A Phase 3, Open-label, Multicenter Study to Evaluate Long-term Immunogenicity and Boostability of Immune Responses in Adults Who Received Different Primary Vaccination Regimens of Pre-exposure Prophylaxis With Purified Chick-Embryo Cell Rabies Vaccine Administered Concomitantly or Separately From a Japanese Encephalitis Vaccine.
Phase: PHASE3
Conditions: Virus Diseases, Rabies
Sponsor: GlaxoSmithKline

Protocol Amendment 2
Study ID:  205214
Official Title of Study: A Phase 3, Open-label, Multicenter Study to Evaluate Long-
term Immunogenicity and Boostability of Immune Responses in Adults who Received 
Different Primary Vaccination Regimens of Pre-exposure Prophylaxis with Purified 
Chick-Embryo Cell Rabies Vaccine Administered Concomitantly or Separately from a 
Japanese Encephalitis Vaccine
NCT ID: NCT02545517
Other Identifiers: V49_23E1
Date of Document: 25 Feb 2019

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 1 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
EudraCT number: 2015-000382-31
CLINICAL STUDY PROTOCOL V49_23E1 Amendment 2
A Phase 3, Open-label, Multicenter Study to Evaluate Long-term Immunogenicity 
and Boostability of Immune Responses in Adults who Received Different Primary 
Vaccination Regimens of Pre-exposure Prophylaxis with Purified Chick-Embryo 
Cell Rabies Vaccine Administered Concomitantly or Separately from a Japanese 
Encephalitis Vaccine
Phase 3 PCEC Rabies Vaccine Long-term Immunogenicity and Boostability 
Property of GlaxoSmithKline Biologicals S.A. (hereafter referred to as GSK)
Confidential
May not be used, divulged, published or otherwise disclosed without written
consent of GSK.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 2 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
TABLE OF CONTENTS
TABLE OF CONTENTS.....................................................................................................2
PROTOCOL SYNOPSIS V49_23E1, VERSION 2.0 (AMENDED 25 FEBRUARY
2019).........................................................................................................................12
LIST OF ABBREVIATIONS (AMENDED 25 FEBRUARY 2019)................................27
1.0 
BACKGROUND AND RATIONALE ....................................................................29
1.1 
Background (Amended 25 February 2019) .........................................................29
1.2 
Rationale..............................................................................................................30
2.0 
OBJECTIVES...........................................................................................................31
2.1 
Primary Objectives ..............................................................................................31
2.2
Secondary Objective............................................................................................31
3.0 
STUDY DESIGN .....................................................................................................32
3.1 
Overview of Study Design (Amended 25 February 2019)..................................32
3.2 
Study Period.........................................................................................................35
3.3 
Blinding Procedures.............................................................................................35
3.4 
Data Collection (Amended 25 February 2019) ...................................................36
3.4.1 Data Collected from Subjects.......................................................................36
3.4.2 Tools Used for Data Collection....................................................................36
3.5 
Collection of Clinical Specimens ........................................................................36
3.6 
Stopping/Pausing Guidelines...............................................................................37
3.7 
Data Monitoring Committee................................................................................37
3.8 
Premature Withdrawal from Study (Amended 25 February 2019) .....................38
3.9 
End of Study ........................................................................................................40
4.0 
SELECTION OF STUDY POPULATION..............................................................41
4.1 
Inclusion Criteria .................................................................................................41
4.2 
Exclusion Criteria (Amended 25 February 2019) ...............................................42
4.3 
Criteria for Delay of Vaccination ........................................................................44
5.0 
STUDY PROCEDURES (AMENDED 25 FEBRUARY 2019)..............................45
5.1 
Scheduled Clinic Visits - Pre-vaccination Clinic Visit(s) ...................................45

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 3 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
5.1.1 Informed Consent .........................................................................................45
5.1.2 Screening ......................................................................................................46
5.1.3 Enrolment .....................................................................................................47
5.1.4 Randomization..............................................................................................47
5.2 
Ad Hoc Clinic Visit(s) - Vaccination Clinic Visit(s)...........................................48
5.2.1 Post-vaccination Procedures.........................................................................48
5.2.2 Post-vaccination Reminder Calls..................................................................49
5.3 
Additional Clinic Visit(s) - Post-vaccination Visit(s) .........................................49
5.3.1 Follow-up (Additional) Clinic Visit(s).........................................................49
5.3.2 Safety Follow-up Calls .................................................................................50
5.4 
Unscheduled Visits ..............................................................................................50
5.5 
Study Termination Visit ......................................................................................50
5.5.1 Early Termination Visit................................................................................51
6.0 
TREATMENT OF SUBJECTS................................................................................52
6.1 
Study Vaccine(s) (Amended 25 February 2019).................................................52
6.2 
Non-Study Vaccines ............................................................................................52
6.3 
Vaccine Preparation and Administration (Amended 25 February 2019) ............52
6.4 
Vaccine Administration Error or Overdose of Vaccine ......................................54
6.5 
Prior and Concomitant Medications and Vaccines..............................................54
6.6 
Vaccine Supply, Labeling, Storage and Tracking ...............................................55
7.0 
ASSESSMENTS (AMENDED 25 FEBRUARY 2019) ..........................................57
7.1 
Safety Assessment ...............................................................................................57
7.1.1 Solicited Adverse Events..............................................................................57
7.1.2 Unsolicited Adverse Events..........................................................................57
7.1.3 Evaluation of Adverse Events ......................................................................58
7.1.4 Serious Adverse Events................................................................................58
7.1.4.1 Adverse Events of Special Interest........................................................59
7.1.5 Methods for Recording Adverse Events and Serious Adverse Events.........59
7.1.5.1 Post-Study Events..................................................................................61

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 4 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
7.1.6 Pregnancies...................................................................................................61
7.1.7 Safety Laboratory Measurements.................................................................61
7.2 
Efficacy Assessment............................................................................................61
7.3 
Immunogenicity Assessment...............................................................................62
8.0 
STATISTICAL CONSIDERATIONS .....................................................................63
8.1 
Endpoints .............................................................................................................63
8.1.1 Primary Endpoint(s)......................................................................................63
8.1.1.1 Primary Safety Endpoint(s) (Amended 25 February 2019)...................63
8.1.1.2 Primary Efficacy Endpoint(s)................................................................63
8.1.1.3 Primary Immunogenicity Endpoint(s) (Amended 25 February 2019) ..63
8.1.2 Secondary Endpoint(s)..................................................................................63
8.1.2.1 Secondary Safety Endpoint(s) ...............................................................63
8.1.2.2 Secondary Efficacy Endpoint(s)............................................................63
8.1.2.3 Secondary Immunogenicity Endpoint(s) (Amended 25 February 2019)
...............................................................................................................63
8.1.3 Exploratory Endpoint(s) ...............................................................................64
8.1.3.1 Exploratory Safety Endpoint(s).............................................................64
8.1.3.2 Exploratory Efficacy Endpoint(s)..........................................................64
8.1.3.3 Exploratory Immunogenicity Endpoint(s).............................................64
8.2 
Success Criteria ...................................................................................................64
8.2.1 Success Criteria for Primary Objective(s)....................................................64
8.2.1.1 Success Criteria for Primary Safety Objective(s)..................................64
8.2.1.2 Success Criteria for Primary Efficacy Objective(s) ..............................64
8.2.1.3 Success Criteria for Primary Immunogenicity Objective(s)..................64
8.2.2 Success Criteria for Secondary Objective(s)................................................64
8.2.2.1 Success Criteria for Secondary Safety Objective(s)..............................64
8.2.2.2 Success Criteria for Secondary Efficacy Objective(s) ..........................65
8.2.2.3 Success Criteria for Secondary Immunogenicity Objective(s)..............65
8.3 
Analysis Sets........................................................................................................65

