Safety Study of GSK Biologicals' Human Papillomavirus Vaccine (GSK-580299) in Healthy Female Control Subjects From the Primary NCT00294047 Study
Phase: PHASE3
Conditions: Infections, Papillomavirus
Sponsor: GlaxoSmithKline

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Amendment 2 
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1 
 
Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals 
Rue de l’Institut 89 
B-1330 Rixensart, Belgium 
Primary Study vaccine 
and number 
GlaxoSmithKline (GSK) Biologicals’ human 
papillomavirus (HPV) vaccine containing HPV-16/18 L1 
virus-like particles (VLPs) and AS04 adjuvant 
(GSK580299) 
eTrack study number 
and Abbreviated Title 
113621(HPV-067 EXT 015) 
Investigational New 
Drug (IND) number 
BB-IND7920 
Date of protocol 
Final: 18 May 2010  
Date of protocol 
amendments/ 
administrative change 
Administrative Change 1 Final: 18 Aug 2010 
Amendment 1 Final: 9 Dec 2010 
Amendment 2 Final: 13 Jan 2011 
Title 
Safety study of GSK Biologicals’ human papillomavirus 
vaccine (GSK-580299) in healthy female control subjects 
from the GSK HPV-015 study 
Detailed Title 
A phase IIIb, open-label, multi-centre immunization study 
to evaluate the safety of GlaxoSmithKline (GSK) 
Biologicals’ HPV-16/18 L1 VLP AS04 vaccine 
administered intramuscularly according to a 0, 1, 6-month 
schedule in healthy female subjects who received the 
placebo control in the GSK HPV-015 study 
Co-ordinating author 
, Scientific Writer 
Contributing authors 
(Amended 13 Jan 2011) 
• 
, Manager, Clinical Development, 
HPV vaccines 
• 
, Global Study Manager, HPV vaccines 
• 
 and 
, Biostatisticians 
• 
, Senior Manager, Epidemiology and 
Safety 
• 
, Expert Scientist, Clinical 
Regulatory Affairs, Clinical Registration and 
Labelling 
• 
, Clinical Data Coordinators, Clinical 
Data Management 
• 
, Director, HPV Vaccines, Global 
Clinical Research and Development 
• 
, Director, HPV Vaccines, Global 
Clinical Research and Development 
GSK Biologicals’ Protocol DS v 13.1 
Copyright 2010 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited. 
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2 
Protocol Amendment 2 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
113621(HPV-067 EXT 015) 
IND number 
BB-IND7920 
Date of protocol amendment 
Amendment 2 Final: 13 Jan 2011 
Detailed Title  
A phase IIIb, open-label, multi-centre immunization 
study to evaluate the safety of GlaxoSmithKline 
(GSK) Biologicals’ HPV-16/18 L1 VLP AS04 
vaccine administered intramuscularly according to a 
0, 1, 6-month schedule in healthy female subjects 
who received the placebo control in the GSK HPV-
015 study 
Sponsor signatory 
Dominique Descamps MD, Director, Clinical 
Development, HPV Vaccines, GlaxoSmithKline 
Biologicals 
Signature 
 
 
 
Date 
 
 
 
 

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Amendment 2 
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Protocol Amendment 2 Rationale 
Administrative Change 
number: 
Amendment 2 
Rationale/background for changes: 
The exclusion criterion “Administration of any chronic drug therapy to be continued 
during the study period” has been removed to be in line with the original HPV-015 
study protocol. 
Upon request of regulatory authorities, the list of pIMDs has been updated to include 
the term “undifferentiated spondyloarthritides”. 
In addition, the list of contributing authors has been updated. Cross-referencing to the 
first amendment has been removed for clarity. 

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Protocol Amendment 2 Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any mutually agreed future 
protocol amendments or protocol administrative changes, and with any other study 
conduct procedures and/or study conduct documents provided by GlaxoSmithKline 
Biologicals (GSK Biologicals). 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements.  
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational product(s) and other study-related duties and 
functions as described in the protocol. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally authorised 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 product, 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 1 year following completion of the study.  
• 
Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities. 
• 
Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study. 

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eTrack study number and 
Abbreviated Title 
113621(HPV-067 EXT 015) 
IND number  
BB-IND7920 
Date of protocol amendment 
Amendment 2 Final: 13 Jan 2011 
Detailed Title 
A phase IIIb, open-label, multi-centre immunization 
study to evaluate the safety of GlaxoSmithKline 
(GSK) Biologicals’ HPV-16/18 L1 VLP AS04 
vaccine administered intramuscularly according to a 
0, 1, 6-month schedule in healthy female subjects 
who received the placebo control in the GSK HPV-
015 study 
Investigator name 
 
Signature 
 
Date 
 
 

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SYNOPSIS 
Detailed Title 
A phase IIIb, open-label, multi-centre immunization study to 
evaluate the safety of GlaxoSmithKline (GSK) Biologicals’ 
HPV-16/18 L1 VLP AS04 vaccine administered 
intramuscularly according to a 0, 1, 6-month schedule in 
healthy female subjects who received the placebo control in 
the GSK HPV-015 study 
Indication 
Cervarix is indicated in females from 10 years of age onwards 
for the prevention of persistent infection, premalignant 
cervical lesions and cervical cancer (squamous-cell carcinoma 
and adenocarcinoma) caused by oncogenic Human 
Papillomavirus (HPV) types. 
Rationale for the 
study and study 
design 
Subjects in the HPV-015 study either received the HPV-16/18 
L1 VLP AS04 vaccine or placebo control [Al(OH)3], 
following a 0, 1, 6-month vaccination schedule. According to 
the HPV-015 protocol, once the HPV-015 study was 
concluded, the control placebo group would be offered the 
HPV-16/18 L1 VLP AS04 vaccine as well.  
As recommended by the study Independent Data Monitoring 
Committee (IDMC), unblinding and cross-over immunization 
of control recipients with the HPV vaccine will be provided 
after completion of their end of study activities as follows: 
• 
For subjects who complete study activities after the 
database is frozen for final analysis, unblinding will occur 
within 4-6 months after last subject last visit (LSLV) of 
the final study visit. 
• 
Subjects who will not participate in any of the extensions 
will be given the option of unblinding before the database 
is frozen for final analysis upon individual request. 
The HPV-16/18 L1 VLP AS04 vaccine is licensed in the 
participating countries, but it is not indicated for the age group 
(26 years and above) involved in the HPV-015 study and this 
study. Approximately 600 subjects from the control placebo 
group are expected to enrol in this study. 
This study is thus being conducted to enable all women, who 
received the control placebo in the HPV-015 study, to also 
receive HPV-16/18 L1 VLP AS04 vaccine. Safety data in 
terms of SAEs, medically significant conditions and 
pregnancy (and their outcomes) will be collected during the 
study period. 
Objective(s) 
• 
To assess the safety of the HPV-16/18 L1 VLP AS04 
vaccine throughout the study period. 

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Study design 
• 
Experimental design: Phase IIIB, multi-centric, single-
group: HPV vaccine group (HPV-16/18 L1 VLP AS04).  
• 
Treatment allocation: sequential allocation of subjects 
to receive the HPV-16/18 L1 VLP AS04 vaccine 
• 
Blinding: open-label 
• 
Treatment group: HPV vaccine group (HPV-16/18 L1 
VLP AS04) 
• 
Vaccination schedule: Three doses of HPV-16/18 L1 
VLP AS04 vaccine (20 µg HPV-16, 20 µg HPV-18) 
administered intramuscularly according to a 0, 1, 6-month 
schedule. 
• 
Control: uncontrolled 
• 
Type of study: e.g. self-contained, extension of study 
HPV-015  
• 
Data collection: eCRF   
• 
Duration of the study: Approximately 12 months per 
subject.  
• 
Study visits per subject: Three scheduled visits are 
planned at Months 0, 1, 6. There will be a telephone 
contact with the subject at Month 12 (i.e. six months after 
the third dose of the HPV-16/18 L1 VLP AS04 vaccine). 
• 
Safety monitoring:  
 All serious adverse events (SAEs) occurring 
throughout the study period (i.e. from Day 0 up to the 
telephone contact at Month 12) will be reported for all 
subjects. 
 Medically significant conditions (including potential 
immune-mediated diseases [pIMDs]) will be reported 
for all subjects throughout the study period. 
 Pregnancies and pregnancy outcomes will be reported 
for all subjects throughout the study period. 
Number of subjects 
Approximately 600 subjects are planned to participate to this 
cross-over vaccination study. 
Endpoints 
Safety 
• 
Serious adverse events (SAEs) 
• 
Occurrence, intensity and causal relationship to 
vaccination of SAEs throughout the study  
• 
Medically significant conditions(including pIMDs)   

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• 
Occurrence, intensity and causal relationship to 
vaccination of medically significant conditions 
(including pIMDs) throughout the study 
• 
Pregnancies and pregnancy outcomes  
• 
Occurrence of pregnancies and pregnancy outcomes 
throughout the study 

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TABLE OF CONTENTS 
PAGE 
SYNOPSIS ...................................................................................................................... 6 
LIST OF ABBREVIATIONS .......................................................................................... 13 
GLOSSARY OF TERMS ............................................................................................... 14 
TRADEMARKS ............................................................................................................. 16 
1. 
INTRODUCTION .................................................................................................... 17 
1.1. 
Background ................................................................................................ 17 
1.2. 
GlaxoSmithKline Biologicals’ HPV Vaccine ................................................. 17 
1.3. 
Rationale for the study and study design .................................................... 19 
2. 
STUDY OBJECTIVE .............................................................................................. 19 
3. 
STUDY DESIGN OVERVIEW ................................................................................ 19 
4. 
STUDY COHORT ................................................................................................... 21 
4.1. 
Number of subjects/centres ........................................................................ 21 
4.2. 
Inclusion criteria for enrolment .................................................................... 21 
4.3. 
Exclusion criteria for enrolment (Amended 13 January 2011) ..................... 22 
5. 
CONDUCT OF THE STUDY .................................................................................. 23 
5.1. 
Regulatory and ethical considerations, including the informed 
consent process.......................................................................................... 23 
5.2. 
Subject identification and randomisation of treatment ................................. 24 
5.2.1. 
Subject identification .................................................................... 24 
5.2.2. 
Randomisation of treatment ......................................................... 24 
5.2.3. 
Randomisation of subjects to assay subsets ................................ 24 
5.3. 
Method of blinding ...................................................................................... 24 
5.4. 
General study aspects ................................................................................ 24 
5.5. 
Outline of study procedures ........................................................................ 25 
5.6. 
Detailed description of study procedures .................................................... 26 
5.6.1. 
Procedures prior to study participation ......................................... 26 
5.6.1.1. 
Informed consent ........................................................ 26 
5.6.2. 
Procedures prior to the first vaccination ....................................... 26 
5.6.2.1. 
Check inclusion and exclusion criteria ........................ 26 
5.6.2.2. 
Collect demographic data ........................................... 26 
5.6.2.3. 
Medical history and history-directed physical 
examination ................................................................ 26 
5.6.3. 
Procedures at each vaccination visit ............................................ 26 
5.6.3.1. 
Urine pregnancy test .................................................. 26 
5.6.3.2. 
Check contraindications to vaccination (only 
prior to second and third vaccine dose) ...................... 26 
5.6.3.3. 
Check and record concomitant 
medication/vaccination ............................................... 27 
5.6.3.4. 
Assess pre-vaccination body temperature .................. 27 
5.6.3.5. 
Vaccination ................................................................. 27 

