
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.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
126
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
127
Section 5.7.3.1: Cervical Cytology
All original cervical samples collected will be prepared by trained laboratory personnel 
using the ThinPrep® 2000 Processor to transfer and fix the cells onto glass slides. All 
cytology specimens will be processed and then evaluated according to the Bethesda 
2001 classification system for reporting cervical cytology diagnoses.
Cervical cytology will be performed using the ThinPrep® PapTest. (Cytyc Corporation, 
Boxborough, MA, USA). Cervical cells for ThinPrep® cytology will be collected using 
the sampling device provided rinsed into a collection vial containing PreservCyt® 
medium. Specimens will be stored according to the CICAMS/CFC procedure until 
shipment to CICAMS/CFC. Cytological specimens must be shipped at ambient 
temperature within one month of collection.
From the PreservCyt® specimen (original sample), one 1 mL aliquot will be prepared 
and withdrawn prior to ThinPrep® slide preparation (to avoid possible specimen-to-
specimen contamination) for HPV DNA testing. The remaining sample will be used for 
cytological analysis at CICAMS/CFC.
In case a commercialized test/equipment is not available, an equivalent test/equipment 
may be used after approval by GSK.
Section 5.7.3.2: Polymerase chain reaction (PCR) typing of HPV DNA from 
PreservCyt specimens
To test for HPV DNA, SPF10 primers which amplify a 65 nucleotide region of the 
HPV L1 gene for most of the known HPV isolates are used; the generic amplification 
products are detected by hybridization on a microtitre plate (DEIA). HPV-positive 
specimens will be typed by reverse hybridization line probe assay (LiPA), using 25
HPV-specific hybridization probes enabling detection of 14 oncogenic HPV types 
[HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68] and 11 non-
oncogenic HPV types [HPV-6, -11, -34, -40, -42, -43, -44, -53, -54, -70 and -74]. All 
HPV positive samples will also be tested by HPV-16 specific PCR and HPV-18 specific 
PCR. Redundant testing using generic SPF10 PCR with LiPA, followed by HPV-16/18 
type-specific PCR (TS-PCR) affords maximum test sensitivity. The results of this 
testing algorithm will be considered definitive for all HPV-16, -18, -31, -33, -35, -39, -
45, -51, -52, -56, -58, -59, -66 and -68 and HPV-6, -11, -34, -40, -42, -43, -44, -53, -54, -
70 and -74 related study endpoints using HPV DNA testing from PreservCyt® 
specimens.
Section 5.7.3.3: Hybrid Capture II testing
Clinical management will be guided by Hybrid Capture II testing (see Section 5.4.2). 
After ThinPrep® cytology slides have been prepared, residual PreservCyt® specimens 
on slides read as ASC-US will be tested for HPV DNA. Testing will be done by 
CICAMS/CFC using the HCII test (Digene Corp., Gaithersburg, MD, USA). Probe B 
will be used and is designed to detect infections with 13 oncogenic HPV types (HPV 
types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) [Vernick, 2003]. This test is 
fast, reliable and accurate, but does not provide type-specific data. Therefore, 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
127
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
128
additional HPV DNA testing by PCR will be required to define trial endpoints, as 
discussed above. 
Vaginal and vulvar biopsies will be handled according to the same procedures as 
cervical biopsies.
Section 5.7.3.4: Histopathology
Biopsy specimens obtained during the trial will be fixed in buffered formalin (provided 
by the sponsor) and shipped to CICAMS/CFC for histopathological evaluation and 
PCR examination.
Vaginal and vulvar biopsies will be handled according to the same procedures as 
cervical biopsies.
Section 5.7.3.4.1: Histopathological analysis
Histopathological analysis will be performed by CICAMS/CFC. All biopsies will be 
reported independently by two designated, expert pathologists. In case of disagreement 
in diagnosis between the two pathologists, a third expert panel member will examine 
the specimen and a consensus diagnosis will be reached. These diagnoses will be 
placed in the results reporting system and made available electronically at each site 
within a designated timeframe (e.g. 7 days) of receipt at CICAMS/CFC. These results 
will be used for patient management. CICAMS/CFC will expedite reports on specimens 
marked urgent, engage in telephone consultation with clinicians and send slides to 
sites for review by local pathologists on request. Tissue blocks will be retained by 
CICAMS/CFC and, at the discretion of the sponsor, may be evaluated by additional 
techniques to assess the presence of HPV, expression of HPV genes, host responses 
elicited by HPV or other mechanisms involved in cervical carcinogenesis.
Specimens from subjects having biopsies performed outside the study (e.g. very urgent 