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 5 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
8.3.1 All Enrolled Set ............................................................................................65
8.3.2 All Exposed Set ............................................................................................65
8.3.3 Safety Set......................................................................................................65
8.3.4 Full Analysis Set (FAS) Immunogenicity Set ..............................................65
8.3.5 Per Protocol (PP) Set Immunogenicity Set...................................................66
8.3.6 Other Analysis Sets.......................................................................................66
8.3.7 Subgroups .....................................................................................................66
8.3.8 Protocol Deviations ......................................................................................67
8.4 
Statistical Analysis Plan ......................................................................................67
8.4.1 Analysis of Demographic and Baseline Characteristics...............................67
8.4.2 Analysis of Primary Objective(s) .................................................................67
8.4.2.1 Analysis of Primary Safety Objective ...................................................67
8.4.2.1.1 
Analysis of Extent of Exposure......................................................67
8.4.2.1.2 
Analysis of Solicited Local, Systemic and Other Adverse Events.67
8.4.2.1.3 
Analysis of Unsolicited Adverse Events (Amended 25 February 
2019)...............................................................................................67
8.4.2.1.4 
Analysis of Safety Laboratory Values............................................68
8.4.2.2 Analysis of Primary Efficacy Objective(s)............................................68
8.4.2.2.1 
Statistical Hypotheses.....................................................................68
8.4.2.2.2 
Analysis Sets ..................................................................................68
8.4.2.2.3 
Statistical Methods .........................................................................68
8.4.2.3 Analysis of Primary Immunogenicity Objective(s)...............................69
8.4.2.3.1 
Statistical Hypotheses.....................................................................69
8.4.2.3.2 
Analysis Sets (Amended 25 February 2019)..................................69
8.4.2.3.3 
Statistical Methods (Amended 25 February 2019).........................69
8.4.3 Analysis of Secondary Objective(s) .............................................................70
8.4.3.1.1 
Analysis of Extent of Exposure......................................................70
8.4.3.1.2 
Analysis of Solicited Local, Systemic and Other Adverse Events.70
8.4.3.1.3 
Analysis of Unsolicited Adverse Events ........................................70

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 6 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
8.4.3.1.4 
Statistical Hypotheses.....................................................................70
8.4.3.1.5 
Analysis Sets ..................................................................................71
8.4.3.1.6 
Statistical Methods .........................................................................71
8.4.3.2 Analysis of Secondary Efficacy Objective(s)........................................71
8.4.3.2.1 
Statistical Hypotheses.....................................................................71
8.4.3.2.2 
Analysis Sets ..................................................................................71
8.4.3.2.3 
Statistical Methods .........................................................................71
8.4.3.3 Analysis of Secondary Immunogenicity Objective(s)...........................71
8.4.3.3.1 
Statistical Hypotheses.....................................................................71
8.4.3.3.2 
Analysis Sets ..................................................................................71
8.4.3.3.3 
Statistical Methods .........................................................................71
8.4.4 Analysis of Exploratory Objectives..............................................................72
8.4.4.1 Analysis of Exploratory Safety Objective(s).........................................72
8.4.4.2 Analysis of Exploratory Efficacy Objective(s) .....................................72
8.4.4.3 Analysis of Exploratory Immunogenicity Objective(s).........................72
8.5 
Sample Size and Power Considerations of Primary Objectives ..........................72
8.6 
Interim Analyses..................................................................................................72
9.0 
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING......74
9.1 
Source Documentation.........................................................................................74
9.2 
Study Monitoring, Auditing and Source Data Verification.................................75
10.0 DATA MANAGEMENT .........................................................................................76
10.1 Data Entry and Management (Amended 25 February 2019)...............................76
10.2 Data Clarification.................................................................................................76
10.3 Data Protection ....................................................................................................76
11.0 RECORD RETENTION ..........................................................................................77
12.0 USE OF INFORMATION AND PUBLICATION..................................................78
13.0 ETHICAL CONSIDERATIONS .............................................................................79
13.1 Regulatory and Ethical Compliance ....................................................................79
13.2 Informed Consent Procedures..............................................................................79

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 7 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
13.3 Responsibilities of the Investigator and IRB/EC.................................................80
13.4 Protocol Amendments .........................................................................................81
14.0 REFERENCE LIST..................................................................................................82
7.1.2   Unsolicited Adverse Events ........................................................................100

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 8 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Protocol Amendment 2 Rationale
Amendment number:
Amendment 2
Rationale/background for changes: 

Clarification of the timeframe between each yearly Scheduled Visit: Visit 1 date
has to be used as reference for calculating next visit date (e.g. Visit 1: 31 JAN 15,
then Visit 2: 31 JAN 16 ± 28 days, Visit 3: 31 JAN 17 ± 28 days) (Table 2a).

Clarification of the time window between the Scheduled Clinic Visit and the Ad
hoc Visit: the previous wording was not clear enough, team agreed to precise that
booster administration at the Ad hoc Visit should happen between 6 to 9 months
after the Scheduled Clinic Visit (Table 2b).

Clarification that physical exams have to be done by practitioners in accordance
with their institutional policy (Table 2a and 2b, Section 5.1.2 Screening). It has
been specified that collection of vital signs must be done during all Ad hoc Visits
prior booster administration. During the other visits (Scheduled and Additional),
they could be measured at the discretion of the investigator (Section 5.1.2
Screening).

Clarification on the number of additional booster doses a subject may receive: if,
after a first booster dose, the adequate RVNA level is not reached at two
consecutive determinations, a subject may receive an additional booster. If he/she
is still a non-responder, the investigator should manage at its discretion. (Synopsis;
Section 3.1 Overview of Study Design; Section 5.2 Ad hoc Clinic Visits; Section 6.3
Vaccine Preparation and Administration).

Clarification on premature withdrawal from the study: there was no mention on the
procedure to follow in case a subject misses the Ad hoc Visit and the possible
booster dose. This has been added to the relevant section, specifying that in this
case the subject could come to the next following Scheduled Visit and having a
blood draw according to protocol. In case RVNA concentrations <0.5 IU/mL, a
booster may be given. (Section 3.8 Premature Withdrawal from Study).

Clarification on Exclusion Criteria: prior to Scheduled Visit criteria have been
added, as they were not previously detailed (only criteria prior to study entry and
booster vaccination were stated).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 9 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Some clarification to the criteria to be checked prior the Ad hoc Visit has been 
added: if a subject received corticosteroids, antineoplastic and immunomodulating 
agents or radiotherapy within 90 days prior the Ad hoc Visit (and not prior to 
informed consent as previously stated) or receipt or planning to receive them 
during the participation to the study, they have to be withdrawn. Subjects should be 
excluded if they received any non-study rabies vaccine (Section 4.2 Exclusion 
Criteria).

Clarification on assignment of the Subject ID: this is a unique ID number and is the
same as the one attributed during the parental study V49_23 (Section 5.1.2
Screening). It has been specified that since current year, 2019, a centralized
Randomization System on internet (SBIR) has been implemented for treatment
allocation. The study staff need to access the system and to enter the subject
identification number for obtaining a treatment number for each subject (footnote e
in Table 2b; Section 5.1.4 Randomization; Section 6.3 Vaccine Preparation and
Administration).

Update the name of the document used for identification of the health care
practitioners to Study Staff Delegation of Responsibilities (SS DoR) (Section
5.1.2 Screening).

Global rewording of Section 7 Assessment for simplification and clarification
of the text.