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5.6.3.6. 
Recording of medically significant conditions 
and SAEs ................................................................... 27 
5.6.4. 
Procedures during follow-up phone contact ................................. 27 
5.6.4.1. 
Study conclusion ........................................................ 28 
5.7. 
Biological sample handling and analysis ..................................................... 28 
5.7.1. 
Immunological correlates of protection ......................................... 28 
6. 
STUDY VACCINE AND ADMINISTRATION .......................................................... 28 
6.1. 
Description of study vaccine ....................................................................... 28 
6.2. 
Storage and handling of study vaccine ....................................................... 29 
6.3. 
Dosage and administration of study vaccine ............................................... 29 
6.4. 
Replacement of unusable vaccine doses .................................................... 30 
6.5. 
Contraindications to subsequent vaccination .............................................. 30 
6.6. 
Concomitant medication/vaccination ........................................................... 31 
6.6.1. 
Time window for recording concomitant 
medication/vaccination in the eCRF ............................................. 31 
7. 
HEALTH ECONOMICS .......................................................................................... 31 
8. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .................................... 32 
8.1. 
Safety definitions ........................................................................................ 32 
8.1.1. 
Definition of an adverse event ...................................................... 32 
8.1.2. 
Definition of a serious adverse event ........................................... 33 
8.1.3. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................ 34 
8.1.4. 
Medically significant conditions .................................................... 34 
8.1.4.1. 
Potential immune-mediated diseases ......................... 34 
8.2. 
Pregnancy .................................................................................................. 36 
8.3. 
Detecting and recording adverse events, serious adverse events 
and pregnancies ......................................................................................... 36 
8.3.1. 
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies ..................................... 36 
8.3.2. 
Evaluation of adverse events and serious adverse events ........... 38 
8.3.2.1. 
Active questioning to detect adverse events 
and serious adverse events ........................................ 38 
8.3.2.2. 
Assessment of adverse events ................................... 39 
8.3.2.2.1. 
Assessment of intensity .......................... 39 
8.3.2.2.2. 
Assessment of causality ......................... 39 
8.3.2.3. 
Assessment of outcomes............................................ 40 
8.3.2.4. 
Medically attended visits ............................................. 41 
8.4. 
Reporting and follow-up of adverse events, serious adverse events 
and pregnancies ......................................................................................... 41 
8.4.1. 
Prompt reporting of serious adverse events and other 
events to GSK Biologicals ............................................................ 41 
8.4.2. 
Regulatory reporting requirements for serious adverse 
events .......................................................................................... 42 
8.4.3. 
Completion and transmission of SAEs reports to GSK 
Biologicals ................................................................................... 42 
8.4.3.1. 
Back-up system in case the electronic SAE 
reporting system does not work .................................. 42 

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8.4.3.2. 
Updating of SAE information after freezing of 
the subject's eCRF ..................................................... 43 
8.4.4. 
Reporting of pIMDs to GSK Biologicals ........................................ 43 
8.4.5. 
Follow-up of adverse events and serious adverse events ............ 43 
8.5. 
Treatment of adverse events ...................................................................... 44 
8.6. 
Unblinding ................................................................................................... 44 
8.7. 
Emergency unblinding ................................................................................ 44 
8.8. 
Subject card ................................................................................................ 45 
9. 
SUBJECT COMPLETION AND WITHDRAWAL .................................................... 45 
9.1. 
Subject completion ..................................................................................... 45 
9.2. 
Subject withdrawal ...................................................................................... 46 
9.2.1. 
Subject withdrawal from the study ............................................... 46 
9.2.2. 
Subject withdrawal from investigational vaccine........................... 46 
10. DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES ............. 47 
10.1. 
Study endpoints .......................................................................................... 47 
10.2. 
Estimated sample size ................................................................................ 47 
10.3. 
Study cohorts to be evaluated ..................................................................... 47 
10.3.1. 
Total Vaccinated Cohort .............................................................. 47 
10.4. 
Derived and transformed data ..................................................................... 47 
10.5. 
Conduct of analyses ................................................................................... 47 
10.6. 
Statistical methods ...................................................................................... 48 
10.6.1. 
Analysis of demographics/baseline characteristics ...................... 48 
10.6.2. 
Analysis of safety ......................................................................... 48 
11. ADMINISTRATIVE MATTERS ............................................................................... 48 
11.1. 
Remote Data Entry instructions .................................................................. 48 
11.2. 
Monitoring by GSK Biologicals .................................................................... 49 
11.3. 
Archiving of data at study sites ................................................................... 50 
11.4. 
Audits ......................................................................................................... 50 
11.5. 
Posting of information on Clinicaltrials.gov .................................................. 51 
11.6. 
Ownership, confidentiality and publication .................................................. 51 
11.6.1. 
Ownership ................................................................................... 51 
11.6.2. 
Confidentiality .............................................................................. 51 
11.6.3. 
Publication ................................................................................... 51 
11.6.4. 
Provision of study results to investigators, posting to the 
clinical trials registers and publication .......................................... 52 
12. COUNTRY SPECIFIC REQUIREMENTS ............................................................... 52 
13. REFERENCES ....................................................................................................... 52 

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LIST OF TABLES 
PAGE 
Table 1 
List of study procedures ......................................................................... 25 
Table 2 
Intervals between study visits ................................................................. 25 
Table 3 
Study vaccine ......................................................................................... 28 
Table 4 
Dosage and administration ..................................................................... 29 
Table 5 
List of potential immune-mediated diseases (Amended 13 
January 2011) ........................................................................................ 35 
Table 6 
Reporting periods for adverse events, serious adverse events 
and pregnancies..................................................................................... 37 
Table 7 
Time frames for submitting SAEs and other events reports to 
GSK Biologicals ..................................................................................... 41 
 
LIST OF FIGURES 
PAGE 
Figure 1 
Study visits and study procedures .......................................................... 20 
 
LIST OF APPENDICES 
PAGE 
Appendix A 
Amendments and Administrative Changes to the Protocol ..................... 55 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse event 
Al(OH)3 
Aluminium hydroxide 
AS04 
GlaxoSmithKline’s proprietary adjuvant system 
consisting of aluminium salt plus 3-O-desacyl-4'-
monophosphoryl lipid A (MPL)  
CIN 
Cervical Intraepithelial Neoplasia 
CIN2+ 
CIN2, CIN3, AIS or invasive cervical cancer 
eCRF 
electronic Case Report Form 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
HIV 
Human Immunodeficiency Virus 
HPV 
Human papillomavirus 
ICF 
Informed Consent Form 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
LSLV 
Last Subject Last Visit 
µg 
microgram 
mg 
milligram 
ml 
millilitre 
MPL 
3-O-desacyl-4'-monophosphoryl lipid A  
pIMD 
potential Immune-Mediated Disease 
RDE 
Remote Data Entry 
SAE 
Serious Adverse Event 
SPM 
Study Procedures Manual 
VLP 
Virus-like particles 

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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 (when applicable, as 
mentioned in the product label) for example abstinence, 
combined or progestogen oral contraceptives, injectable 
progestogen, implants of levonorgestrel, oestrogenic 
vaginal ring, percutaneous contraceptive patches or 
intrauterine device (IUD) or intrauterine system (IUS), 
vasectomy with documented azoospermia of the sole 
male partner or male condom combined with a vaginal 
spermicide (foam, gel, film, cream or suppository) or 
male condom combined with a female diaphragm, either 
with or without a vaginal spermicide (foam, gel, film, 
cream, or suppository).  
For azoospermia, ‘documented’ refers to the laboratory 
report of azoospermia, required for acceptable 
documentation of successful vasectomy in the subject’s 
male partner. 
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 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. 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
eTrack: 
GSK’s tracking tool for clinical trials. 
Global Study Manager 
An individual assigned by GSK Biologicals Headquarters 
who is responsible for assuring the co-ordination of the 
operational aspects and proper conduct of a clinical study, 
including compliance with International Conference on 
Harmonisation (ICH) Harmonised Tripartite Guideline 
for Good Clinical Practice (GCP) and GSK policies and 
standard operating procedures. 

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Investigational 
vaccine/product: 
(Synonym of 
Investigational Medicinal 
Product) 
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorisation when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use.  
Medically Significant 
Condition: 
Medically significant conditions are defined as AEs 
prompting emergency room or physician visits that are 
not (1) related to common diseases or (2) routine visits 
for physical examination or vaccination, or SAEs that are 
not related to common diseases. 
Common diseases include: upper respiratory infections, 
sinusitis, pharyngitis, gastroenteritis, urinary tract 
infections, cervicovaginal yeast infections, menstrual 
cycle abnormalities and injury. 
Medically significant conditions include potential 
immune-mediated diseases (pIMDs). 
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. 
pIMD 
Potential immune-mediated diseases (pIMDs) are a subset 
of Medically Significant Conditions that include 
autoimmune diseases and other inflammatory and/or 
neurological disorders of interest which may or may not 
have an autoimmune aetiology.  
Site Monitor: 
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites. 
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 product(s) 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, 
identified by a unique number, according to the study 
randomisation or treatment allocation. 

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TRADEMARKS 
The following trademarks are used in the present protocol. 
Note: In the body of the Protocol (including the synopsis), the names of the 
vaccines/products and/or medications will be written without the subscript symbol ™ or 
®. 
Trademarks of the GlaxoSmithKline 
group of companies 
 
generic description 
Cervarix™ 
 
Human papillomavirus vaccine types 16 and 
18 (Recombinant, AS04 adjuvanted, 
adsorbed)  
 

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1. 
INTRODUCTION 
1.1. 
Background 
Cervical cancer is the most important manifestation of genital human papillomavirus 
(HPV) infection and is one of the leading causes of cancer mortality in women worldwide 
[Parkin, 2001a; Parkin, 2001b]. Papillomaviruses, members of the papovaviridae family, 
are non-enveloped deoxyribonucleic acid (DNA) viruses which can cause a variety of 
proliferative epithelial lesions in humans, including benign papillomas (warts) and 
invasive cancer [Lowy, 2001; Zur Hausen , 2002].  
Currently, over 200 different types of HPVs have been recognized. Based on whether 
they infect basal epithelial cells of the skin or the inner lining of tissues, they are 
categorized as cutaneous or mucosal types [Burd, 2003]. At least 30 HPV types have 
been identified that infect the genital mucosa [Bosch, 1995]. HPV types are also 
classified by their relative malignant potential into low-risk (LR) types (e.g. HPV-6, -11, 
-42, -43, and -44) and high-risk (HR) or oncogenic types (e.g. HPV-16, -18, -31, -33, -34, 
-35, -39, -45, -51, -52, -56, -58, -59, -66, -68 and -70) [Burd, 2003]. Persistent infection 
with an oncogenic HPV type has been clearly associated with the development of 
cervical cancer [Schiffman, 2005] and the association between cervical cancer and 
infection with a HR HPV type is supported both by strong epidemiological evidence and 
the detection of HPV DNA in up to 99.7% of cervical cancers worldwide [Schiffman 
2005; Burd 2003]. 
The distribution of HPV types varies within countries and between regions. HPV-16 and 
HPV-18 are the first and second most common types in all regions, with some variation 
in their distribution. HPV-16 is the most prevalent oncogenic HPV type and is present in 
approximately 54% of cervical tumor specimens worldwide. HPV-18 is associated with 
approximately 17% of cervical cancers, with the remaining tumors containing DNA from 
other oncogenic HPV types such as HPV-45 and -31. In combination, these two HPV 
types (HPV-16 and HPV-18) account for approximately 70% of cervical cancer cases 
globally [Clifford 2003]. 
In the general population, the estimated worldwide prevalence of HPV among women is 
between 5% and 40% [Baseman, 2005; Franco, 1999]. This wide variation reflects 
underlying population characteristics (i.e. age range, geographic area, risk behaviours), 
the use of different HPV DNA test methods, and also differences in the sexual activity of 
the individuals studied. Assuming a conservative prevalence of 10% in developed 
countries and 15% in developing countries, one author estimated 270 million HPV 
infections amongst women globally [Bosch, 2002]. 
1.2. 
GlaxoSmithKline Biologicals’ HPV Vaccine 
GlaxoSmithKline (GSK) Biologicals has developed a candidate prophylactic HPV 
vaccine based on L1 proteins of HPV-16 and HPV-18 formulated with AS04 (comprised 
of aluminium hydroxide [Al(OH)3] and 3-O-desacyl-4’-monophosphoryl lipid A [MPL]). 
The vaccine contains HPV-16 and HPV-18 L1 VLP proteins produced using an 