clinical need such as suspected invasive cancer) can be examined and entered into the 
study.
Section 5.7.3.5: HPV DNA PCR testing in tissue
The formalin fixed and paraffin embedded tissue blocks used for histopathological 
analysis will be sectioned for PCR examination at CICAMS/CFC using an appropriate 
clean technique. Sections will be tested for HPV DNA using PCR methodology. 
Samples of lesions will be selected for further analysis using micro-dissection as 
appropriate. To test for HPV DNA, SPF10 primers which amplify a 65 nucleotide 
region of the HPV L1 gene for most of the known HPV isolates are used; the generic 
amplification products are detected by hybridization on a microtitre plate (DEIA). 
HPV-positive specimens will be typed by reverse hybridization line probe assay (LiPA), 
using 25 type-specific hybridization probes. This typing process enables detection of 14 
oncogenic HPV types [HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 
and -68] and 11 non-oncogenic HPV types [HPV-6, -11, -34, -40, -42, -43, -44, -53, -54, 
-70 and -74]. All HPV positive samples will also be tested by HPV-16 specific PCR and 
HPV-18 specific PCR. Redundant testing using generic SPF10 PCR with LiPA, 
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
128
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
129
followed by HPV-16/18 type-specific PCR (TS-PCR) affords maximum test sensitivity. 
The results of this testing algorithm will be considered definitive for all HPV-16, -18, -
31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68 and HPV-6, -11, -34, -40, -42, -
43, -44, -53, -54, -70 and -74 related study endpoints using HPV DNA testing from
histopathology. 
Any remaining histopathological sample may be used to further characterize HPV 
infections and associated molecular changes. Histopathological samples may also be 
used for the purpose of validating HPV assays.
Because the proper role of HPV DNA PCR testing in clinical management is 
undefined, the results of this testing will be released to investigators and subjects only 
at the end of the study.
In cases where multiple HPV types are detected in the samples, additional exploratory 
assays, such as laser microdissection may be performed to investigate the causal role of 
individual HPV types.
Please refer to APPENDIX A for more details on the laboratory assays. Any remaining 
cytological sample may be used to further characterize HPV infections and associated 
molecular changes. This may include sequencing, determination of viral load using 
quantitative HPV PCR or subtyping of HPV detected.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
129
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
130
Table 7
Laboratory Assays
Assay type
Marker
Assay method
Test kit/ 
Manufacturer
Assay unit
Assay
cut-off
Laboratory
Qualitative 
cervical cytology
Bethesda 2001 
System for 
reporting 
cervical 
cytology 
diagnoses
MICRLI
(Microscopy of 
cervical 
cytology)
ThinPrep® 
PapTest™
No unit
N/A
CICAMS/CFC
Qualitative 
Histopathology
CIN 
classification
MICRLI
(Microscopy of 
tissue 
sections)
Not applicable
Qualitative
Qualitative
CICAMS/CFC
Qualitative 
("generic") PCR 
for HPV DNA
(using SPF10 
primers) + LiPA 
on cervical swab
HPV-16, 18, 31, 
33, 35, 39, 45, 
51, 52, 56, 58, 
59, 66, 68, 6, 
11, 34, 40, 42, 
43, 44, 53, 54, 
70 and 74
PCR
HPV SPF10 
PCR DEIA
No unit
N/A
CICAMS/CFC
nucleic acid 
hybridization
HPV SPF10 
PCR LIPA
No unit
N/A
CICAMS/CFC
Qualitative 
("generic") PCR 
for HPV DNA
(using SPF10 
primers) + LiPA 
on cervical 
tissue
HPV-16, 18, 31, 
33, 35, 39, 45, 
51, 52, 56, 58, 
59, 66, 68, 6, 
11, 34, 40, 42, 
43, 44, 53, 54, 
70 and 74
PCR
HPV SPF10 
PCR DEIA
No unit
Qualitative
N/A
Qualitative
CICAMS/CFC
nucleic acid 
hybridization
HPV SPF10 
PCR LIPA
No unit
N/A
CICAMS/CFC
Qualitative 
("type-specific") 
PCR for HPV 
DNA on cervical 
swab
HPV-16
PCR
HPV TS16 
PCR/DEIA
No unit
N/A
CICAMS/CFC
HPV-18
PCR
HPV TS18 
PCR/DEIA
No unit
N/A
CICAMS/CFC
Qualitative 
("type-specific") 
PCR for HPV 
DNA on cervical 
tissue
HPV-16
PCR
HPV TS16 
PCR/DEIA
No unit
N/A
CICAMS/CFC
HPV-18
PCR
HPV TS18 
PCR/DEIA
No unit
N/A
CICAMS/CFC
Qualitative
HPV-16, 18, 31, 
33, 35, 39, 45, 
51, 52, 56, 58, 
59 and 68 
(Oncogenic 
probe [cocktail 
B])
NAH Nucleic 
acid 
hybridization
Hybrid 
Capture® 2 
HPV DNA 
Test/Digene 
Corporation
No unit
Qualitative
N/A
Qualitative
CICAMS/CFC
CICAMS/CFC: Cancer Institute/Hospital Chinese Academy Medical Sciences and Cancer Foundation of China
PCR: Polymerase Chain Reaction
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
130
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
131
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.
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.
Section 6.2: Storage and handling of study vaccine
Temperature excursion form was changed to temperature excursion application.
Section 6.7.1: Recording of concomitant medications/products and concomitant 
vaccinations