To clarify that ONLY SAEs (and the associated concomitant medications)
experienced by subjects who received the rabies booster and those collected
during Physical examinations must be reported period (Tables 2a and 2b;
Section 3.4.1 Data Collected from Subjects; Section 7.1.4 Serious Adverse
Events).
Clarification of period of collection: for those subjects, SAEs and the
associated concomitant medications will be collected starting from the time
of booster administration until the completion of safety follow-up period
(Study design and Safety Endpoint in Synopsis; footnote b in Table 2a;
Section 3.1 Overview of Study Design; Section 7 Assessment; Section 7.1.4
Serious Adverse Events; Section 8.1.1.1 Primary Safety Endpoints; Section
5.3.1 Follow-up Clinic Visit). Safety follow-up period is defined as the day of
the next Scheduled Clinic Visit after booster vaccination or the date of Early
Termination Visit, whichever is earlier.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 10 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014

To clarify the procedures for reporting AEs:
- SAEs (and any medication or other therapeutic measures used to treat the AE)
will be recorded in the eCRF as well as in the VSAE form.
- Any AEs (e.g. after blood draw) will be recorded ONLY in the source documents
(Section 3.4.2 Tools Used for Data Collection; Section 7.1.5 Methods for
Recording Adverse Events and Serious Adverse Events).

Rewording of the paragraph related to the recording of pre-existing event or
condition that results in hospitalization for clarification purpose (Section
7.1.5 Methods for Recording Adverse Events and Serious Adverse Events).

Clarification for post-study events collection: all SAEs that occur outside the
protocol-specified safety follow-up period and that the investigator considers
to be caused by the study vaccine must be reported to GSK or its designee
(Section 7.1.5.1 Post-Study Events).

Specification on vaccine preparation and administration: vaccine has to be
administered intramuscularly in the deltoid area of the non-dominant arm.
Alternatively, it can be administered in the deltoid area of the dominant arm
if subjects experience local AEs on primary vaccination site (Section 6.3
Vaccine Preparation and Administration).

Clarification on vaccine tracking at the conclusion of the study: all unused
supply vaccine and supplementary labels are destroyed either locally (upon
approval from Sponsor) or returned to the Sponsor or depot, as applicable
(Section 3.8 Premature Withdrawal from Study - Administrative reason;
Section 6.6 Vaccine Supply, Labeling, Storage and Tracking). Authorization
for use (AFU) wording has been removed throughout the protocol as it is no
longer used (Section 6.6 Vaccine Supply, Labeling, Storage and Tracking).

To clarify the reporting of pregnancies:
- Any pregnancy outcome meeting the definition of a SAE reported in
subjects who received booster administration needs to be reported within 24
hours of the site becoming aware of the event to GSK or delegate using the
VSAE Report Form and be recorded in the CRF(s). The Pregnancy Form
must also be updated for further internal processing.
- Any pregnancy outcome meeting the definition of SAEs reported in subjects who
have NOT received booster administration need to be reported within 24 hours of
the site becoming aware of the event to GSK or delegate using the VSAE

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 11 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Report Form, although such SAEs will not be a part of the Clinical database and do 
not need to be recorded in the CRF(s). The Pregnancy Form must also be updated 
for further internal processing. (Section 7.1.6 Pregnancies).

To correct some typographical errors.