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expression system based on the use of insect cells and recombinant Baculoviruses 
encoding L1 proteins of HPV-16 and HPV-18. The recombinant expressed proteins 
undergo self-assembly to form empty viral capsids referred to as virus-like particles 
(VLPs) [Kirnbauer, 1992]. A study comparing different vaccine formulations 
demonstrated that the highest antibody titres were induced by AS04-adjuvanted vaccine 
formulations [Giannini, 2006]. The AS04 adjuvant system is comprised of aluminium 
salts (Al(OH)3) and 3-O-desacyl-4’-monophosphoryl lipid A (MPL) and is also used in 
other vaccines, including a hepatitis B vaccine licensed in Europe for use in 
haemodialysis patients from the age of 15 years and above under the name Fendrix as 
well as in an investigational HSV vaccine.  
To date, more than 60 000 adolescent and adult females aged 9 years and above have 
received at least one dose of the HPV vaccine in clinical studies. A pooled safety analysis 
of data from almost 30 000 adolescent and adult females aged 10 years and above, of 
whom 16 142 received at least one dose of HPV vaccine, showed the vaccine to be 
generally well tolerated in women of all ages [Descamps, 2009]. In this publication , 
subjects from the HPV-015 trial were included and the safety profile in women aged 26 
and above was similar to the one in 15-25 year olds who received the vaccine. 
Results of a large multinational phase III trial in women aged 15-25 years demonstrated 
high vaccine efficacy against cervical intraepithelial neoplasia grade 2 and above 
(CIN2+), CIN1+ and persistent infection (6-month and 12-month definition) associated 
with HPV-16 and/or HPV-18, significant vaccine efficacy against CIN2+ and CIN3+ 
irrespective of HPV type in the lesion as well as evidence of protection against HPV 
types 31, 33 and 45 [Paavonen, 2009]. This study also demonstrated the vaccine to be 
generally well tolerated in a broad range of women including those of different 
nationalities and ethnicities [Paavonen, 2007]. 
A long-term efficacy follow-up study in women aged 15-25 years at the time of first 
vaccination demonstrated high vaccine efficacy against incident and persistent HPV-
16/18 infections and their associated cervical lesions up to 6.4 years of follow-up [Gall, 
2007; Harper, 2004; Harper, 2006; The GlaxoSmithKline Vaccine HPV-007 Study 
Group, 2009]. 
When tested in young female adolescents, the vaccine induced immune responses that 
were approximately 2-fold higher than those elicited in women 15-25 years of age 
[Pedersen, 2007]. In women up to 55 years of age, the vaccine induced sustained HPV 
antibody levels up to Month 24 after the first vaccine dose and these antibody levels 
remained significantly higher than those seen after natural infection [Schwarz, 2009]. 
The first major market in which the vaccine under evaluation in this study was licensed is 
Australia, where licensure was obtained in May 2007 for use in 10 to 45 year old females. 
The vaccine is marketed under the trade name Cervarix. In September 2007, the vaccine 
was licensed in the European Union for the prevention of high-grade cervical 
intraepithelial neoplasia (CIN grades 2 and 3) and cervical cancer causally related to 
HPV types 16 and 18. In October 2009, Cervarix has also been approved by the United 
States Food and Drug Administration (US FDA) for use in females 10 through 25 years 
of age. The vaccine is currently licensed in over 100 countries worldwide. 

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Please refer to the current Investigator Brochure for a review of pre-clinical and clinical 
studies, and the potential risks and benefits of the candidate prophylactic HPV-16/18 
vaccine formulated with AS04. 
1.3. 
Rationale for the study and study design 
Subjects in the HPV-015 study either received the HPV-16/18 L1 VLP AS04 vaccine or 
placebo control [Al(OH)3], following a 0, 1, 6-month vaccination schedule. According to 
the HPV-015 protocol, once the HPV-015 study was concluded, the control placebo 
group would be offered the HPV-16/18 L1 VLP AS04 vaccine as well.  
As recommended by the study Independent Data Monitoring Committee (IDMC), 
unblinding and cross-over immunization of control recipients with the HPV vaccine will 
be provided after completion of their end of study activities as follows: 
• 
For subjects who complete study activities after the database is frozen for final 
analysis, unblinding will occur within 4-6 months after last subject last visit (LSLV) 
of the final study visit. 
• 
Subjects who will not participate in any of the extensions will be given the option of 
unblinding before the database is frozen for final analysis upon individual request. 
The HPV-16/18 L1 VLP AS04 vaccine is licensed in the participating countries, but it is 
not indicated for the age group (26 years and above) involved in the HPV-015 study and 
this study. Approximately 600 subjects from the control placebo group are expected to 
enrol in this study. 
This study is thus being conducted to enable all women, who received the control placebo 
in the HPV-015 study, to also receive HPV-16/18 L1 VLP AS04 vaccine. Safety data in 
terms of SAEs, medically significant conditions and pregnancy (and their outcomes) will 
be collected during the study period. 
2. 
STUDY OBJECTIVE 
• 
To assess the safety of the HPV-16/18 L1 VLP AS04 vaccine throughout the study 
period. 
Refer to Section 10.1 for the definition of the study endpoint. 
3. 
STUDY DESIGN OVERVIEW 
An overview of the study design is presented in Figure 1. 

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Figure 1 
Study visits and study procedures  
 
 
 
HPV-16/18 L1 VLP AS04 
HPV vaccine group (Approximate N = 600) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 1  
 
Month 0 
 
 
 
 
Visit 2 
 
Month 1 
 
 
 
 
Visit 3 
 
Month 6 
 
 
 
 
Telephone 
contact 
Month 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 1  
 
 
 
Vaccination 2 
 
 
 
 
Vaccination 3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study 
conclusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Experimental design: Phase IIIB multi-centric, single-group: HPV vaccine group 
(HPV-16/18 L1 VLP AS04).  
• 
Treatment allocation: sequential allocation of subjects to receive the HPV-16/18 L1 
VLP AS04 vaccine 
• 
Blinding: open-label 
• 
Treatment group: HPV vaccine group (HPV-16/18 L1 VLP AS04) 
• 
Vaccination schedule: Three doses of HPV-16/18 L1 VLP AS04 vaccine (20 µg 
HPV-16, 20 µg HPV-18) administered intramuscularly according to a 0, 1, 6-month 
schedule. 
• 
Control: uncontrolled . 
• 
Type of study: e.g. self-contained, extension of study HPV-015  
• 
Data collection: eCRF  
• 
Duration of the study: Approximately 12 months per subject.  
• 
Study visits per subject: Three scheduled visits are planned at Months 0, 1, 6. There 
will be a telephone contact with the subject at Month 12 (i.e. six months after the 
third dose of the HPV-16/18 L1 VLP AS04 vaccine). 
• 
Safety monitoring:  
• 
All serious adverse events (SAEs) occurring throughout the study period (i.e. 
from Day 0 up to the telephone contact at Month 12) will be reported for all 
subjects. 
• 
Medically significant conditions (including pIMDs) will be reported for all 
subjects throughout the study period.  
• 
Pregnancies and pregnancy outcomes will be reported for all subjects throughout 
the study 

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4. 
STUDY COHORT 
4.1. 
Number of subjects/centres 
Overview of the recruitment plan: 
Of all subjects participating in the HPV-015 conclusion visits who received the control 
placebo in the HPV-015 study, approximately 600 subjects are expected to enrol in this 
study. Subjects who participated in the HPV-015 study may decide to conclude their 
participation in the HPV-015 study at Visit 9, Visit 11 or at the last study visit in HPV-
015 planned under protocol amendment 4. 
These subjects will be contacted and invited to participate in this cross-over vaccination 
study with GSK Biologicals’ HPV-16/18 L1 VLP AS04 vaccine. Enrolment should take 
place within two years after the subject has completed the HPV-015 study. 
4.2. 
Inclusion criteria for enrolment 
All subjects must satisfy ALL the following criteria at study entry: 
• 
Subjects who the investigator believes can and will comply with the requirements of 
the protocol  
• 
A subject previously enrolled in the HPV-015 study, who received the control 
vaccine, and who cannot receive the commercially available HPV-16/18 L1 VLP 
AS04 vaccine because the subject is above the age for which the vaccine is licensed. 
• 
Written informed consent obtained from the subject  
• 
Free of obvious health problems 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 current tubal ligation, hysterectomy, 
ovariectomy or post-menopause.   
Refer to the Glossary Of Terms for the definition of 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.   
Refer to the Glossary Of Terms for the definition of adequate contraception.  

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4.3. 
Exclusion criteria for enrolment (Amended 13 Jan 2011) 
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: 
• 
Pregnant or breastfeeding (women must be at least three months post-pregnancy and 
not breastfeeding to enter the study).  
• 
A woman planning to become pregnant, likely to become pregnant (as determined by 
the investigator) or planning to discontinue contraceptive precautions during the 
vaccination phase of the study, i.e. up to two months after the last vaccine dose. 
• 
Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine within 30 days preceding the first dose of study vaccine, or planned 
use during the study period.   
• 
Previous vaccination against HPV or planned administration of another HPV vaccine 
during the study other than that foreseen in the protocol.  
• 
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs within six months prior to 
the first vaccine dose. For corticosteroids, this will mean prednisone greater than or 
equal to 20 mg/day, or equivalent. Inhaled and topical steroids are allowed  
• 
Planned administration/administration of a vaccine not foreseen by the study 
protocol within 30 days (i.e., Day 0-29) of each dose of vaccine, with the exception 
of administration of routine meningococcal, hepatitis B, hepatitis A, inactivated 
influenza, diphtheria/tetanus and/or diphtheria/tetanus-containing vaccine up to 8 
days before each dose of study vaccine. Enrolment will be deferred until the subject 
is outside of specified window. 
• 
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 product (pharmaceutical product or device). 
NOTE: Subjects enrolled in this study may also be eligible for a four-year 
gynaecological follow-up of the HPV-015 study (HPV-062), in which no 
investigational product will be administered. Subjects may participate to both studies 
at the same time.  
• 
Previous administration of MPL or AS04 adjuvant.  
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).  
• 
Cancer or autoimmune disease under treatment.  
• 
Administration of immunoglobulins and/or any blood products within the 3 months 
preceding the first dose of study vaccine or planned administration during the study 
period.  
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine including latex.  

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• 
History of any neurological disorders or seizures.  
• 
Acute disease and/or fever at the time of enrolment.  
Fever is defined as temperature ≥ 37.5°C (99.5°F) on oral, axillary or tympanic 
setting, or ≥ 38.0°C (100.4°F) on rectal setting.  
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.  
Enrolment will be deferred until condition is resolved. 
• 
Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality, as determined by physical examination or laboratory 
screening tests.  
5. 
CONDUCT OF THE STUDY 
5.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki.  
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 as appropriate.  
• 
Investigator reporting requirements as stated in the protocol. 
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both. 
Freely given and written 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 

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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. 
5.2. 
Subject identification and randomisation of treatment 
The target will be to enrol approximately 600 eligible subjects to receive the HPV-16/18 
L1 VLP AS04 vaccine in this study . 
5.2.1. 
Subject identification 
A new identification number will be assigned to the subject to preserve the blind for 
HPV-015 data during this HPV-015 extension study. 
5.2.2. 
Randomisation of treatment 
A sequential numbering of the vaccine doses will be performed at GSK Biologicals, 
Rixensart, using a standard SAS® (Statistical Analysis System) program. The vaccine 
doses labeled with those treatment numbers will be distributed to the study centres. No 
randomization will be performed: at each vaccination, the treatment number must be 
recorded by the investigator/co-investigator or delegate in the eCRF (Vaccine 
Administration Section). 
5.2.3. 
Randomisation of subjects to assay subsets  
Not applicable. 
5.3. 
Method of blinding  
Since this is an open-label study with a single treatment group, no blinding will be 
applied.  
5.4. 
General study aspects 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM provides the 
investigator and the site personnel with administrative and detailed technical information 
that does not impact the safety of the subjects. 