Any concomitant vaccination administered in the period starting 30 days before the 
first dose of study vaccine and ending at Call 2 (Day -29 to Month 12).last contact 
for each subject.

Any concomitant medications/products/vaccines listed in Section 6.7.2.
Section 6.7.2: Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol analyses
As a per protocol analysis of protective effect will be performed, this section was added.
Not applicable.
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. See Section 10.5 for cohorts to be analysed.

Previous vaccination against HPV outside of study HPV-039.

History of long-acting immune-modifying drugs administered at any time (e.g. 
infliximab).

Drug and/or alcohol abuse.
Section 8.1.1: Definition of an adverse event
The following text was added:
Collection of solicited AEs is not planned in this study. All other AEs will be recorded 
as UNSOLICITED AEs.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
131
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
132
Section 8.1.4.1: Potential immune mediated diseases
A new table on pIMDs which became effective in November 2017 was added to replace 
the older version, as follows.
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), 

Autoimmune hemolytic 
anemia

Autoimmune 
thrombocytopenia

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/cardiomyopathySarcoidosis

Stevens-Johnson syndrome

Sjögren’s syndrome

Idiopathic pulmonary fibrosis

Goodpasture syndrome

Raynaud’s phenomenon
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
132
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
133
Henoch-Schonlein purpura, 
Behcet's syndrome, 
leukocytoclastic vasculitis.
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
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
133
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
134
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve neuropathy, 
including paralysis and 
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.

Demyelinating peripheral 
neuropathies including:
-
Chronic inflammatory 
demyelinating 
polyneuropathy, 
-
Multifocal motor 
neuropathy 
-
Polyneuropathies 
associated with 
monoclonal 
gammopathy.

Narcolepsy.