To update the List of Abbreviations and acronyms throughout the text.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 12 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
PROTOCOL SYNOPSIS V49_23E1, VERSION 2.0 (Amended 25 February 2019)
Name of Sponsor:
GlaxoSmithKline 
Biologicals S.A.
Protocol number:
V49_23E1
Generic name of study vaccine(s):
Rabies, whole virus vaccine (inactivated)
Title of Study: 
A Phase 3, Open-label, Multicenter Study to Evaluate Long-term Immunogenicity and 
Boostability of Immune Responses in Adults who Received Different Primary 
Vaccination Regimens of Pre-exposure Prophylaxis with Purified Chick-Embryo Cell 
Rabies Vaccine Administered Concomitantly or Separately from a Japanese 
Encephalitis Vaccine
Study Period: Approximately seven years 
for each individual subject.
Clinical Phase: 3
Background and Rationale: Rabies is an acute encephalitis due to a lyssavirus 
infection which is nearly always fatal (World Health Organization [WHO] 2013). 
Rabies is entirely preventable with the implementation of i) pre-exposure prophylaxis 
vaccination, for anyone who is at continual, frequent or increased risk for exposure to 
the rabies virus, or ii) prompt and accurate post exposure prophylaxis after suspected or 
proven exposure to rabies virus.
Among WHO pre-qualified rabies vaccines, Rabipur® is a highly purified, potent and 
efficacious chick-embryo cell vaccine indicated for active immunization against rabies 
in individuals of all ages. This includes pre-exposure prophylaxis, in both primary series 
and booster dose, and post exposure prophylaxis.
Persistence of adequate antibody concentrations for up to two years after immunization 
with Rabipur® was found in a limited number of GSK pre-exposure prophylaxis (PrEP) 
studies. According to WHO, reinforcing doses are generally required every 2-5 years 
and there is no evidence on the best timing for booster administration after 5 years. For 
this reason, the onset, extent and duration of (sero)protection and the requirement for 
and timing of booster vaccination following a primary series according to an accelerated 
or a conventional PrEP regimen deserves further investigation.
The aim of this study is to evaluate the long-term (up to approx.10 years) persistence 
and to assess the boostability of immune responses in subjects who received a primary 
series of accelerated or conventional rabies PrEP IM regimen in V49_23 study.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 13 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Name of Sponsor:
GlaxoSmithKline 
Biologicals S.A.
Protocol number:
V49_23E1
Generic name of study vaccine(s):
Rabies, whole virus vaccine (inactivated)
Study Objectives:
Primary Objectives:
Immunogenicity Objectives:
1. To compare the long-term (up to approx.10 years) persistence of antibody responses
(i.e. time until antibody concentrations drop below 0.5 IU/mL) in subjects who
received a primary series of accelerated or conventional rabies PrEP intramuscular
(IM) regimen in the parent study V49_23.
2. To evaluate the antibody responses to a booster dose of Purified Chick Embryo Cell-
Culture (PCEC) rabies vaccine administered to subjects with Rabies Virus
Neutralizing Antibody (RVNA) concentrations <0.5 IU/mL following a primary
series of accelerated or conventional rabies PrEP IM regimen in the parent study
V49_23.
Safety Objective:
To evaluate the safety of a booster dose of PCEC rabies vaccine following a primary 
series of accelerated or conventional rabies PrEP IM regimen in the parent study 
V49_23.
Secondary Objective:
Immunogenicity Objective:
To evaluate the long-term (up to approx.10 years) immunogenicity in subjects who 
received a primary series of accelerated or conventional rabies PrEP intramuscular (IM) 
regimen in the parent study V49_23.
Study Design: This is a phase 3, open-label, multicenter, extension of V49_23 study in
healthy adults. In the parent study (V49_23) subjects from ≥18 years to ≤65 years of age 
were randomized to one of four vaccination groups, three of which for rabies pre-
exposure prophylaxis according to conventional (1.0 mL dose of PCEC rabies vaccine 
administered IM on each of days 1, 8 and 29) regimen, alone or in combination with 
Japanese Encephalitis (JE) vaccination according to the study group (see Table 1 below)
or to a new, one-week, accelerated (1.0 mL dose of PCEC rabies vaccine administered 
IM on each of days 1, 4 and 8) regimen in combination with JE vaccination. 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 14 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Name of Sponsor:
GlaxoSmithKline 
Biologicals S.A.
Protocol number:
V49_23E1
Generic name of study vaccine(s):
Rabies, whole virus vaccine (inactivated)
Table 1
Vaccine Groups in Studies V49_23 and V49_23E1
V49_23 study
V49_23E1 study
Study Vaccine Group
Regimen of Primary
Vaccine 
Administration
N of subjects who 
received full PrEP 
and completed the 
study
Study Vaccine Group
Maximum N of 
subjects who will be 
invited for enrollment
(at the start of the
extension study)
Regimen of Booster
Vaccination
Conventional Rabies 
with concomitant JE 
vaccination
(Conv-R/JE)
Rabies PrEP
Days 1, 8 and 29 
JE primary series
Days 1 and 29  
N=158 subjects
Conv-R/JE
N= up to 158 subjects
A single PCEC rabies 
booster dose (1.0 mL) 
IM for subjects with 
RVNA concentrations 
<0.5IU/mL
Accelerated Rabies 
with concomitant JE 
vaccination
(Acc-R/JE)
Rabies PrEP
Days 1, 4 and 8
JE primary series
Days 1 and 8 
N=209 subjects
Acc-R/JE
N= up to 209 subjects
A single PCEC rabies 
booster dose (1.0 mL) 
IM for subjects with 
RVNA concentrations 
<0.5IU/mL
Conventional Rabies
vaccination alone
(Conv-R)
Rabies PrEP
Days 1, 8 and 29
N=211 subjects
Conv-R
N= up to 211 subjects
A single PCEC rabies 
booster dose (1.0 mL) 
IM for subjects with 
RVNA concentrations 
<0.5IU/mL
Conventional JE 
vaccination alone
(Conv-JE)
JE primary series
Days 1 and 29 
N=52 subjects
NA
NA
Note: To preserve blinding in the parent study, placebo was administered at specified time points; refer to 
the V49_23 Protocol for details.
There will be minimum 8 Scheduled Clinic Visits for each eligible enrolled subject over 
7 years. 
Subjects who were randomized into one of the 3 rabies vaccination groups of the parent 
study V49_23, who received the full PrEP rabies regimen and completed V49_23 study
following study protocol will be invited to take part to this study.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 15 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Name of Sponsor:
GlaxoSmithKline 
Biologicals S.A.
Protocol number:
V49_23E1
Generic name of study vaccine(s):
Rabies, whole virus vaccine (inactivated)
Subjects who were randomized to the JE conventional group in the parent study V49_23 
will not be invited to take part to this extension study.
Subjects will receive their booster doses based on their individual antibody 
concentrations measured over time (booster will be administered only to those subjects 
with RVNA concentrations <0.5 IU/mL), medical history and physical examination, to 
ensure that they are in good health according to the investigator’s opinion and meet all 
inclusion criteria and none of the exclusion criteria. 
Blood samples (approximately 7 mL of blood at each Scheduled Clinic Visit) will be 
drawn in all subjects on extension study Day 1 (i.e. approximately three years [Year 3] 
after completion of rabies primary series in the parent study V49_23) and then at 
subsequent year intervals from extension study Day 1 (Year 3) onwards (Year 4, 5, 6, 7, 
8, 9 and 10 after primary series in the parent study V49_23), to investigate the kinetics 
of RVNA concentrations.
Subjects with RVNA concentrations <0.5 IU/mL at Visit 1 of this extension study or at 
the following Year 4 to Year 9 annual Scheduled Clinic Visits will receive a booster 
immunization (a single dose of 1.0 mL to be administered intramuscularly preferably in 
the deltoid region of the non-dominant arm) with GSK PCEC rabies vaccine during the 
next Ad hoc Clinic Visit. 
Subjects receiving a booster vaccination will be observed at the site for at least 30 
minutes after immunization for any immediate reactions. 
To investigate the prompt boostability of immune responses, additional blood samples 
will be drawn during Additional Clinic Visit which is approximately 7 days after the Ad 
hoc Clinic Visits.
During Scheduled Clinic Visit and Additional Clinic Visit, subjects will be observed for 
at least 15 minutes after the blood draw for any adverse event.
For subjects receiving PCEC rabies booster vaccination, Serious Adverse Events 
(SAEs) and the associated concomitant medications will be collected starting from the 
time of booster administration until completion of safety follow-up period (the day of 
the next Scheduled Clinic Visit after booster vaccination or on the date of Early 
Termination Visit, whichever is earlier).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 16 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Name of Sponsor:
GlaxoSmithKline 
Biologicals S.A.
Protocol number:
V49_23E1
Generic name of study vaccine(s):
Rabies, whole virus vaccine (inactivated)
Number of Subjects planned: Up to 578 subjects, who successfully completed rabies 
PrEP regimens in V49_23 study and did not have protocol deviations which can impact 
the immunogenicity response (e.g., wrong vaccination), will be invited to participate to
this extension study.
Study Population and Subject Characteristics: 
Inclusion criteria: Subjects who signed the informed consent prior to the study entry, 
who received the full primary vaccination series according to either the conventional 
rabies plus JE (Conv-R/JE), or the accelerated rabies plus JE (Acc-R/JE), or the 
conventional rabies (Conv-R) PrEP regimens in V49_23 study and who completed the 
parent study.
Exclusion criteria: Subjects with documented medical history of exposure to rabies or 
rabies post exposure prophylaxis after completion of the parent study (V49_23) and 
before V49_23E1 study start will be excluded.
Subjects who completed the parent study V49_23 but who received a wrong vaccine 
and/or did not receive the full 3doses of rabies vaccine following the conventional or 
accelerated vaccination regimen during V49_23.
The list of inclusion and exclusion criteria is included in protocol section 4.0, Selection 
of Study Population.
Study Procedures: Every year of the study for each subject there might be up to three 
different clinic visits in chronological sequence: 

Scheduled Clinic Visits, for all subjects enrolled; 

Ad hoc Clinic Visits, only for subjects with RVNA concentrations <0.5 IU/mL, 
(during these visits a booster dose of rabies vaccine will be administered); 