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5.5. 
Outline of study procedures 
Table 1 
List of study procedures 
Type of contact 
visit 1 
visit 2 
visit 3 
phone contact 
12  
Timepoint (s) 
months 0  
months 1  
months 6  
months 12  
Informed consent  
●  
 
 
 
Check inclusion/exclusion criteria  
●  
 
 
 
Check contraindications  
 
●  
●  
 
Medical history  
●  
 
 
 
Record administration of any HPV vaccine other 
than that foreseen by the study protocol  
●  
●  
●  
●  
Collect demographic data   
●  
 
 
 
History-directed physical examination  
●   
 
 
 
Urine sample for pre-vaccination pregnancy test  
●  
●  
●  
 
Pre-vaccination body temperature  
●  
●  
●  
 
Vaccination  
●  
●  
●  
 
Record administration of any concomitant 
medication, vaccination or medical treatment  
●  
●  
●  
●  
Reporting of medically significant conditions 
(including pIMDs)  
●  
●  
●  
●  
Reporting of serious adverse events  
●  
●  
●  
●  
Reporting of pregnancies (and outcomes)  
●  
●  
●  
●  
Safety follow-up contact  
 
 
 
●  
Study Conclusion   
 
 
 
●  
The investigator or his/her designee will contact the subjects by telephone approximately six months after the third 
vaccine dose to obtain information on the occurrence of any of the safety endpoints. 
● is used to indicate a study procedure that requires documentation in the individual eCRF  
It is the investigator’s responsibility to ensure that the intervals between visits/contacts 
are followed. The intervals between vaccination visits, and the interval between the last 
vaccination visit and the telephone contact at Month 12 are provided in Table 2. It is 
preferable to follow these intervals as closely as possible.  
Table 2 
Intervals between study visits 
Interval 
Optimal length of interval 
(months) 
Recommended interval  
between scheduled visits/contact (months) 
1 ( visit  1 visit 2) 
1 – 2.5 
1   
2 ( visit 1 visit 3) 
5 - 12   
6   
3 ( visit 3 phone contact) 
6 - 7   
6   

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5.6. 
Detailed description of study procedures 
5.6.1. 
Procedures prior to study participation 
5.6.1.1. 
Informed consent 
Before performing any other study procedure, the signed/thumb printed informed consent 
of the subject needs to be obtained. Refer to Section 5.1 for the requirements on how to 
obtain informed consent as appropriate.  
5.6.2. 
Procedures prior to the first vaccination  
5.6.2.1. 
Check inclusion and exclusion criteria 
Check all applicable inclusion and exclusion criteria as described in Sections 4.2 and 4.3 
before enrolment.  
5.6.2.2. 
Collect demographic data 
Record demographic data such as age, gender and ethnicity in the subject’s eCRF. 
5.6.2.3. 
Medical history and history-directed physical examination 
Perform a history-directed medical and physical examination and record any pre-existing 
or concurrent conditions or signs and/or symptoms present in a subject prior to the start 
of the study in the eCRF. Treatment of any abnormality observed during this examination 
has to be performed according to local medical practice outside this study or by referral 
to an appropriate health care provider. 
5.6.3. 
Procedures at each vaccination visit 
5.6.3.1. 
Urine pregnancy test 
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study vaccine administration. The study vaccine may only be administered if the 
pregnancy test is negative. 
5.6.3.2. 
Check contraindications to vaccination (only prior to second and third 
vaccine dose) 
Contraindications to vaccination are to be checked at the beginning of each vaccination 
visit. Refer to Section 6.5.  

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5.6.3.3. 
Check and record concomitant medication/vaccination 
Concomitant medication/vaccination must be recorded in the eCRF as described in 
Section 6.6. Refer also to Section 6.6 for details on the medication/vaccination forbidden 
and/or allowed during the study. 
5.6.3.4. 
Assess pre-vaccination body temperature 
The axillary, rectal, oral or tympanic body temperature of all subjects needs to be 
measured prior to any study vaccine administration. The preferred route for recording 
temperature in this study will be oral or axillary. If the subject has fever [fever is defined 
as temperature  37.5°C (99.5°F) on oral or, axillary or tympanic setting, or  38.0°C 
(100.4°F) on rectal setting] on the day of vaccination, the vaccination visit will be 
rescheduled within the interval for this visit (see Table 2). 
5.6.3.5. 
Vaccination 
• 
After completing the 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 vaccination temporarily precludes vaccination, the visit will be rescheduled 
within the interval for this visit. 
• 
The vaccinees will be observed closely for at least 30 minutes, with appropriate 
medical treatment readily available in case of anaphylaxis following the 
administration of vaccine. 
5.6.3.6. 
Recording of medically significant conditions and SAEs 
• 
Refer to Section 8.3 for procedures for the Investigator to record AEs (medically 
significant conditions only) and SAEs that are related to study participation or GSK 
concomitant medication/vaccination and to Section 8.4 for guidelines on how to 
report these AEs/SAEs to GSK Biologicals. 
• 
The subjects will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious.  
• 
Refer to the Refer to the Glossary Of Terms for the definition of medically 
significant conditions 
5.6.4. 
Procedures during follow-up phone contact 
• 
The investigator or his/her designee will contact the subjects by telephone 
approximately 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 medically significant conditions and SAEs are also performed during 

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this phone contact and are described in Section 5.6.3.3 and Section 5.6.3.6, 
respectively. 
5.6.4.1. 
Study conclusion 
The investigator will review safety data collected during the entire cross-vaccination 
study to ensure accuracy and completeness and will complete the Study Conclusion 
screen in the eCRF. 
5.7. 
Biological sample handling and analysis 
Not applicable. 
5.7.1. 
Immunological correlates of protection 
No correlate of protection has been demonstrated for the HPV-16 and HPV-18 antigens 
used as part of the HPV-16/18 L1 VLP AS04 vaccine. 
6. 
STUDY VACCINE AND ADMINISTRATION 
6.1. 
Description of study vaccine 
The candidate vaccine to be used 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. 
The composition of the HPV-16/18 L1 VLP AS04 vaccine is presented in Table 3.  
Table 3 
Study vaccine 
Vaccine name 
Formulation 
Presentation 
Volume 
Number of 
doses 
HPV-16/18 L1 VLP AS04  Each 0.5 ml dose contains:  
- 20 µg HPV-16 L1 VLP 
- 20 µg HPV-18 L1 VLP 
- 50 µg MPL 
- 0.5 mg aluminium as Al(OH)3 
- 8 mM sodium dihydrogen 
phosphate dihydrate 
- 150 mM sodium chloride  
- water for injection  
Liquid in pre-filled syringes  
0.6 ml 
3 
MPL = 3-O-desacyl-4’-monophosphoryl lipid A; Al(OH)3 = aluminium hydroxide; L1 = structural protein of HPV 
ml = millilitre; g = microgram 

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6.2. 
Storage and handling of study vaccine 
The study vaccine to be administered to the subjects must be stored in a safe and locked 
place with no access by unauthorised personnel.  
The study vaccine must be stored at the defined temperature range (i.e. +2 to +8°C/36F 
to 46F). Please refer to the Module on Clinical Trial Supplies in the SPM for more 
details on storage of the study vaccine. The storage temperature of the vaccine will be 
monitored daily with temperature monitoring device(s) (at the minimum calibrated) and 
will be recorded as specified in the SPM.  
The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact. 
Any temperature deviation outside the range 0 to +8C/32 to 46F must be reported to the 
sponsor as soon as detected. Following an exposure to a temperature deviation, vaccine 
will not be used until written approval has been given by the Sponsor. 
In case of temperature deviation between 0 and +2°C/32 and 36°F, the impacted study 
vaccine can still be administered, but the site must take adequate actions to go back to the 
defined range +2 to +8°C/36 to 46°F and avoid re-occurrence of such a temperature 
deviation. 
Please refer to the Module on Clinical Trial Supplies in the SPM for details and 
instructions on the Temperature deviation process, packaging and accountability of the 
study vaccine. 
6.3. 
Dosage and administration of study vaccine 
GSK Biologicals will supply the HPV-16/18 L1 VLP AS04 vaccine as 0.6 ml liquid in 
pre-filled syringes to be administered (0.5ml) into the deltoid of the non-dominant arm on 
a 0, 1, 6 month schedule (refer to Table 4). Additional syringes will be provided to each 
site to replace broken, lost or damaged syringes as needed. 
The HPV-16/18 L1 VLP AS04 vaccine is provided as individual pre-filled syringes for 
single use. Each syringe must be brought to room temperature and resuspended (by 
inversion) prior to injection by standard aseptic technique. The study vaccine must be 
used as soon as possible after preparation of the syringe. 
Table 4 
Dosage and administration 
Type of contact and 
timepoint 
Dose 
Vaccine/Product 
Route 1 
Site 2 
Side 3 
visit  1 ((months 0 ) 
1  
HPV-16/18 L1 VLP AS04  
IM  
D  
N-D  
visit  2 ( months  1) 
1  
HPV-16/18 L1 VLP AS04  
IM   
D   
N-D   
visit  3 ( months 6  ) 
1  
HPV-16/18 L1 VLP AS04   
IM   
D   
N-D   
1 Intramuscular (IM) 
2 Deltoid (D) 
3 Non-dominant (N-D) 

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6.4. 
Replacement of unusable vaccine doses 
Additional vaccine doses will be provided to replace those that are unusable (see the 
Module on Clinical Trial Supplies in the SPM for details). 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomisation when applicable), at least 5% additional doses will be supplied to 
replace those that are unusable.  
6.5. 
Contraindications to subsequent vaccination 
The following events constitute absolute contraindications to further administration of the 
HPV-16/18 L1 VLP AS04 vaccine. If any of these events occur during the study, the 
subject must not receive additional doses of vaccine but may continue other study 
procedures at the discretion of the investigator (see Section 8.4.5).  
• 
Anaphylaxis following the administration of the vaccine. 
• 
Pregnancy (see Section 8.2)  
• 
Any serious adverse event (SAE) judged to be related to 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). 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including human immunodeficiency virus (HIV) infection. 
The following events constitute contraindications to administration of the HPV-16/18 L1 
VLP AS04 vaccine at that point in time; if any of these events occur at the time 
scheduled for vaccination, the subject may be vaccinated at a later date, within the time 
window specified in the protocol (see Section 5.5), or withdrawn at the discretion of the 
investigator (see Section 8.4.5).  
• 
Acute disease and/or fever at the time of vaccination.  
• 
Fever is defined as temperature ≥ 37.5°C (99.5°F) on oral, axillary or tympanic 
setting, or  38.0°C (100.4°F) on rectal setting. The preferred route for recording 
temperature in this study will be oral or axillary. 
• 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered the HPV-16/18 L1 VLP AS04 
vaccine.  

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6.6. 
Concomitant medication/vaccination 
At each study visit/contact, the investigator should question the subject if she received 
any HPV vaccine other than that foreseen in the study protocol at any time during the 
study period. The trade name of the vaccine, route of administration and date(s) of 
administration should be recorded in the eCRF. Refer to Sections 4.3 and 6.5. 
At each study visit/contact, the investigator should question the subject about any 
medication taken and vaccination received by the subject. 
All concomitant medication/vaccination, with the exception of vitamins and/or dietary 
supplements, are to be recorded in the eCRF. This also applies to concomitant medication 
administered prophylactically in anticipation of reaction to the vaccination and any 
medication intended to treat an AE.  
A prophylactic medication is a 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  37.5°C (99.5°F) on oral, axillary 
or tympanic setting, or  38.0°C (100.4°F) on rectal setting]).  
Any treatments and/or medications specifically contraindicated, administered at any time 
during the study period are to be recorded with generic name of the medication (trade 
names are allowed for combination drugs only), medical indication, total daily dose, 
route of administration, start and end dates of treatment. Refer to Sections 4.3 and 6.5. 
Similarly, concomitant medication administered for the treatment of a SAE, at any time, 
must be recorded on the SAE Report / SAE screens in the eCRF, as applicable. Refer to 
Section 8.1.2 for the definition of a SAE. 
6.6.1. 
Time window for recording concomitant medication/vaccination 
in the eCRF 
All concomitant medications, with the exception of vitamins and/or dietary supplements, 
administered at ANY time during the period starting with the administration of each dose 
of study vaccine and ending 30 days after each dose of study vaccine must be recorded in 
the eCRF. 
Any vaccine not foreseen in the study protocol administered in the period beginning 30 
days preceding each dose of study vaccine and ending 30 days after each dose of study 
vaccine must be recorded in the eCRF.  
Any investigational medication or vaccine administered throughout the study (i.e. from 
Day 0 through Month 12) must be recorded in the eCRF. 
7. 
HEALTH ECONOMICS 
Not applicable. 