Systemic lupus 
erythematosus and 
associated conditions

Systemic scleroderma 
(Systemic sclerosis), 
including:
-
Diffuse Scleroderma
-
CREST syndrome

Idiopathic inflammatory 
myopathies, including:
-
Dermatomyositis 
-
Polymyositis 

Anti-synthetase syndrome.

Rheumatoid Arthritis and 
associated conditions 
including: 
-
Juvenile Idiopathic 
Arthritis
-
Still’s disease.

Polymyalgia rheumatica.

Spondyloarthropathies, 
including: 
-
Ankylosing Spondylitis, 
-
Reactive Arthritis 
(Reiter's Syndrome),
-
Undifferentiated 
Spondyloarthritis,
-
Psoriatic Arthritis,
-
Enteropathic arthritis.

Relapsing Polychondritis.

Mixed Connective Tissue 
disorder.

Gout

Psoriasis.

Vitiligo.

Erythema nodosum.

Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid 
and dermatitis 
herpetiformis).

Lichen planus.

Sweet’s syndrome.

Localised Scleroderma 
(Morphoea).
Vasculitis
Blood disorders
Others

Large vessels vasculitis 
including: 
-
Giant Cell Arteritis 
(Temporal Arteritis),
-
Takayasu's Arteritis. 

Medium sized and/or small 
vessels vasculitis including: 
-
Polyarteritis nodosa,
-
Kawasaki's disease, 
-
Microscopic 
Polyangiitis, 
-
Wegener's 
Granulomatosis 
(granulomatosis with 
polyangiitis), 
-
Churg–Strauss 
syndrome (allergic 
granulomatous angiitis
or eosinophilic 
granulomatosis with 
polyangiitis), 
-
Buerger’s disease 

Autoimmune hemolytic 
anemia.

Autoimmune 
thrombocytopenia.

Antiphospholipid syndrome.

Pernicious anemia.

Autoimmune aplastic 
anemia.

Autoimmune neutropenia.

Autoimmune pancytopenia.

Autoimmune 
glomerulonephritis 
including:
-
IgA nephropathy, 
-
Glomerulonephritis 
rapidly progressive, 
-
Membranous 
glomerulonephritis, 
-
Membranoproliferative 
glomerulonephritis, 
-
Mesangioproliferative 
glomerulonephritis. 
-
Tubulointerstitial 
nephritis and uveitis 
syndrome.

Ocular autoimmune 
diseases including:
-
Autoimmune uveitis 
-
Autoimmune retinitis.

Autoimmune myocarditis.

Sarcoidosis.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
134
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
135
(thromboangiitis 
obliterans), 
-
Necrotizing vasculitis 
(cutaneous or 
systemic), 
-
anti-neutrophil 
cytoplasmic antibody 
(ANCA) positive 
vasculitis (type 
unspecified),
-
Henoch-Schonlein 
purpura (IgA vasculitis), 
-
Behcet's syndrome,
-
Leukocytoclastic 
vasculitis.

Stevens-Johnson 
syndrome.

Sjögren’s syndrome.

Alopecia areata.

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 
(Hashimoto thyroiditis).

Grave's or Basedow’s 
disease.

Diabetes mellitus type I.

Addison’s disease.

Polyglandular autoimmune 
syndrome.