Additional Clinic Visits, only for subjects who received a booster vaccination 
during Ad hoc Clinic Visits.  
Scheduled Clinic Visit: For all enrolled subjects there will be overall 8 blood draws (of 
approximately 7 mL each) scheduled during the course of the extension study; each of 
these blood draws will be taken at each Scheduled Clinic Visit, from extension study 
Day 1 (Year 3 after completion of PrEP in the parent study V49_23) and then yearly 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 17 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Name of Sponsor:
GlaxoSmithKline 
Biologicals S.A.
Protocol number:
V49_23E1
Generic name of study vaccine(s):
Rabies, whole virus vaccine (inactivated)
through Year 10.
Ad hoc Clinic Visits: Only subjects with RVNA concentrations <0.5 IU/mL at the first 
visit of this extension study (Day 1, Year 3) or at the following yearly Scheduled Clinic 
Visits (from Year 4 to Year 9) will receive a booster vaccination (a single dose of 1.0 
mL to be administered intramuscularly preferably in the deltoid region of the non-
dominant arm) with GSK PCEC rabies vaccine. The booster dose will be given in an 
“Ad hoc Clinic Visit” which is planned to occur as soon as the results of the antibody 
assay will be available and within approximately 6 to 9 months from the blood draw 
taken during a previous “Scheduled Clinic Visit”. Prior to receipt of booster 
vaccination, subjects must be evaluated to confirm that they are eligible for vaccination. 
Subjects who will receive a booster vaccination will be observed at the site for at least 
30 minutes after vaccination for any immediate reactions and will continue yearly 
procedures up to Year 10. 
For subjects receiving PCEC rabies booster vaccination, SAEs and the associated 
concomitant medications will be collected starting from the booster administration and 
until the day of next Scheduled Clinic Visit.
Additional Clinic Visit: To investigate the prompt boostability of the immune 
response, additional blood samples will be drawn approximately 7 days after the Ad hoc 
Clinic Visits, only for subjects who will receive booster dose of PCEC rabies vaccine.
If, after having received a booster dose, the subject does not reach the adequate antibody 
concentration (i.e., RVNA ≥0.5 IU/mL) at two consecutive determinations, neither at 7 
days after the booster dose (i.e. Additional Clinic Visit) nor at the next yearly evaluation 
(i.e., Scheduled Clinic Visit), an additional booster dose may be administered at the 
following Ad hoc Clinic Visit. If the subject is still non-responder, subsequent 
management should be at the discretion of the investigator.
Should a subject have RVNA concentrations below 0.5 IU/mL at blood draw performed 
at the final Scheduled Clinic Visit (Year 10), the investigator will invite the subject to 
receive a booster dose of the rabies vaccine outside the study following standard clinical 
practice and there will be no further analyses performed on this additional vaccination.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 18 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Name of Sponsor:
GlaxoSmithKline 
Biologicals S.A.
Protocol number:
V49_23E1
Generic name of study vaccine(s):
Rabies, whole virus vaccine (inactivated)
Study Vaccine: Rabipur®, purified chick-embryo cell derived (PCEC) rabies vaccine, 
GSK Vaccines GmbH (formerly Novartis Vaccines and Diagnostics GmbH), Marburg, 
Germany. After reconstitution, a booster dose consists of 1.0 mL of PCEC rabies 
vaccine, containing rabies virus [inactivated strain Flury Low Egg Passage (LEP)®] with 
a potency ≥2.5 IU/mL, and is to be administered via intramuscular (IM) injection.
Primary Endpoints: 
Immunogenicity Endpoints: 
The primary immunogenicity endpoints will be based on the RVNA concentrations at 
Year 3, 4, 5, 6, 7, 8, 9 and 10 following a primary series of accelerated or conventional 
rabies PrEP IM regimen during the parent study V49_23, as measured by rapid 
fluorescent focus inhibition test (RFFIT). RFFIT assays will be performed at a delegate, 
qualified laboratory, as specified by GSK.
Measures of immunogenicity will be summarized by the vaccination regimen received 
in the parent study V49_23, as follows:

Time to first RVNA concentrations <0.5 IU/mL.  

Geometric Mean Concentrations (GMCs) and Geometric Mean Ratios (GMRs) for 
subjects receiving the booster dose, as measured by antibody concentration at 7 days 
after the booster dose vs. antibody concentration before the booster dose.

Percentages of subjects with RVNA concentrations ≥0.5 IU/mL, as measured by 
RFFIT assay at 7 days after the booster dose and at subsequent Scheduled Clinic 
Visits.
Safety Endpoint: 
For subjects receiving PCEC rabies booster vaccination, Serious Adverse Events 
(SAEs) and the associated concomitant medications will be collected starting from the 
time of booster administration until completion of safety follow-up period (the day of 
the next Scheduled Clinic Visit after booster vaccination or on the date of Early 
Termination Visit, whichever is earlier).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 19 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Name of Sponsor:
GlaxoSmithKline 
Biologicals S.A.
Protocol number:
V49_23E1
Generic name of study vaccine(s):
Rabies, whole virus vaccine (inactivated)
Number and percentages of SAEs will be summarized only for subjects receiving a 
booster dose by the vaccination regimen received in the parent study V49_23 and 
overall.
Secondary Endpoints: 
Immunogenicity Endpoints:

Geometric Mean Antibody Concentrations (GMCs) at Year 3, 4, 5, 6, 7, 8, 9 and 10;

Reverse Cumulative Distribution Plots (RCDPs) at Year 3, 4, 5, 6, 7, 8, 9 and 10;

Percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL, as measured by 
RFFIT assay at Year 3, 4, 5, 6, 7, 8, 9 and 10.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 20 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Name of Sponsor:
GlaxoSmithKline 
Biologicals S.A.
Protocol number:
V49_23E1
Generic name of study vaccine(s):
Rabies, whole virus vaccine (inactivated)
Statistical Analyses: 
Time to first RVNA concentrations <0.5 IU/mL
Kaplan-Meier estimate of the survival function, along with 95% CIs, will be computed 
and displayed per each vaccination regimen. The Cox regression model will be used to 
compare the 3 vaccine regimens every year.
Geometric Mean Concentration (GMC) and Geometric Mean Ratio (GMR)
RVNA GMCs will be based on the logarithmically transformed (base10) values. 
GMCs, with the associated 95% confidence intervals will be computed for each vaccine 
group (assigned from parent study) at Year 3, 4, 5, 6, 7, 8, 9 and 10 by taking the 
exponential of the corresponding log-transformed (least squares) means and 95% 
confidence intervals, from an ANOVA model with fixed factors for group and center. 
Group differences along with 95% CIs will also be computed. Subjects will be included 
in this analysis until they receive the booster dose and they will be excluded thereafter.
For subjects receiving a booster dose, analysis of boostability will be conducted 7 days
(and also approximately 6 to 9 months) after administration of the booster dose by 
providing GMRs and associated 95% CIs, considering the antibody value at the booster 
visit as baseline (denominator) and the antibody concentration at 7 days (and also 
approximately between 6 to 9 months) after booster as the numerator.
Reverse Cumulative Distribution Plots at Year 3, 4, 5, 6, 7, 8, 9 and 10;
Reverse cumulative distribution plots will be provided at Year 3, 4, 5, 6, 7, 8, 9 and 10 
by vaccination regimen group. 
Percentages of subjects with RVNA concentrations ≥0.5 IU/mL
As a form of supplementary information, also percentage of subjects with RVNA 
concentrations ≥0.5 IU/mL, as measured by RFFIT assay at Year 3, 4, 5, 6, 7, 8, 9 and 
10 will be presented in a tabular fashion.
Interim Analyses: 
In order to understand complete evolution of the antibody decay over time and the effect 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 21 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Name of Sponsor:
GlaxoSmithKline 
Biologicals S.A.
Protocol number:
V49_23E1
Generic name of study vaccine(s):
Rabies, whole virus vaccine (inactivated)
of the booster dose, every year, an immunogenicity and safety analysis will be carried 
out and the results will be stored in the internal clinical data repository. 
Two Clinical Study Reports (CSR) are planned: 

One interim CSR will be released after all subjects will complete Scheduled 
Clinic Visit 4 (i.e. Year 6). This CSR will include both immunogenicity and 
safety analyses halfway through study. The interim CSR might be submitted 
to the Health Authority in case results support indication for the booster dose 
at a given time after the primary regimen.