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8. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The investigator or site staff is/are responsible during the study for the detection and 
documentation of events meeting the criteria and definition of an adverse event (AE) or 
serious adverse event (SAE) as provided in this protocol.  
Each subject will be instructed to contact the investigator immediately should they/the 
subject manifest any signs or symptoms they perceive as serious. 
NOTE: The term AE denotes both non-serious and serious adverse events. In this study, 
only SAEs and non-serious AEs that are medically significant conditions will be 
reported. 
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: 
• 
Medically significant conditions (please refer to Section 8.1.4 for the definition of 
medically significant condition).  
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after investigational product administration 
even though it may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concurrent medication (overdose per se should not be 
reported as an AE/SAE). 
• 
Signs, symptoms temporally associated with vaccine administration. 
Examples of an AE DO NOT include: 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 

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• 
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.  
AEs may include 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). 
Example of events to be recorded in the medical history section of the eCRF: 
• 
Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
start of the study (i.e. prior to the first study vaccination). 
NOTE: In this study, only SAEs and non-serious AEs that are medically significant 
conditions will be reported. 
8.1.2. 
Definition of a serious adverse event  
A serious adverse event (SAE) is any untoward medical occurrence that: 
a. 
Results in death. 
b. Is life-threatening. 
NB: 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. 
NB: 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 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. 
d. Results in disability/incapacity, or 
NB: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study subject. 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 

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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  
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 AEs or SAEs if they meet the 
definition of an AE, as defined in Section 8.1.1 or of a SAE, as defined in Section 8.1.2. 
Clinically significant abnormal laboratory findings or other abnormal assessments that 
are detected during the study or are present at baseline and significantly worsen following 
the start of the study will be reported as medically significant conditions or SAEs, if 
applicable. 
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. 
Medically significant conditions 
Medically significant conditions are defined as: 
• 
AEs prompting emergency room or physician visits that are: 
1. not related to common diseases, or  
2. not related to routine visits for physical examination or vaccination 
• 
SAEs that are not related to common diseases. 
Common diseases include: upper respiratory infections, sinusitis, pharyngitis, 
gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle 
abnormalities and injury. 
Medically significant conditions include pIMDs. 
8.1.4.1. 
Potential immune-mediated diseases 
Potential immune-mediated diseases (pIMDs) are a subset of medically significant 
conditions 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 the table below. 
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other immune-mediated diseases have an autoimmune origin (i.e. 
pathophysiology involving systemic or organ-specific pathogenic autoantibodies) and 
should also be recorded as a pIMD. 

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Onset of a new pIMD or exacerbation of a pre-existing pIMD (serious or non-serious) 
will be recorded in the SAE screen of the subject's eCRF. 
Table 5 
List of potential immune-mediated diseases (Amended 13 Jan 2011) 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve disorders, 
including paralyses/paresis 
(e.g. Bell’s palsy), and neuritis 
(e.g. optic neuritis) 
• 
Multiple sclerosis (including 
variants) 
• 
Transverse myelitis 
• 
Guillain-Barré syndrome, 
(including Miller Fisher 
syndrome and other variants) 
• 
Other demyelinating diseases 
(including acute disseminated 
encephalomyelitis) 
• 
Myasthenia gravis (including 
Lambert-Eaton myasthenic 
syndrome)  
• 
Non-infectious encephalitis/ 
encephalomyelitis  
• 
Neuritis (including peripheral 
neuropathies) 
• 
Systemic lupus erythematosus  
• 
Scleroderma (including, 
CREST syndrome and 
morphoea) 
• 
Systemic sclerosis 
• 
Dermatomyositis  
• 
Polymyositis  
• 
Antisynthetase syndrome 
• 
Rheumatoid arthritis,  
• 
Juvenile chronic arthritis, 
(including Still’s disease) 
• 
Polymyalgia rheumatica  
• 
Reactive arthritis 
• 
Psoriatic arthropathy 
• 
Ankylosing spondylitis 
(including undifferentiated 
spondyloarthritides) 
• 
Relapsing polychondritis 
• 
Mixed connective tissue 
disorder 
• 
Psoriasis 
• 
Vitiligo 
• 
Raynaud’s phenomenon 
• 
Erythema nodosum 
• 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid and 
dermatitis herpetiformis) 
• 
Cutaneous lupus 
erythematosus 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
Liver disorders 
Gastrointestinal disorders 
Metabolic diseases 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing cholangitis 
• 
Autoimmune cholangitis. 
• 
Crohn’s disease  
• 
Ulcerative colitis  
• 
Ulcerative proctitis  
• 
Celiac disease 
• 
Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis) 
• 
Grave's or Basedow’s disease 
• 
Diabetes mellitus type I 
• 
Addison’s disease 
Vasculitides 
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, 
thromboangiitis obliterans (Buerger’s disease), 
necrotizing vasculitis, allergic granulomatous 
angiitis, Henoch-Schonlein purpura, anti-
neutrophil cytoplasmic antibody positive 
vasculitis, Behcet's syndrome, leukocytoclastic 
vasculitis.  
• 
Vasculitides secondary to other immune 
mediated diseases such as lupus vasculitis and 
rheumatoid vasculitis. 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune thrombocytopenias 
• 
Antiphospholipid syndrome 
• 
Pernicious anemia 
• 
Autoimmune glomerulonephritis (including IgA 
nephropathy, glomerulonephritis rapidly 
progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and 
mesangioproliferative glomerulonephritis) 
• 
Uveitis 
• 
Autoimmune myocarditis/cardiomyopathy 
• 
Sarcoidosis 
• 
Stevens-johnson syndrome 
• 
Sjögren’s syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Goodpasture syndrome 

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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. 
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. 
Pregnancy 
Any female subjects that 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 pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or a 
SAE, as described in Section 8.1.1 and 8.1.2, and will be followed as described in Section 
8.4.5. 
A spontaneous abortion is always considered to be a SAE and will be reported as 
described in Section 8.4. Furthermore, any SAE occurring as a result of a post-study 
pregnancy AND considered by the investigator to be reasonably related in time to the 
receipt of the investigational product will be reported to GSK Biologicals as described in 
Section 8.4. 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. 
Information on pregnancies identified during screening/prior to vaccine administration is 
not required to be collected and communicated to safety. 
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 standard time period for collecting and recording medically significant conditions 
will begin at the first receipt of study vaccine and will end 6 months following the 
administration of the last dose of study vaccine (i.e. at study conclusion) for each subject. 
Medically significant conditions should be recorded in the AE screen of the subjects 
eCRF if they are non-serious and in the SAE screen of the subject’s eCRF if they are 
serious. When the medically significant condition is considered as a pIMD, it always has 
to be reported in the SAE screen of the subject’s eCRF. See also Section 8.4 for 
instructions on reporting of pIMDs. 

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The standard time period for collecting and recording pregnancies will begin at the first 
receipt of study vaccine and will end 6 months following administration of the last dose 
of study vaccine (i.e. at study conclusion). See section 8.4 for instructions on reporting of 
pregnancies. 
The standard time period for collecting and recording SAEs will begin at the first receipt 
of study vaccine and will end 6 months following administration of the last dose of study 
vaccine (i.e. at study conclusion). See section 8.4 for instructions on reporting of SAEs. 
Any conditions or signs and/or symptoms present in a subject prior to study HPV-067 
need not be recorded. (Amended 13 Jan 2011) 
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (e.g. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine or any fatal SAE will be collected and 
recorded from the time the subject consents to participate in the study until she/he is 
discharged. 
An overview of the protocol-required reporting periods for adverse events and serious 
adverse events is given in Table 6. 
Table 6 
Reporting periods for adverse events, serious adverse events and 
pregnancies 
Study activity 
Pre-vacc. 
(Consent 
obtained) 
Visit 1 
 
Visit 2 
 
Visit 3 
Telephone contact 
Day 0 
Month 1 
Month 6 
Month 12 
Study Conclusion 
1st  
vacc. 
2nd  
vacc. 
3rd  
vacc. 
6  months post 3rd vaccination 
Reporting of SAEs, 
medically significant 
conditions (including 
pIMDs), pregnancies 
and pregnancy 
outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reporting of fatal 
SAEs and SAEs 
related to study 
participation or 
concurrent GSK 
vaccine/drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-vacc: pre-vaccination; Vacc: vaccination. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 6. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE, 
including a death, at any time after a subject has been discharged from the study, and 
he/she considers the event reasonably related to the investigational product, the 
investigator will promptly notify the Study Contact for Reporting SAEs. 

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8.3.2. 
Evaluation of adverse events and serious adverse events 
8.3.2.1. 
Active questioning to detect adverse events and serious adverse 
events 
The investigator will inquire about the occurrence of SAEs and medically significant 
conditions, pregnancies and pregnancy outcomes at each visit during the study and at the 
telephone contact at Month 12. 
All AEs either observed by the investigator or one of his clinical collaborators or reported 
by the subject spontaneously or in response to a direct question will be evaluated by the 
investigator for the detection and documentation of events meeting the criteria and 
definition of SAEs and/or medically significant conditions. AEs not previously 
documented in the study will be recorded on the Adverse Event screen within the 
subject's eCRF, if applicable. The nature of each event, date and time (where appropriate) 
of onset, outcome, intensity and relationship to the HPV vaccine should be entered. 
Details of any corrective treatment should be recorded on the appropriate page of the 
eCRF. Refer to Section 6.6. 
As a consistent method of soliciting 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?’ 
AEs already documented in the eCRF, i.e. at a previous assessment, and designated as 
“not recovered/not resolved” or “recovering/resolving” should be reviewed at subsequent 
visits, as necessary. If these have resolved, the documentation in the eCRF should be 
completed. 
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 on the eCRF or SAE screens as applicable. It is not acceptable for the 
investigator to send photocopies of the subject’s medical records to GSK Biologicals 
instead of the appropriate completed AE/SAE screens in 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. 
The electronic system using SAE screens in the eCRF will be the primary mode for 
reporting SAEs to GSK Biologicals during the study period. In case this electronic 
system for reporting SAEs does not work or after freezing of the subject's eCRF, paper 
SAE Report Forms and the facsimile (Fax) system should be used to report SAEs. Refer 
to Section 8.4.3.1 for details of the back-up reporting system. 

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8.3.2.2. 
Assessment of adverse events 
8.3.2.2.1. Assessment of intensity 
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all other AEs, including SAEs reported during the study. The assessment will be 
based on the investigator’s clinical judgement. 
The intensity of each AE and SAE recorded in the eCRF or SAE screens, as applicable, 
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/adolescents, such an AE would, for example, prevent 
attendance at work/school 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 utilised 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. 
8.3.2.2.2. Assessment of causality 
The investigator is obligated to assess the relationship between investigational product 
and the occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. Alternative plausible causes, based on natural history of the 
underlying diseases, concomitant therapy, other risk factors and the temporal relationship 
of the event to the investigational product will be considered and investigated. The 
investigator will also consult the Investigator Brochure and/or Product Information for 
marketed products, in the determination of 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 SAE to GSK Biologicals. The investigator may change his/her 
opinion of causality in light of follow-up information, amending the SAE information 
accordingly. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 

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Causality of all other AEs than local (injection site) reactions should be assessed by the 
investigator using the following question: 
Is there a reasonable possibility that the AE may have been caused by the investigational 
product? 
NO 
: 
The AE is not causally related to administration of the study 
vaccine(s). There are other, more likely causes and administration 
of the study vaccine(s) is not suspected to have contributed to the 
AE. 
YES 
: 
There is a reasonable possibility that the vaccine(s) contributed to 
the AE.  
Non-serious and serious AEs will be evaluated as two distinct events. If an event meets 
criteria to be determined ‘serious’ (see Section 8.1.2 for definition of serious adverse 
event), additional examinations/tests will be performed by the investigator in order to 
determine ALL possible contributing factors applicable to 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). 
8.3.2.3. 
Assessment of outcomes 
Outcome of any non-serious AE or SAE reported during the entire study will be assessed 
as: 
• 
Recovered/resolved 
• 
Not recovered/not resolved 
• 
Recovering/resolving 
• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only). 