Autoimmune hypophysitis.
Section 8.2.1: Pregnancy
It was clarified that female subjects from control group of HPV-039 study who are 
pregnant or lactating at the time of vaccination must not receive additional doses of study 
vaccine but may continue other study procedures at the discretion of the investigator.
Subjects from HPV group(Ctrl-HPV-039-group) who are pregnant or lactating at the 
time of vaccination must not receive additional doses of study vaccine but may continue 
other study procedures at the discretion of the investigator.
Section 8.3.1: Time period for detecting and recording serious adverse events and 
pregnancies
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine (Day 1) and will end six months following administration of the last dose of 
study vaccine (Call 2 [Month 12]) for each vaccinated subject. See Section 8.4 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 for all subjects and 
recorded from the time the subject consents to participate in the study until she/he is 
discharged from the study.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
135
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
136
The table on “Reporting periods for collecting safety information” was updated to add 
reporting periods for each of the groups.
Section 8.3.3: Evaluation of serious adverse events
The title of this section was updated to “Evaluation of adverse events and serious adverse 
events.” Correspondingly, the text in this section was updated to refer to AEs/SAEs 
rather than only SAEs.
Section 8.4.3.1: Back-up system in case the electronic reporting system does not 
work
The following statement was deleted: “The final valid information for regulatory 
reporting will be the information reported through the electronic SAE reporting system.”
Section 10: Statistical methods
The statistical section was updated to update the objectives, endpoints, and to add interim 
analysis.
Section 10.1: Primary endpoint

Safety endpoint (Ctrl-HPV-039 group)

HPV group 
o
Occurrence of SAEs related to study vaccine.
Section 10.2: Secondary endpoints

Safety endpoints

HPV group (Ctrl-HPV-039 group)
o
Occurrence of pIMDs throughout the study.
o
Occurrence of pregnancies and pregnancy outcomes throughout the study. 
o
Occurrence of SAEs.
o
Any AE/SAE leading to premature discontinuation from the study. 

All subjects
o
Occurrence of SAEs related to study participation.

Virological endpoints

Incident cervical infection associated with HPV-16 and/or HPV-18 (by PCR). 

Incident cervical infection associated with any oncogenic HPV type (e.g. 
HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68 or 
combination of oncogenic HPV types; by PCR).
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
136
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
137
Section 10.3: Tertiary endpoints

Virological endpoint

Incident infection associated with HPV-16/18, any other oncogenic type, 
irrespective of HPV type.

Cytological endpoints

Any cytological abnormality (i.e., ASC-US) associated with HPV-16 and/or 
HPV-18 cervical infection (by PCR). 

Any cytological abnormality associated with any oncogenic HPV type (e.g. 
HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68 or 
combination of oncogenic HPV types; by PCR).

Any cytological abnormality irrespective of the HPV type. 

Histopathological endpoints

Histopathologically-confirmed CIN1+ associated with HPV-16 and/or HPV-
18 (by PCR). 

Histopathologically-confirmed CIN2+ associated with HPV-16 and/or HPV-
18 (by PCR).
CIN2+ is defined as CIN2, CIN3, LCGIN, HCGIN, adenocarcinoma in-situ 
(AIS) or invasive cervical cancer.

Histopathologically-confirmed CIN1+ associated with cervical infection with 
any oncogenic HPV type (e.g. HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -
56, -58, -59, -66 and -68 or combination of oncogenic HPV types; by PCR).

Histopathologically-confirmed CIN2+ associated with cervical infection with 
any oncogenic HPV type (e.g. HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -
56, -58, -59, -66 and -68 or combination of oncogenic HPV types; by PCR).

Histopathologically-confirmed CIN1+ lesions irrespective of HPV type.

Histopathologically-confirmed CIN2+ lesions irrespective of HPV type.

Histopathologically-confirmed VIN1+ associated with HPV-16 and/or HPV-
18 infection (by PCR).

Histopathologically-confirmed VaIN1+ associated with HPV-16 and/or HPV-
18 infection (by PCR).

Histopathologically-confirmed VIN1+ associated with any oncogenic HPV 
type (e.g. HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -
68 or combination of oncogenic HPV types; by PCR).

Histopathologically-confirmed VaIN1+ associated with any oncogenic HPV 
type (e.g. HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -
68 or combination of oncogenic HPV types; by PCR).

Histopathologically-confirmed VIN1+ irrespective of HPV type.