The final CSR will be released at the completion of the study and will include all 
study data from Visit 1 (Year 3) to Visit 8 (Year 10).
Further details regarding the interim analyses are contained in section 8.6, Interim 
Analyses.
Data Monitoring Committee: No Data Monitoring Committee will be convened for 
this study.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 22 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Table 2
Time and Events Tables 
Table 2a
Scheduled Clinic Visits: For All Subjects (Amended 25 February 2019)
Visit Type
Scheduled Clinic Visit
Final 
Scheduled 
Clinic Visit
Study Period
Day 1   Year 3
Year 4
Year 5
Year 6
Year 7
Year 8
Year 9
Year 10
Visit Window (Days)*
n/a
-28 to +28
-28 to +28
-28 to +28
-28 to +28
-28 to +28
-28 to +28
-28 to +28
Visit Number
1
2
3
4
5
6
7
8
Study Event
References
Screening and Safety
Informed Consent a
Section 5.1.1
X
Medical History
Section 5.1.2
X
X
X
X
X
X
X
X
Physical Examd
Section 5.1.2 
X
X
X
X
X
X
X
X
Exclusion/Inclusion Criteria
Section 4.0
X
X
X
X
X
X
X
X
Prior and Concomitant 
Medications
Sections 5.1.2 and
6.5
X
Assess SAEs and Relevant 
Concomitant Medications b
Sections 7.1.4, 5.1.2 
and 6.5
X
X
X
X
X
X
X
Observe for at Least 15 Minutes 
Post Blood Draw and Assess AEs 
(if any)
Section 7.1.3
X
X
X
X
X
X
X
X
Immunogenicity
Serology Blood Draw
Section 3.5
X
X
X
X
X
X
X
X
Study Completion Procedures
Study Termination c
Section 5.5
X

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 23 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
a Confirm consent form signed prior to any procedures.
b SAEs and the associated concomitant medications will be collected ONLY from those subjects who will receive booster vaccine during the Ad hoc Clinic Visit, 
starting from the time of booster administration until completion of safety follow-up period (the day of the next Scheduled Clinic Visit after booster 
vaccination or on the date of Early Termination Visit, whichever is earlier).
c Subjects who terminate the study early are recommended to complete certain study-related procedures. See section 5.5 for further details.
d Physical exams have to be done by practitioners in accordance with their institutional policy. Should the physical assessment reveal any abnormal values or 
events, which fall under definition of SAE, these must be documented in the CRF Adverse Events Form and reported to sponsor.
*Visit 1 date to be used as reference for calculating next visit date (e.g. V1: 31 JAN 15, V2: 31 JAN 16 ± 28 days, V3: 31 JAN 17 ± 28 days).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 24 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Table 2b 
Ad hoc and Additional Clinic Visit (Amended 25 February 2019)
Visit Type
Clinic Visit
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Study Period
Year 3, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 1
Year 3, 
7 days
after Ad 
hoc Clinic 
Visit 1.1
Year 4, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 2
Year 4,
7 days 
after Ad 
hoc Clinic 
Visit 2.1
Year 5, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 3
Year 5, 
7 days 
after Ad 
hoc Clinic 
Visit 3.1
Year 6, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 4
Year 6, 
7 days 
after Ad 
hoc Clinic 
Visit 4.1
Year 7, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 5
Year 7, 
7 days 
after Ad 
hoc Clinic 
Visit 5.1
Year 8, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 6
Year 8, 
7 days 
after Ad 
hoc Clinic 
Visit 6.1
Year 9, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 7
Year 9, 
7 days 
after Ad 
hoc Clinic 
Visit 7.1
Visit Window (Days)
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
Visit Number
1.1
1.2
2.1
2.2
3.1
3.2
4.1
4.2
5.1
5.2
6.1
6.2
7.1
7.2
Study Event
References
Medical 
History c
Section 
5.1.2
X
X
X
X
X
X
X
Physical Examc
Sections 
5.1.2 and
5.2
X
X
X
X
X
X
X
Pregnancy 
Testc, d
Sections 
3.5 and 
5.1.2
X
X
X
X
X
X
X
Verification of 
Relevant 
Exclusion/Inclu
sion Criteriac
Section 4.0
X
X
X
X
X
X
X
Vaccinatione
Section 5.2
X
X
X
X
X
X
X

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 25 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Visit Type
Clinic Visit
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Study Period
Year 3, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 1
Year 3, 
7 days
after Ad 
hoc Clinic 
Visit 1.1
Year 4, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 2
Year 4,
7 days 
after Ad 
hoc Clinic 
Visit 2.1
Year 5, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 3
Year 5, 
7 days 
after Ad 
hoc Clinic 
Visit 3.1
Year 6, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 4
Year 6, 
7 days 
after Ad 
hoc Clinic 
Visit 4.1
Year 7, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 5
Year 7, 
7 days 
after Ad 
hoc Clinic 
Visit 5.1
Year 8, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 6
Year 8, 
7 days 
after Ad 
hoc Clinic 
Visit 6.1
Year 9, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 7
Year 9, 
7 days 
after Ad 
hoc Clinic 
Visit 7.1
Visit Window (Days)
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
Visit Number
1.1
1.2
2.1
2.2
3.1
3.2
4.1
4.2
5.1
5.2
6.1
6.2
7.1
7.2
Study Event
References
30 Minutes 
Post Booster 
Injection 
Assessment
Section 
5.2.1
X
X
X
X
X
X
X
Assess SAEs 
and Relevant 
Concomitant 
Medications f
Sections 
7.1.4, 5.1.2
and 6.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity
Serology Blood 
Draw
Section 3.5
X
X
X
X
X
X
X
Observe for at 
Least15 
Minutes Post 
Blood Draw 
and Assess AEs 
(if any)
Section 
7.1.3
X
X
X
X
X
X
X

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 26 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Visit Type
Clinic Visit
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Study Period
Year 3, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 1
Year 3, 
7 days
after Ad 
hoc Clinic 
Visit 1.1
Year 4, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 2
Year 4,
7 days 
after Ad 
hoc Clinic 
Visit 2.1
Year 5, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 3
Year 5, 
7 days 
after Ad 
hoc Clinic 
Visit 3.1
Year 6, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 4
Year 6, 
7 days 
after Ad 
hoc Clinic 
Visit 4.1
Year 7, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 5
Year 7, 
7 days 
after Ad 
hoc Clinic 
Visit 5.1
Year 8, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 6
Year 8, 
7 days 
after Ad 
hoc Clinic 
Visit 6.1
Year 9, 
between
6 to 9
months
after 
Schedule
d Clinic 
Visit 7
Year 9, 
7 days 
after Ad 
hoc Clinic 
Visit 7.1
Visit Window (Days)
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
Visit Number
1.1
1.2
2.1
2.2
3.1
3.2
4.1
4.2
5.1
5.2
6.1
6.2
7.1
7.2
Study Event
References
a Ad hoc Clinic Visit (which is planned to occur as soon as the results of the antibody assay will be available and within approximately 6 to 9 months from the 
blood draw taken during a previous “Scheduled Clinic Visit”) is only applicable for those subjects with RVNA concentrations <0.5 IU/mL during this extension 
study. See sections 3.1 and 3.9 for further details.  
b Additional Clinic Visit (within approximately 7 days from Ad hoc Clinic Visit) only applicable for subjects who will receive a booster dose of PCEC rabies 
vaccine during Ad hoc Clinic Visit. 
c Procedure to be performed prior to vaccination. Physical exams have to be done by practitioners in accordance with their institutional policy. Should the 
physical assessment reveal any abnormal values or events, which fall under definition of SAE, these must be documented in the CRF Adverse Events Form 
and reported to sponsor.
d Only for female subject of childbearing potential who are eligible to receive the booster dose. 
e GSK Biologicals’ Randomization System on Internet (SBIR) will be used for Treatment allocation.
f SAEs and the associated concomitant medications will be collected starting from the booster administration until the completion of safety follow-up period (the 
day of the next Scheduled Clinic Visit after booster vaccination or on the date of Early Termination Visit, whichever is earlier). 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 27 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
LIST OF ABBREVIATIONS (Amended 25 February 2019)
AE
Adverse Event
CBER
Center for Biologics Evaluation and Research
CCEEVs
Cell Culture or Embryonated Egg-Based rabies Vaccines
CI
Confidence Interval
CRO
Contract Research Organization
CSR
Clinical Study Report
eCRF
electronic Case Report Form
EC
Ethic Committee
EDC
Electronic Data Capture
EMA
European Medicines Agency
FAS
Full Analysis Set
FDA
U.S. Food and Drug Administration
GCP
Good Clinical Practices
GMC
Geometric Mean Concentration
GMR
Geometric Mean Ratio
HR
Hazard Ratios
ICF
Informed Consent Form
ICH
International Conference for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use
ID
Identification (Subject ID)
IM
Intramuscular
IRB
Institutional Review Board