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8.3.2.4. 
Medically attended visits 
For each symptom the subject experiences, the subject will be asked if she received 
medical attention defined as hospitalisation, an emergency room visit or a visit to or from 
medical personnel (medical doctor) for any reason and this information will be recorded 
in the eCRF. 
8.4. 
Reporting and follow-up of adverse events, serious adverse 
events and pregnancies 
8.4.1. 
Prompt reporting of serious adverse events and other events to 
GSK Biologicals 
SAEs will be reported promptly to GSK as described in Table 7 once the investigator 
determines that the event meets the protocol definition of an SAE. 
Pregnancies will be reported promptly to GSK as described in Table 7 once the 
investigator becomes aware of a pregnancy in the time period defined in Section 8.3. The 
subject will be followed to determine the outcome of the pregnancy. At the end of the 
pregnancy, whether that be full-term or premature, information on the status of the 
mother and child will be forwarded to GSK. Generally, follow-up should be no longer 
than 6 to 8 weeks following the estimated delivery date.  
Any pIMDs that occur in the time period defined in Section 8.3.1will be reported 
promptly to GSK within the timeframes described in Table 7, once the investigator 
becomes aware of the pIMD. 
Table 7 
Time frames for submitting SAEs and other events reports to GSK 
Biologicals 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a Previous 
Report 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours* 
SAE report/SAE screen 
24 hours* 
SAE report/SAE screen 
Pregnancy 
24 hours* 
Pregnancy Report Form 
24 hours* 
Pregnancy Report Form 
pIMDs 
24 hours** 
SAE report/SAE screen 
24 hours* 
SAE report/SAE screen 
* Time frame allowed after receipt or awareness of the information. 
** Time frame allowed after the diagnosis is established and known to the investigator. 
In case the electronic reporting system is temporarily unavailable, a back-up system is in 
place. Please refer to Section 8.4.3 for a detailed description. 
Study Contact for Reporting SAEs 
Please see the Sponsor Information Sheet for contact details.  
Back-up Study Contact for Reporting SAEs  
 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Fax: 
 or 
 
24/24 hour and 7/7 day availability 
PPD
PPD

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8.4.2. 
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 investigational product and unexpected. The 
purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation. 
8.4.3. 
Completion and transmission of SAEs reports to GSK Biologicals 
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator will complete and submit the information in the SAE screens in eCRF within 
24 hours. The SAE screens in eCRF will always be completed as thoroughly as possible 
with all available details of the event and will be submitted by the investigator. If the 
investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying GSK of the event and completing the 
SAE screens in eCRF. The SAE screens in eCRF should be updated when additional 
relevant information is received WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. 
8.4.3.1. 
Back-up system in case the electronic SAE reporting system does not 
work 
If the SAE reporting system has been down for 24 hours, the investigator or his/her 
delegate should fax an SAE report form directly to the GSK Central Safety department 
(please refer to Section 8.4.1) within 24 hours. The maximum timeline for reporting 
SAEs to central safety is therefore 48 hours.  
NB. 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 delegate 
must update the SAE screens in the eCRF within 24 hours.  
The final valid information for regulatory reporting will be the information reported 
through the electronic system.  
When additional information is received on a SAE after freezing of the subject’s eCRF, 
new or updated information is to be recorded on the paper SAE Report Form, with all 

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changes signed and dated by the investigator. The updated SAE Report Form should be 
sent to GSK Biologicals WITHIN 24 HOURS of receipt of the follow-up information. 
In rare circumstances, if the electronic system for reporting SAEs does not work and in 
the absence of facsimile equipment, notification by telephone is acceptable, with a copy 
of the SAE Report Form sent by email or by mail. Initial notification via the telephone 
does not replace the need for the investigator to complete and submit SAE screens in the 
eCRF (or complete and sign the SAE Report Form if back-up system need to be used). 
In the event of a death determined by the investigator to be related to vaccination, 
completion of SAE screens in the eCRF/sending of the fax (if electronic SAE reporting 
system does not work or after freezing of the subject’s eCRF) must be accompanied by 
telephone call to the Study Contact for Reporting SAEs. 
8.4.3.2. 
Updating of SAE information after freezing of the subject's eCRF 
When additional information is received on a SAE after freezing of the subject's eCRF, 
new or updated information should be recorded on a SAE Report Form, with all changes 
signed and dated by the investigator. The updated form should be faxed to the GSK 
Biologicals Clinical Safety and Pharmacovigilance department or to the Study Contact 
for Reporting SAEs (refer to the Sponsor Information Sheet) WITHIN 24 HOURS of 
receipt of the follow-up information. 
8.4.4. 
Reporting of pIMDs to GSK Biologicals 
Once onset of a new pIMD or exacerbation of a pre-existing pIMD is diagnosed (serious 
or non-serious) in a study subject, the investigator (or designate) must complete the 
information in the SAE screens of the eCRF WITHIN 24 HOURS after the he/she 
becomes aware of the diagnosis. A field on the SAE screen allows to specify that the 
event is a pIMD and whether it is serious or non serious. The SAE screens 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 SAE screens should still be completed within 24 
hours. Once additional relevant information is received, the SAE screens in the eCRF 
should be updated WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. 
Refer to Sections 8.4.3.1 and 8.4.3.2 for back-up system and updating of SAE 
information after freezing of the subject's eCRF. 
8.4.5. 
Follow-up of adverse events and serious adverse events 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide further information to GSK Biologicals on the subject’s condition. 

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All AEs (medically significant conditions only) and SAEs 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 end of the study. 
Investigators will follow-up subjects: 
• 
With SAEs 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.  
• 
Or, in the case of other non-serious AEs (medically significant conditions only), until 
they complete the study or they are lost to follow-up.   
Clinically significant laboratory abnormalities will be followed up until they have 
returned to normal, or a satisfactory explanation has been provided. Additional 
information (including but not limited to laboratory results) relative to the subsequent 
course of such abnormalities noted for any subject must be made available to the Site 
Monitor. 
GSK Biologicals may request that the investigator perform or arrange for the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or 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 a copy of any available post-mortem findings, 
including histopathology. 
8.5. 
Treatment of adverse events 
Treatment of any adverse event is at the sole discretion of the investigator and according 
to current good medical practice. Any medication administered for the treatment of an 
AE should be recorded in the subject’s eCRF. Refer to Section 6.6. 
8.6. 
Unblinding 
Not applicable. 
8.7. 
Emergency unblinding 
This study will be open label, i.e. both the investigator and the subject will be aware of 
the vaccine being administered to the subjects. Therefore, the information given 
hereunder is limited to the unblinding of SAEs to any third parties (e.g. any doctor other 
than the study investigator), in accordance with GSK Biologicals’ standard operating 
procedures. 
The investigator, or other physician managing the subject, should contact GSK 
Biologicals’ Central Safety Physician to discuss the need for emergency unblinding. 
Alternatively the investigator may contact the local contact who will contact the GSK 
Central Safety Physician.  

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The investigator, or person designated by the investigator, should contact GSK 
Biologicals’ Central Safety physician directly or via the local safety contact (see below 
and Study Contact for Emergency Code Break in Sponsor Information page) to discuss 
the need for emergency unblinding.  
An investigator should request for unblinding of the subject’s treatment code only in the 
case of a medical emergency, or in the event of a serious medical condition, when 
knowledge of the investigational study vaccine(s)/product(s) is essential for the clinical 
management or welfare of the subject.  
The GSK Biologicals’ Central Safety Office will be allowed to access the individual 
randomisation code. The code will be broken by the GSK Biologicals’ Central Safety 
physician (see below and Study Contact for Emergency Code Break in Sponsor 
Information) only in the case of medical events that the investigator/physician in charge 
of the subject feels cannot be treated without knowing the identity of the study vaccine. 
GSK Biologicals Central Safety Physician  
(Study Contact for Emergency Code Break) 
Phones for 7/7 day availability: 
+
 (GSK Biologicals Central Safety Physician on-call) 
Back-up phone contact: 
+
 
8.8. 
Subject card 
Study subjects must be provided with the address and telephone number of the main 
contact for information about the trial. 
Investigator/delegate should therefore provide a “subject card” to each subject. The aim 
of this card is to inform any physician having to deal with a subject in an emergency 
situation that the subject is in a clinical trial and that he/she can contact the trial 
investigator for more relevant information. 
Subjects must be instructed to keep these cards in their possession at all times. 
9. 
SUBJECT COMPLETION AND WITHDRAWAL 
9.1. 
Subject completion 
A subject who is available for the concluding contact foreseen in the protocol is 
considered to have completed the study. 
PPD
PPD

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9.2. 
Subject withdrawal 
Subjects who are withdrawn because of SAEs/AEs must be clearly distinguished from 
subjects who are withdrawn for other reasons. Investigators will follow subjects who are 
withdrawn as result of a SAE/AE until resolution of the event (see Section 8.4). 
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 contact foreseen in the protocol.  
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis. 
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact. 
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up.  
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject herself, or by the investigator, as well as which of the following possible 
reasons was responsible for withdrawal: 
• 
Serious adverse event 
• 
Non-serious adverse event 
• 
Protocol violation (specify) 
• 
Consent withdrawal, not due to an adverse event 
• 
Moved from the study area 
• 
Lost to follow-up 
• 
Death 
• 
Other (specify). 
9.2.2. 
Subject withdrawal from investigational vaccine 
A ‘withdrawal’ from the investigational vaccine refers to any subject who does not 
receive the complete treatment, i.e. when no further planned dose is administered from 
the date of withdrawal. A subject withdrawn from the investigational vaccine may not 
necessarily be withdrawn from the study as further study procedures or follow-up may be 
performed (safety or immunogenicity) if planned in the study protocol.  

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Information relative to premature discontinuation of the investigational 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 
• 
Non-serious adverse event 
• 
Other (specify). 
10. 
DATA EVALUATION: CRITERIA FOR EVALUATION OF 
OBJECTIVES 
10.1. 
Study endpoints 
• 
Occurrence, intensity and causal relationship to vaccination of medically significant 
conditions (including pIMDs) throughout the study 
• 
Occurrence, intensity and causal relationship to vaccination of SAEs throughout the 
study 
• 
Occurrence of pregnancies and pregnancy outcomes throughout the study 
10.2. 
Estimated sample size 
No sample size is calculated for this study. Approximately 600 subjects who received the 
control placebo in the HPV-015 study, will be invited to participate in this study for 
cross-over vaccination with GSK Biologicals’ HPV-16/18 L1 VLP AS04 vaccine. 
10.3. 
Study cohorts to be evaluated 
10.3.1. 
Total Vaccinated Cohort 
The Total Vaccinated Cohort will include all vaccinated subjects (i.e. subjects who 
received at least one dose of HPV-16/18 L1 VLP AS04 vaccine in this study) for whom 
safety data are available. 
10.4. 
Derived and transformed data 
Not applicable. 
10.5. 
Conduct of analyses 
SAEs, other medically significant conditions, pregnancies and pregnancy outcomes will 
be described in detail. These safety data will be presented in a clinical study report. 

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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. 
10.6. 
Statistical methods 
10.6.1. 
Analysis of demographics/baseline characteristics 
Demographic characteristics (age, region, race) of each study cohort will be tabulated. 
The mean age (plus range and standard deviation) of the enrolled subjects will be 
calculated. 
The distribution of subjects enrolled among the study sites will be tabulated. 
10.6.2. 
Analysis of safety 
The analysis will be performed on the Total vaccinated cohort.  
No inferential analysis will be performed. Analyses of safety endpoints will only be 
descriptive. 
The proportion of subjects with at least one report of an SAE and/or at least one 
medically significant condition (including pIMDs) will be tabulated with exact 95% 
confidence interval (CI) throughout the study period. 
SAEs and other medically significant conditions (including pIMDs) will be described in 
detail. SAEs and other medically significant conditions (including pIMDs) will be further 
evaluated for their clinical relevance and relationship to vaccination. 
Pregnancies and pregnancy outcomes will be described in detail. 
11. 
ADMINISTRATIVE MATTERS 
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled.  
11.1. 
Remote Data Entry instructions 
Remote Data Entry (RDE), a validated computer application, 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. 

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While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data.  
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties. 
11.2. 
Monitoring by GSK Biologicals 
Monitoring visits by a GSK Site Monitor are for the purpose of confirming that GSK 
Biologicals’ sponsored studies are being conducted in accordance with the ethical 
principles that have their origins in the Declaration of Helsinki and that are consistent 
with GCP and the applicable regulatory requirement(s) (verifying continuing compliance 
with the protocol, amendment(s), reviewing the investigational product accountability 
records, verifying that the site staff and facilities continue to be adequate to conduct the 
study).  
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 RDE review and a Source Document 
Verification (SDV). By SDV we understand verifying RDE 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 RDE. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the RDE will serve as the source must be identified, agreed and 
documented in the source documentation agreement form.  
For RDE, the monitor will mark completed and approved screens at each visit. 
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements. When reviewing data collection procedures, the discussion will also 
include identification, agreement and documentation of data items for which the eCRF 
entries will serve as the source document. 
GSK will monitor the study to verify that, amongst others, the:  
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 

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• 
Study is conducted in accordance with the currently approved protocol and any 
amendments, 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. 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures. 
11.3. 
Archiving of data at study sites 
Following closure of the study, the investigator must maintain all site study records in a 
safe and secure location. The records must be maintained to allow easy and timely 
retrieval, when needed (e.g. audit or inspection), and, whenever feasible, to allow any 
subsequent review of data 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 for studies with an eCRF); however, caution needs 
to be exercised before such action is taken. The investigator must assure that all 
reproductions are legible and are a true and accurate copy of the original and meet 
accessibility and retrieval standards, including re-generating a hard copy, if required. 
Furthermore, the investigator must ensure there is an acceptable back-up of these 
reproductions and that an acceptable quality control process exists for making these 
reproductions. 
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to that site for the study, as dictated by ICH GCP, any institutional 
requirements or applicable laws or regulations, or GSK standards/procedures; otherwise, 
the minimum retention period will default to 15 years.  
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to, the following: archival at an off-site facility, 
transfer of ownership of the records in the event the investigator leaves the site.  
11.4. 
Audits 
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. 