Histopathologically-confirmed VaIN1+ irrespective of HPV type.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
137
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
138
For the above mentioned tertiary endpoints, VIN (Vulvar Intraepithelial Neoplasia) is 
defined as VIN1+ or VIN2+, and VaIN (Vaginal Intraepithelial Neoplasia) is defined 
as VaIN1+ or VaIN2+.
Section 10.4: Determination of sample size
Since the objectives of the study are descriptive, the sample size for this study is not 
estimated using any power based computations.
Sample size for this study depends on the recruitment of the subjects who previously 
participated in study HPV-039. Up to 6051 subjects who participated in the HPV-039 
study will be invited to participate in this study, of which 3025 subjects did not receive 
the HPV vaccine and are therefore eligible to receive the HPV vaccine in this study.
It is estimated that approximately 1500 to 3000 subjects from the control group in 
HPV-039 will effectively participate in this study and will receive at least one dose of 
HPV vaccine and will be available for the evaluation of the primary objective of the 
study.
The exact 95% confidence interval (CI) for different sample sizes and the value 
observed for the percentage of subjects reporting at least one related SAE is presented 
in the table below. 
Table 13
Exact two-sided 95% CI for different sample sizes and the value 
observed for the percentage of subjects reporting at least one related 
SAE
No. of evaluable subjects to be expected (N)
Subjects who reported related SAEs post vaccination
n
%
Exact 95% CI
LL
UL
3000
1
0.0
0.0
0.2
3
0.1
0.0
0.3
5
0.2
0.1
0.4
15
0.5
0.3
0.8
30
1.0
0.7
1.4
1500
1
0.1
0.0
0.4
3
0.2
0.0
0.6
5
0.3
0.1
0.8
8
0.5
0.2
1.0
10
1.0
0.6
1.6
n = Number of subjects who reported related SAEs.
% = (n/N) *100; LL = Lower limit; UL = Upper limit
Reference: HPV-039 (107638): At least one SAE throughout the study period (72 Months) in HPV Group = 1.9% 
[95% CI: 1.4; 2.4]. At least one related SAE was reported by one subject in control group.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
138
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
139
Section 10.5: Cohort for Analyses
Section 10.5.1: Total enrolled set
The total enrolled set includes all subjects enrolled in study HPV-092 EXT 039.
Section 10.5.2: Exposed set HPV-092
The Exposed Set (ES) includes all vaccinated subjects in HPV-092 EXT 039 for whom 
data were available.
Section 10.5.3: Per-protocol set (PPS-HPV-092)
The Per-Protocol Set (PPS) will include all evaluable subjects, i.e.,

Who meet all eligibility criteria.

Who do not meet any of the criteria for elimination from an PPS analysis during 
the study (see Section 6.7.2).

For whom data concerning endpoint measures are available.

Who belong to the ATP cohort for efficacy of the study HPV-039.
Total Vaccinated Cohort (TVC) and the ATP cohort for the analysis of efficacy in 
study HPV-039 will be used for the analysis of protective effect.
Section 10.6: Derived and transformed data
The follow-up time for each subject starts:
at the day after first vaccination (Month 0 study HPV-039) if analyses were 
done on the TVC of HPV-039, or
at the day after third vaccination (Month 6 study HPV-039) if analyses were 
done on the ATP cohort of efficacy of HPV-039.
The follow-up time for each subject ends:

at the time of the event (e.g. the start of incident infection or the time of the 
histopathological endpoint),

at Visit 1 in HPV-092 study (Month 120 EXT-039) for subjects who returned 
for HPV-092 but did not have an event, or 