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 28 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
IU
International Unit
KM
Kaplan-Meier 
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Milliliter
PCEC
Purified Chick-Embryo Cell Culture
PEP
Post Exposure Prophylaxis
PrEP
Pre-Exposure Prophylaxis
RCDP
Reverse Cumulative Distribution Plots
RFFIT
Rapid Fluorescent Focus Inhibition Test
RVNA
Rabies Virus Neutralizing Antibodies
SAE
Serious Adverse Event
SBIR
Source DataBase for Internet Randomization
SmPC
Summary of Product Characteristics
WHO
World Health Organization

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 29 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
1.0 
BACKGROUND AND RATIONALE
1.1 
Background (Amended 25 February 2019)
Rabies is a disease caused by the rabies virus (family Rhabdoviridae, genus Lyssavirus), 
which is shed in the saliva of infected and symptomatic animals. The transfer via a bite 
from an infected animal is the most efficient route of transmission. Upon transmission 
and after a variable incubation period, it migrates to the central nervous system and leads 
to an acute, progressive encephalomyelitis that is nearly always fatal. The incubation 
period in humans is usually several weeks to months, but ranges from <1 week to >1 year 
(World Health Organization [WHO] 2013). Without intensive care, death occurs within 
2 weeks after the appearance of clinical symptoms (WHO 2013). 
Rabies occurs in more than 150 countries and territories, indicating its worldwide 
presence. More than 60,000 people die of rabies every year and 95% of these deaths occur 
in Asia and Africa (WHO 2013). Rabies has in fact the highest case fatality ratio of any 
currently recognized infectious disease, being almost always fatal (WHO 2013).
Pre-exposure (PrEP) or post exposure prophylaxis (PEP) as per the recommend regimens 
are the only means of protection against rabies virus infection. 
Pre-exposure prophylaxis is recommended for anyone who is at continual, frequent or 
increased risk for exposure to the rabies virus, as a result of her/his residence or 
occupation, including travelers in high-risk areas (WHO 2013).
Post-exposure prophylaxis: after suspected or proven exposure to rabies virus, prompt use 
of modern cell culture or embryonated egg-based rabies vaccines (CCEEVs) with proper 
wound management and simultaneous administration of rabies immunoglobulin 
(depending on the category of exposure) is almost invariably effective in preventing 
rabies, even after severe exposure (WHO 2013).
Protection against rabies is dependent on the presence of Rabies Virus Neutralizing 
Antibodies (RVNA). WHO recommended method to measure RVNA serum 
concentrations is Rapid Fluorescent Focus Inhibition Test (RFFIT). A neutralizing 
antibody titer of ≥0.5 IU/mL is regarded by the WHO as being an ‘adequate’ antibody 
response following rabies vaccination, and is used as a threshold in clinical trials. 
Rabipur® is a Purified Chick-Embryo Cell Culture (PCEC) rabies vaccine indicated for 
active immunization against rabies in individuals of all ages. This includes pre-exposure 
prophylaxis (i.e. before possible risk of exposure to rabies), in both primary series and 
booster dose, and post exposure prophylaxis (i.e. after suspected or proven exposure to 
rabies).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 30 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
The target subjects for this study have already received a primary series of PrEP with 
Rabipur® either following a conventional (days 1, 8 and 29) regimen alone or in 
combination with JE vaccination or following an accelerated (days 1, 4 and 8) regimen in 
combination with JE vaccination in the parent study V49_23.  
Although in clinical trials persistence of adequate antibody concentrations for 2 years 
after immunization with Rabipur® without additional booster has been observed in 100% 
of subjects, and experience shows that Rabipur® booster doses are generally required 
every 2-5 years following the conventional PrEP regimen, as recommended by WHO and 
following current Rabipur® Summary of Product Characteristics (SmPC), the 
requirement for and the timing of booster vaccination following an accelerated pre-
exposure prophylaxis regimen have never been evaluated previously and will be 
characterized in this study.
1.2 
Rationale
The purpose of this study is to evaluate the long-term (up to approx.10 years after primary 
series for PrEP) persistence and to assess the boostability of immune responses in subjects 
who participated and completed V49_23 study and received either the full primary 
vaccination series according to the conventional rabies plus JE (Conv-R/JE), or the 
accelerated rabies plus JE (Acc-R/JE), or the conventional rabies (Conv-R) PrEP alone 
regimens.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 31 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
2.0 
OBJECTIVES
2.1 
Primary Objectives
Immunogenicity Objectives
3. To compare the long-term (up to approx.10 years) persistence of antibody responses 
(i.e. time until antibody concentrations drop below 0.5 IU/mL) in subjects who 
received a primary series of accelerated or conventional rabies PrEP intramuscular 
(IM) regimen in the parent study V49_23.
4. To evaluate the antibody responses to a booster dose of PCEC rabies vaccine 
administered to subjects with RVNA concentrations <0.5 IU/mL following a primary 
series of accelerated or conventional rabies PrEP IM regimen in the parent study 
V49_23.
Safety Objective
To evaluate the safety of a booster dose of PCEC rabies vaccine following a primary 
series of accelerated or conventional rabies PrEP IM regimen in the parent study V49_23.
2.2
Secondary Objective
Immunogenicity Objective:
To evaluate the long-term (up to approx.10 years) immunogenicity in subjects who 
received a primary series of accelerated or conventional rabies PrEP IM regimen in the 
parent study V49_23.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 32 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
3.0 
STUDY DESIGN
3.1 
Overview of Study Design (Amended 25 February 2019)
Introduction of study design:
This is a phase 3, open-label, multicenter, extension of V49_23 study in adult subjects.
In the parent study (V49_23) subjects from ≥18 years to ≤65 years of age were
randomized to one of four vaccination groups, three of which for rabies pre-exposure
prophylaxis according to conventional (1.0 mL dose of PCEC rabies vaccine administered 
IM on each of days 1, 8 and 29) alone or in combination with Japanese Encephalitis (JE) 
vaccination or according to a new, one-week, accelerated (1.0 mL dose of PCEC rabies 
vaccine administered IM on each of days 1, 4 and 8) regimen in combination with JE 
vaccination depending on the study group (see Table 3.1-1). 
Subjects who were randomized into one of the 3 rabies vaccination group regimens, who
received the full PrEP rabies regimen and completed V49_23 following study protocol
will be invited to take part to this study.
Subjects who were randomized to the JE conventional group in V49_23 study will not be 
invited to take part to this extension study.
Table 3.1-1 
Vaccine Groups in Studies V49_23 and V49_23E1
V49_23 study
V49_23E1 study
Study Vaccine Group
Regimen of Primary
Vaccine 
Administration
N of subjects who 
received full PrEP and 
completed the study
Study Vaccine Group
Maximum N of 
subjects who will be 
invited for enrollment
(at the start of the
extension study)
Regimen of Booster
Vaccination
Conventional Rabies 
with concomitant JE 
vaccination
(Conv-R/JE)
Rabies PrEP
Days 1, 8 and 29 
JE primary series
Days 1 and 29  
N=158 subjects
Conv-R/JE
N= up to 158 subjects
A single PCEC rabies 
booster dose (1.0 mL) 
IM for subjects with 
RVNA concentrations 
<0.5IU/mL
Accelerated Rabies with 
concomitant JE 
vaccination
(Acc-R/JE)
Rabies PrEP
Days 1, 4 and 8
JE primary series
Days 1 and 8 
N=209 subjects
Acc-R/JE
N= up to 209 subjects
A single PCEC rabies 
booster dose (1.0 mL) 
IM for subjects with 
RVNA concentrations 
<0.5IU/mL