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11.5. 
Posting of information on Clinicaltrials.gov 
Study information from this protocol will be posted on clinicaltrials.gov before enrolment 
of subjects begins. 
11.6. 
Ownership, confidentiality and publication 
11.6.1. 
Ownership 
All information provided by GSK and all data and information generated by the site as 
part of the study (other than a subject’s medical records) are the sole property of GSK. 
All rights, title, and interests in any inventions, know-how or other intellectual or 
industrial property rights which are conceived or reduced to practice by site staff during 
the course of or as a result of the study are the sole property of GSK, and are hereby 
assigned to GSK. 
If a written contract for the conduct of the study which includes ownership provisions 
inconsistent with this statement is executed between GSK and the study site, that 
contract’s ownership provisions shall apply rather than this statement. 
11.6.2. 
Confidentiality 
Documented evidence that a potential investigator is aware and agrees to the confidential 
nature of the information related to the study must be obtained by means of a 
confidentiality agreement. 
All information provided by GSK and all data and information generated by the site as 
part of the study (other than a subject’s medical records) will be kept confidential by the 
investigator and other site staff. This information and data will not be used by the 
investigator or other site personnel for any purpose other than conducting the study. 
These restrictions do not apply to: (i) information which becomes publicly available 
through no fault of the investigator or site staff; (ii) information which it is necessary to 
disclose in confidence to an IEC or IRB solely for the evaluation of the study; (iii) 
information which it is necessary to disclose in order to provide appropriate medical care 
to a study subject; or (iv) study results which may be published as described in the next 
paragraph. If a written contract for the conduct of the study which includes 
confidentiality provisions inconsistent with this statement is executed, that contract’s 
confidentiality provisions shall apply rather than this statement. 
11.6.3. 
Publication 
For multicentre studies, the first publication or disclosure of study results shall be a 
complete, joint multicentre publication or disclosure coordinated by GSK. Thereafter, 
any secondary publications will reference the original publication(s). 

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Prior to submitting for publication, presentation, use for instructional purposes, or 
otherwise disclosing the study results generated by the site (collectively, a ‘Publication’), 
the investigator shall provide GSK with a copy of the proposed Publication and allow 
GSK a period to review the proposed Publication (at least twenty-one working days, or at 
least fifteen working days for abstracts/posters/presentations). Proposed Publications 
shall not include either GSK confidential information other than the study results or 
personal data on any subject, such as name or initials. 
At GSK’s request, the submission or other disclosure of a proposed Publication will be 
delayed a sufficient time to allow GSK to seek patent or similar protection of any 
inventions, know-how or other intellectual or industrial property rights disclosed in the 
proposed Publication. 
If a written contract for the conduct of the study, which includes publication provisions 
inconsistent with this statement is executed, that contract’s publication provisions shall 
apply rather than this statement. 
11.6.4. 
Provision of study results to investigators, posting to the clinical 
trials registers and publication 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
The results summary will be posted to the GSK Clinical Study Register no later than 12 
months after the LSLV or sooner if required by legal agreement, local law or regulation. 
In addition, a manuscript will be submitted to a peer-reviewed journal for publication 
within 18 months of LSLV. When manuscript publication in a peer-reviewed journal is 
not feasible, further study information will be posted to the GSK Clinical Study Register 
to supplement the results summary. 
12. 
COUNTRY SPECIFIC REQUIREMENTS 
Not applicable. 
13. 
REFERENCES 
Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin 
Virol. 2005; 32S: S16-S24. 
Bosch FX, Manos MM, Munoz N et al. Prevalence of human papillomavirus in cervical 
cancer: a worldwide perspective. J Natl Cancer Inst. 1995; 87: 796-802. 
Bosch FX and Munoz N. The viral etiology of cervical cancer. Virus Res. 2002; 89: 183-
190. 

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Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003; 16: 1-
17. 
Clifford GM, Smith JS, Plummer M, et al. Human papillomavirus types in invasive 
cervical cancer worldwide: a meta-analysis. British Journal of Cancer 2003; 88, 63-73. 
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. 
Franco EL, Villa LL, Sobrinho JP, et al. Epidemiology of acquisition and clearance of 
cervical human papillomavirus infection in women from a high-risk area for cervical 
cancer. J Infect Dis. 1999; 180: 1415-1423. 
Gall SA, Teixeira J, Wheeler CM, et al. Substantial impact on precancerous lesions and 
HPV infections through 5.5 years in women vaccinated with the HPV-16/18 L1 VLP 
AS04 candidate vaccine. In: American Association for Cancer Research Annual Meeting: 
Proceedings; 2007 Apr 14-18; Los Angeles, CA. Philadelphia (PA): AACR; 2007. 
Abstract nr:4900. 
Giannini SL, Hanon E, Moris P et al. Enhanced humoral and memory B cellular 
immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt 
combination (AS04) compared to aluminium salt only. Vaccine. 2006; 24: 5937-5949.  
Harper DM, Franco EL, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle 
vaccine in prevention of infection with human papillomavirus types 16 and 18 in young 
women: a randomised controlled trial. The Lancet. 2004; 364: 1757-1765. 
Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a 
bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: 
follow-up from a randomised control trial. The Lancet. 2006; 367: 1247-1255. 
Kirnbauer R, Booy F, Cheng N, et al. Papillomavirus L1 major capsid protein self-
assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci USA. 
1992; 89: 12180-12184.  
Lowy D and Howley P. Papillomaviruses. 2001; Fields Virology (D Knipe, P Howley, 
eds) 2001: 2231-2264. 
Paavonen J, Jenkins D, Bosch FX, et al. Efficacy of a prophylactic adjuvanted bivalent 
L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 
18 in young women: an interim analysis of a phase III double-blind, randomised 
controlled trial. Lancet. 2007; 369: 2161-2170. 
Paavonen J, Naud P, Salmerón J, et al. Efficacy of human papillomavirus (HPV)-16/18 
AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic 
HPV types (PATRICIA): final analysis of a double-blind, randomised study in young 
women. Lancet. 2009; 374: 301-14. 

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Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 
2000. Int J Cancer 2001a; 94: 153–156. 
Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur 
J Cancer 2001b; 37(suppl 8): S4–66. 
Pedersen C, Petaja T, Strauss G, et al. Immunization of adolescent females with human 
papillomavirus type 16 and 18 L1 virus-like particle vaccine containing AS04 adjuvant. J 
Adoles Health 2007; 40: 564-571. 
Schiffman M, Herrero R, DeSalle R, et al. The carcinogenicity of human papillomavirus 
types reflects viral evolution. Virology. 2005; 337(1): 76-84. 
Schwarz TF, Spaczynski M, Schneider A, et al. Immunogenicity and tolerability of an 
HPV-16/18 AS04-adjuvanted prophylactic cervical cancer vaccine in women aged 15–55 
years. Vaccine. 2009;27 (4):581-587. 
The GlaxoSmithKline Vaccine HPV-007 Study Group. Sustained efficacy and 
immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: 
analysis of a randomised placebo-controlled trial up to 6·4 years. Lancet. 2009;374:1975-
1985. 
Zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. 
Nat Rev Cancer. 2002; 2(52): 342-350. 

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Appendix A 
Amendments and Administrative Changes to the 
Protocol 
GlaxoSmithKline Biologicals 
Clinical Research & Development 
Protocol Administrative Change 1 
eTrack study number 
and Abbreviated Title(s) 
113621 HPV-067 EXT 015  
IND number 
BB-IND7920  
Administrative change 
number: 
Administrative change 1 
Administrative change 
date: 
Administrative change 1 Final: 18 May 2010 
Co-ordinating author: 
 Scientific Writer 
Rationale/background for changes:  
Since the double-blind study HPV-015 will be extended by a maximum of three 
additional years, according to Protocol Amendment 4, dated 24 March 2010, it is 
important that central study staff involved in the studies remains blinded till the end of 
study HPV-015 for all subjects who have been participating in HPV-015 and will be 
participating in this study. Therefore, subjects enrolled in HPV-015 extension studies 
such as study HPV-067 cannot retain the HPV-015 subject number as is stated in the 
original protocol. Consequently, different identification numbers will be provided by 
an external statistician. 
Amended text has been indicated in bold italics and deleted text has been indicated 
in strikethrough in the following sections: 
Section 5.2.1. 
Subject identification 
Subjects will retain their identification numbers from study HPV-015. 
A new identification number will be assigned to the subject to preserve the blind for 
HPV-015 data during this HPV-015 extension study. 
PPD

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GlaxoSmithKline Biologicals 
Clinical Research & Development 
Protocol Amendment 1 
eTrack study number 
and Abbreviated Title(s) 
113621 HPV-067 EXT 015  
IND number 
BB-IND7920  
Amendment number 
Amendment 1 
Amendment date: 
Amendment 1 Final: 9 Dec 2010 
Co-ordinating author: 
, Scientific Writer 
Rationale/background for changes:  
Due to their potent immune stimulating effect, there are theoretical concerns that 
modern adjuvants like GSK Biologicals' novel adjuvant systems might result in 
undesirable effects on the body's immune system, which could include onset of new or 
exacerbation of underlying autoimmune diseases in particular. Accordingly, a 
heightened surveillance on the occurrence of any such conditions in recipients of novel 
adjuvant containing vaccines in clinical trials has been put in place by GSK. Protocol 
amendment 1 was hence developed to implement reporting of potential immune-
mediated diseases (pIMDs). 
In addition, the contributing authors, the contact information for Emergency Code 
Break and the formulation of the HPV-16/18 L1 VLP AS04 vaccine were updated. 
Amended text has been indicated in bold italics and deleted text has been indicated 
in strikethrough in the following sections: 
Title page 
Contributing authors 
• 
 and 
, Manager, Clinical Development, HPV 
vaccines 
• 
, Senior Specialist, Biostatistician, Clinical Biometrics 
• 
 and 
, Biostatisticians 
• 
 and 
, Clinical Data Coordinator, Clinical Data 
Management 
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Synopsis 
Study design 
• 
Safety monitoring:  
• 
Medically significant conditions (including potential immune-mediated diseases 
[pIMDs]) will be reported for all subjects throughout the study period. 
Endpoints 
• 
Medically significant conditions (including pIMDs) 
 
Occurrence, intensity and causal relationship to vaccination of medically 
significant conditions (including pIMDs) throughout the study 
List of abbreviations 
pIMD 
potential Immune-Mediated Disease 
Glossary of terms 
Medically Significant 
Condition: 
Medically significant conditions are defined as AEs 
prompting emergency room or physician visits that are 
not (1) related to common diseases or (2) routine visits 
for physical examination or vaccination, or SAEs that are 
not related to common diseases. 
Common diseases include: upper respiratory infections, 
sinusitis, pharyngitis, gastroenteritis, urinary tract 
infections, cervicovaginal yeast infections, menstrual 
cycle abnormalities and injury. 
Medically significant conditions include potential 
immune-mediated diseases (pIMDs). 
pIMD 
Potential immune-mediated diseases (pIMDs) are a 
subset of Medically Significant Conditions that include 
autoimmune diseases and other inflammatory and/or 
neurological disorders of interest which may or may not 
have an autoimmune aetiology. 
Section 3: Study design overview 
• 
Safety monitoring:  
 
Medically significant conditions (including pIMDs) will be reported for all 
subjects throughout the study period. 