last available timepoint for subjects who do not have an event and do not 
return for study HPV-092 EXT 039.
Section 10.7: Analysis of demographics
Demographic characteristics (age) at first visit in study HPV-092 EXT 039 and HPV 
vaccination history in study HPV-039 will be summarised overall and by group using
descriptive statistics. In addition, baseline characteristics (HPV DNA and serostatus) in 
study HPV-039 will be summarised overall and by group for subjects enrolled in study 
HPV-092 EXT 039.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
139
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
140
The mean age (plus range and standard deviation) of the enrolled subjects at Dose 1 in 
study HPV-039 and as a whole, and per group, will be calculated.
The distribution of subjects enrolled among the study sites were tabulated as a whole 
and per group.
Section 10.8: Analysis of safety
Analysis of safety events reported after vaccination in HPV-092 will be performed on 
the Exposed set HPV-092. 
Related SAEs, any AEs/SAEs leading to premature discontinuation of the study, 
pregnancies and pIMDs up to the end of the study (Month 12) will be described in 
detail.
Analysis of SAEs related to study participation will be performed on the total enrolled 
set.
Section 10.9: Analysis of protective effect
The analysis of protective effect will be performed on the ATP cohort for efficacy and 
TVC of study HPV-039, considering the data from the entire follow-up period of 
studies HPV-039 and HPV-092 combined, i.e., pooled analyses (from Month 0 in study 
HPV-039 up to Month 120 in study HPV-092).

Number and percentage of subjects with incident cervical infection associated 
with HPV-16 and HPV-18 will be summarized by group. 

Number and percentage of subjects with incident cervical infection associated 
with any oncogenic HPV type (e.g. HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, 
-56, -58, -59, -66 and -68 or combination of oncogenic HPV types; by PCR) will 
be summarized by group.
Section 10.10: Exploratory analysis of long term efficacy
Analysis of long term efficacy will be exploratory. Vaccine efficacy with a 95% CI will 
be calculated using the conditional exact method.
Efficacy analysis of histopathological, virological and cytological endpoints associated 
with HPV-16/18 will be performed and stratified by HPV-16/18 serostatus (by ELISA) 
at baseline in the study HPV-039 with the primary analysis performed on subjects who 
were seronegative (by ELISA) prior to vaccination in study HPV-039 for the 
corresponding HPV type considered in the analysis. 
Additional efficacy analyses will be performed irrespective of baseline HPV DNA, 
cytology and serostatus.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
140
21-JUN-2018

CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
21-JUN-2018
141
The vaccine efficacy for all endpoints will be calculated using a conditional exact 
method. This method computes an exact CI around the rate ratio (ratio of the 
incidence rates in the HPV group versus the Control group) and takes into account the 
follow-up time of the subjects within each group. Vaccine efficacy is then defined as 
1 minus the rate ratio. In addition, p-values will be calculated using the Fisher’s exact 
test. 
Kaplan-Meier curves for both groups will be generated.
The analysis of long term vaccine efficacy will be performed on the ATP cohort for 
efficacy and TVC of study HPV-039, considering the data from the entire follow-up 
period of studies HPV-039 and HPV-092 combined, i.e., pooled analyses (from Month 
0 in study HPV-039 up to Month 120 in study HPV-092).
Number and percentage of subjects with referrals to treatment according to local 
medical practice will be summarized by group.
Analyses will be further described in detail in the Statistical Analysis Plan (SAP).
Section 10.11: Interpretation of analyses
All analyses will be descriptive with the aim to characterise the observed outcomes. 
These descriptive analyses should be interpreted with caution. Refer to limitations of the 
study in the rationale for study design section.
Section 10.12: 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.
Section 10.12.1: Sequence of analyses

Interim analyses of available safety and protective effect data, may be performed if 
deemed necessary for regulatory or reporting obligations.

A final analysis of all data collected up to Call 2 (Month 12) will be conducted for 
all subjects.
An integrated clinical study report containing all data will be written and made available 
to the investigators.
Section 10.12.2: Statistical considerations for interim analyses
All analyses in the study will be descriptive. Hence, no statistical considerations for 
interim analysis will be done.
Appendices
Appendix A on laboratory to be conducted in this study and Appendix B on laboratory 
which will perform this assays were added.
 
CONFIDENTIAL
205779 (HPV-092 EXT 039)
Protocol Amendment 1 Final
226ae7f3ca9ebe072dfbac3fe4fe0a637c8920d6
141
21-JUN-2018