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Section 5.5: Outline of study procedures 
Table 1 
List of study procedures 
Type of contact 
visit 1 
visit 2 
visit 3  
phone contact  
Timepoint (s) 
months 0  
months 1  
months 6  
months 12  
Reporting of non-serious adverse events that are 
medically significant conditions (including 
pIMDs)  
●  
●  
●  
●  
Section 6.1: Description of study vaccine 
Table 3 
Study vaccine 
Vaccine name 
Formulation 
Presentation Volume Number of 
doses 
HPV-16/18 L1 VLP AS04  Each 0.5 ml dose contains:  
- 20 µg HPV-16 L1 VLP 
- 20 µg HPV-18 L1 VLP 
- 50 µg MPL 
- 0.5 mg aluminium as Al(OH)3 
- 8 mM sodium dihydrogen phosphate dihydrate 
- 4.4 mg  150 mM sodium chloride  
- water for injection  
Liquid in pre-
filled syringes  
0.6 ml 
3 
MPL = 3-O-desacyl-4’-monophosphoryl lipid A; Al(OH)3 = aluminium hydroxide; L1 = structural protein of HPV 
ml = millilitre; g = microgram 
Section 8.1.1: Definition of an adverse event 
Medically significant conditions are AEs prompting emergency room or physician visits 
that are not (1) related to common diseases or (2) routine visits for physical examination 
or vaccination, or SAEs that are not related to common diseases. (SAEs related to 
common diseases will be reported, but are not classified as medically significant 
conditions for analysis purposes.) Common diseases include: upper respiratory infections, 
sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast 
infections, menstrual cycle abnormalities and injury. 
Examples of an AE include: 
• 
Medically significant conditions (please refer to Section 8.1.4 for the definition of 
medically significant condition).  
Section 8.1.4: Medically significant conditions 
Medically significant conditions are defined as: 
• 
AEs prompting emergency room or physician visits that are: 
1. not related to common diseases, or  
2.  not related to routine visits for physical examination or vaccination 
• 
SAEs that are not related to common diseases. 
Common diseases include: upper respiratory infections, sinusitis, pharyngitis, 
gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual 
cycle abnormalities and injury. 

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Medically significant conditions include pIMDs. 
Section 8.1.4.1: Potential immune-mediated diseases 
Potential immune-mediated diseases (pIMDs) are a subset of medically significant 
conditions 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 the table 
below. 
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other immune-mediated diseases have an autoimmune origin (i.e. 
pathophysiology involving systemic or organ-specific pathogenic autoantibodies) and 
should also be recorded as a pIMD. 
Onset of a new pIMD or exacerbation of a pre-existing pIMD (serious or non-serious) 
will be recorded in the SAE screen of the subject's eCRF. 

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Table 5 
List of potential immune-mediated diseases 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve disorders, 
including paralyses/paresis 
(e.g. Bell’s palsy), and 
neuritis (e.g. optic neuritis) 
• 
Multiple sclerosis 
(including variants) 
• 
Transverse myelitis 
• 
Guillain-Barré syndrome, 
(including Miller Fisher 
syndrome and other 
variants) 
• 
Other demyelinating 
diseases (including acute 
disseminated 
encephalomyelitis) 
• 
Myasthenia gravis 
(including Lambert-Eaton 
myasthenic syndrome)  
• 
Non-infectious encephalitis/ 
encephalomyelitis  
• 
Neuritis (including 
peripheral neuropathies) 
• 
Systemic lupus 
erythematosus  
• 
Scleroderma (including, 
CREST syndrome and 
morphoea) 
• 
Systemic sclerosis 
• 
Dermatomyositis  
• 
Polymyositis  
• 
Antisynthetase syndrome 
• 
Rheumatoid arthritis,  
• 
Juvenile chronic arthritis, 
(including Still’s disease) 
• 
Polymyalgia rheumatica  
• 
Reactive arthritis 
• 
Psoriatic arthropathy 
• 
Ankylosing spondylitis 
• 
Relapsing polychondritis 
• 
Mixed connective tissue 
disorder 
• 
Psoriasis 
• 
Vitiligo 
• 
Raynaud’s phenomenon 
• 
Erythema nodosum 
• 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid 
and dermatitis 
herpetiformis) 
• 
Cutaneous lupus 
erythematosus 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
Liver disorders 
Gastrointestinal disorders 
Metabolic diseases 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing 
cholangitis 
• 
Autoimmune cholangitis. 
• 
Crohn’s disease  
• 
Ulcerative colitis  
• 
Ulcerative proctitis  
• 
Celiac disease 
• 
Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis) 
• 
Grave's or Basedow’s 
disease 
• 
Diabetes mellitus type I 
• 
Addison’s disease 
Vasculitides 
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, 
thromboangiitis obliterans (Buerger’s 
disease), necrotizing vasculitis, allergic 
granulomatous angiitis, Henoch-Schonlein 
purpura, anti-neutrophil cytoplasmic antibody 
positive vasculitis, Behcet's syndrome, 
leukocytoclastic vasculitis.  
• 
Vasculitides secondary to other immune 
mediated diseases such as lupus vasculitis 
and rheumatoid vasculitis. 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune thrombocytopenias 
• 
Antiphospholipid syndrome 
• 
Pernicious anemia 
• 
Autoimmune glomerulonephritis (including IgA 
nephropathy, glomerulonephritis rapidly 
progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and 
mesangioproliferative glomerulonephritis) 
• 
Uveitis 
• 
Autoimmune myocarditis/cardiomyopathy 
• 
Sarcoidosis 
• 
Stevens-johnson syndrome 
• 
Sjögren’s syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Goodpasture syndrome 

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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. 
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. 
Section 8.3.1: Time period for detecting and recording adverse events, 
serious adverse events and pregnancies 
The standard time period for collecting and recording medically significant conditions 
will begin at the first receipt of study vaccine and will end 6 months following the 
administration of the last dose of study vaccine (i.e. at study conclusion) for each 
subject. Medically significant conditions should be recorded in the AE screen of the 
subjects eCRF if they are non-serious and in the SAE screen of the subject’s eCRF if 
they are serious. When the medically significant condition is considered as a pIMD, it 
always has to be reported in the SAE screen of the subject’s eCRF. See also Section 8.4 
for instructions on reporting of pIMDs. 
The standard time period for collecting and recording pregnancies will begin at the 
first receipt of study vaccine and will end 6 months following administration of the last 
dose of study vaccine (i.e. at study conclusion). See section 8.4 for instructions on 
reporting of pregnancies. 
The standard time period for collecting and recording SAEs will begin at the first 
receipt of study vaccine and will end 6 months following administration of the last dose 
of study vaccine (i.e. at study conclusion). See section 8.4 for instructions on reporting 
of SAEs. 
Table 6 
Reporting periods for adverse events, serious adverse events and 
pregnancies 
Study activity 
Pre-vacc. 
(Consent 
obtained) 
Visit 1 
 
Visit 2 
 
Visit 3 
Telephone contact 
Day 0 
Month 1 
Month 6 
Month 12 
Study Conclusion 
1st  
vacc. 
2nd  
vacc. 
3rd  
vacc. 
6  months post 3rd vaccination 
Reporting of SAEs, 
medically significant 
conditions (including 
pIMDs), pregnancies 
and pregnancy 
outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Section 8.4.1: Prompt reporting of serious adverse events and other 
events to GSK Biologicals 
Any pIMDs that occur in the time period defined in Section 8.3.1 will be reported 
promptly to GSK within the timeframes described in Table 7, once the investigator 
becomes aware of the pIMD. 
Table 7 
Time frames for submitting SAEs and other events reports to GSK 
Biologicals 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a 
Previous Report 
Time Frame 
Documents 
Time Frame 
Documents 
pIMDs 
24 hours** 
SAE report/SAE screen 
24 hours* 
SAE report/ SAE screen 
Time frame allowed after receipt or awareness of the information. 
** Time frame allowed after the diagnosis is established and known to the investigator. 
Section 8.4.3.2: Updating of SAE information after freezing of the subject's 
eCRF 
When additional information is received on a SAE after freezing of the subject's eCRF, 
new or updated information should be recorded on a SAE Report Form, with all 
changes signed and dated by the investigator. The updated form should be faxed to the 
GSK Biologicals Clinical Safety and Pharmacovigilance department or to the Study 
Contact for Reporting SAEs (refer to the Sponsor Information Sheet) WITHIN 24 
HOURS of receipt of the follow-up information. 
Section 8.4.4: Reporting of pIMDs to GSK Biologicals 
Once onset of a new pIMD or exacerbation of a pre-existing pIMD is diagnosed 
(serious or non-serious) in a study subject, the investigator (or designate) must 
complete the information in the SAE screens of the eCRF WITHIN 24 HOURS after 
the he/she becomes aware of the diagnosis. A field on the SAE screen allows to specify 
that the event is a pIMD and whether it is serious or non serious. The SAE screens 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 SAE screens should still be 
completed within 24 hours. Once additional relevant information is received, the SAE 
screens in the eCRF should be updated WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. 
Refer to Sections 8.4.3.1 and 8.4.3.2 for back-up system and updating of SAE 
information after freezing of the subject's eCRF. 

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Section 8.7: Emergency unblinding 
GSK Biologicals Central Safety Physician  
(Study Contact for Emergency Code Break) 
Mobile pPhones for 7/7 day availability: 
+
 +
 (GSK Biologicals Central Safety Physician on-call) 
Back-up mobile phone contact (all countries): 
+
 +
 
Section 10.1: Study endpoints 
• 
Occurrence, intensity and causal relationship to vaccination of medically significant 
conditions (including pIMDs) throughout the study 
Section 10.6.2: Analysis of safety 
The proportion of subjects with at least one report of an SAE and/or at least one 
medically significant condition (including pIMDs) will be tabulated with exact 95% 
confidence interval (CI) throughout the study period. 
SAEs and other medically significant conditions (including pIMDs) will be described in 
detail. SAEs and other medically significant conditions (including pIMDs) will be 
further evaluated for their clinical relevance and relationship to vaccination. 
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GlaxoSmithKline Biologicals 
Clinical Research & Development 
Protocol Amendment 2 
eTrack study number 
and Abbreviated Title(s) 
113621 HPV-067 EXT 015  
IND number 
BB-IND7920  
Amendment number 
Amendment 2 
Amendment date: 
13 Jan 2011 
Co-ordinating author: 
, Project Manager, Scientific Writing 
Rationale/background for changes:  
The exclusion criterion “Administration of any chronic drug therapy to be continued 
during the study period” has been removed to be in line with the original HPV-015 
study protocol. 
Upon request of regulatory authorities, the list of pIMDs has been updated to include 
the term “undifferentiated spondyloarthritides”. 
In addition, the list of contributing authors has been updated. Cross-referencing to the 
first amendment has been removed for clarity. 
Amended text has been indicated in bold italics in the following sections: 
Title page 
Contributing authors 
• 
, Director, HPV Vaccines, Global Clinical Research and 
Development 
Section 4.3.: Exclusion criteria for enrolment: 
The following criterion has been deleted: 
• 
Administration of any chronic drug therapy to be continued during the study period. 
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Section 8.1.4.1.: Potential immune-mediated diseases 
Table 5 
List of potential immune-mediated diseases 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve disorders, 
including paralyses/paresis 
(e.g. Bell’s palsy), and neuritis 
(e.g. optic neuritis) 
• 
Multiple sclerosis (including 
variants) 
• 
Transverse myelitis 
• 
Guillain-Barré syndrome, 
(including Miller Fisher 
syndrome and other variants) 
• 
Other demyelinating diseases 
(including acute disseminated 
encephalomyelitis) 
• 
Myasthenia gravis (including 
Lambert-Eaton myasthenic 
syndrome)  
• 
Non-infectious encephalitis/ 
encephalomyelitis  
• 
Neuritis (including peripheral 
neuropathies) 
• 
Systemic lupus erythematosus  
• 
Scleroderma (including, 
CREST syndrome and 
morphoea) 
• 
Systemic sclerosis 
• 
Dermatomyositis  
• 
Polymyositis  
• 
Antisynthetase syndrome 
• 
Rheumatoid arthritis,  
• 
Juvenile chronic arthritis, 
(including Still’s disease) 
• 
Polymyalgia rheumatica  
• 
Reactive arthritis 
• 
Psoriatic arthropathy 
• 
Ankylosing spondylitis 
(including undifferentiated 
spondyloarthritides) 
• 
Relapsing polychondritis 
• 
Mixed connective tissue 
disorder 
• 
Psoriasis 
• 
Vitiligo 
• 
Raynaud’s phenomenon 
• 
Erythema nodosum 
• 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid and 
dermatitis herpetiformis) 
• 
Cutaneous lupus 
erythematosus 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
Section 8.3.1.: Time period for detecting and recording adverse events, 
serious adverse events and pregnancies 
Any conditions or signs and/or symptoms present in a subject prior to study HPV-0667 
need not be recorded. 

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