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 33 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
V49_23 study
V49_23E1 study
Conventional Rabies
vaccination alone
(Conv-R)
Rabies PrEP
Days 1, 8 and 29
N=211 subjects
Conv-R
N= up to 211 subjects
A single PCEC rabies 
booster dose (1.0 mL) 
IM for subjects with 
RVNA concentrations 
<0.5IU/mL
Conventional JE 
vaccination alone
(Conv-JE)
JE primary series
Days 1and 29 
N=52 subjects
NA
NA
Up to 578 subjects, who completed rabies PrEP regimens in the parent study V49_23 will 
be invited to participate to this extension study.
All sites will be trained in a uniform fashion and those sites will be monitored to ensure 
consistency in study execution across all centers. 
Informed consent will be performed prior to any study-related procedures. 
Subjects who sign the informed consent will be screened to assess for their eligibility of 
participation in the study.
All individuals who are screened for the study, as defined in this section, should be
recorded on the “subject screening log” where information on the selection of potential
participants in the trial should be collected. The reason why an individual was not
enrolled, the enrollment date and assigned subject number and code which is carried over 
from the parent study, should be recorded by the investigator/study staff. It is the 
responsibility of the investigator/delegate to file this document among those of the 
Investigator Site File to be readily available for on-site monitoring and/or for inspection 
by the relevant authorities.
Subjects will receive their booster doses based on their own antibody concentrations 
(booster will be administered only to those subjects with RVNA concentrations <0.5 
IU/mL), medical history and physical examination to ensure that they are in good health 
according to the investigator’s opinion and meet all inclusion criteria and none of the 
exclusion criteria. 
For all subjects enrolled there will be overall 8 blood draws (of approximately 7 mL each) 
scheduled during the course of the extension study; each of these blood draws will be 
taken at each Scheduled Clinic Visit, from extension study Day 1 (Year 3 after 
completion of PrEP in the parent study V49_23) and then yearly through Year 10. During 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 34 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Scheduled Clinic Visit and Additional Clinic Visit, subjects will be observed for at least 
15 minutes after the blood draw for any adverse event (AE).
A urine pregnancy test will be performed for female subject of childbearing potential who 
are eligible to receive the booster dose prior to vaccination.
Vaccination procedures:
Only those subjects for which the RVNA concentration determined to be <0.5 IU/mL 
based on the blood sample from Visit 1, 2, 3, 4, 5, 6, and 7 (i.e., on Year 3, 4, 5, 6, 7, 8, 
and 9) will receive the booster dose of rabies vaccine in an open label fashion, time of 
each booster dose and blood draw for rabies antibody concentrations needs to be 
meticulously recorded.
If, after having received a booster dose, the subject does not reach the adequate antibody 
concentration of 0.5 IU/mL at two consecutive determinations, neither at 7 days after the 
booster dose (i.e. Additional Clinic Visit) nor at the next yearly evaluation (i.e. Scheduled 
Clinic Visit), an additional booster dose may be administered at the following Ad hoc
Clinic Visit. If the subject is still non-responder, subsequent management should be at 
the discretion of the investigator.
Should a subject have RVNA concentrations below 0.5 IU/mL at blood draw performed 
at the final Scheduled Clinic Visit (Year 10), the investigator will invite the subject to 
receive a booster dose of the rabies vaccine outside the study following standard clinical 
practice and there will be no further analyses performed on this additional vaccination.
Such subject will receive 1.0 mL single dose (freeze-dried powder + diluent [sterile 
water]) for reconstitution and injection of the rabies vaccine intramuscularly.
Post-vaccination evaluations:
The safety data will be collected only from those subjects who received booster dose of 
rabies vaccine during any Ad hoc Clinic Visit.
The safety data in these subjects will include;

At least 30 minutes post-vaccination: the subject will be observed by the 
investigator/delegate at the clinical trial site for any immediate reaction and it will be 
documented in subject’s source document.

Starting from the time of booster administration until completion of safety follow-up
period (the day of the next Scheduled Clinic Visit after booster vaccination or on 
the date of Early Termination Visit, whichever is earlier) SAEs and the associated 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 35 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
concomitant medications will be recorded by interviewing the subject during next 
Clinic Visit and based on the subject’s medical records.
To investigate the prompt boostability of the immune response, during Additional Clinic 
Visits additional blood samples will be drawn approximately 7 days after the booster dose 
only from those subjects who received PCEC rabies booster vaccine during previous Ad 
hoc Clinic Visits. 
In order to understand complete evolution of the antibody decay over time and the effect 
of the booster dose, every year, an immunogenicity and safety analysis will be carried out 
and the results will be stored in the internal clinical data repository.
Two Clinical Study Reports (CSR) are planned: 

One interim CSR will be released after all subjects will complete Scheduled Clinic 
Visit 4 (i.e. Year 6). This CSR will include both immunogenicity and safety 
analyses halfway through the study. The interim CSR might be submitted to 
the Health Authority in case results support indication for the booster dose at a 
given time after the primary regimen.

The final CSR will be released at the completion of the study and will include all 
study data from Visit 1 (Year 3) to Visit 8 (Year 10).
A listing with individual subject antibody titers will be generated by the sponsor to show 
which subjects have rabies neutralizing antibody concentrations <0.5 IU/mL and thus 
qualify to be vaccinated with a booster dose of rabies vaccine during the Ad hoc Clinic 
Visit. The decision will be based on RVNA concentration from the blood sample taken in 
the previous Scheduled Clinic Visits (e.g. booster administration at the Ad hoc Clinic 
Visit 1.1 for subjects with RVNA concentrations <0.5 IU/mL at the Scheduled Clinic 
Visit 1).  
3.2 
Study Period
Each subject should expect to participate in the study for approximately 7 years, from the 
time of enrolment through the last study visit.
3.3 
Blinding Procedures
This is an open label study. The laboratory that will perform the serology analysis will be 
blinded to treatment arm.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 36 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
3.4 
Data Collection (Amended 25 February 2019)
3.4.1 Data Collected from Subjects
The following data will be collected from each subject over the duration of their study 
participation:

Demographic Information.

Medical History.

Concomitant Medications (only when associated to a SAE).
‘Booster vaccination information’, ‘pregnancy test results of women of childbearing 
potential’ and SAEs will be collected from those subjects who will receive booster dose 
of rabies vaccine. 
All data collected must only be identified using the GSK Subject ID. 
3.4.2 Tools Used for Data Collection
Data will be recorded in the subject’s source record and collected on eCRFs.
Any safety information either within 30 minutes of post vaccination and/or up to the day 
of next Scheduled Clinic Visit and which can be considered an AE must be recorded in 
subject’s source document and it must be described as a verbally reported adverse event.
Any AE that occurs during the specified safety collection period which fulfils any of the 
seriousness criteria mentioned in section 7.1.4 must be reported to the sponsor via the 
Vaccines Serious Adverse Event (VSAE) Form which is part of the Investigator Site 
File and therefore entered on the Adverse Event CRF.
Any adverse event that is considered to be caused by the study vaccine and occurs
outside the protocol-specified follow-up period should be reported to the sponsor 
(section 7.1.5.1, Post-study events).
3.5 
Collection of Clinical Specimens
The following clinical specimens are required to be collected from each subject in this 
study:

Blood.

Urine (Only for female subjects of childbearing potential eligible for booster).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 37 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Processing of each blood sample should be completed by a qualified site member and in 
accordance with the study-specific Clinical Specimen Laboratory Manual. Immunological 
assays will be performed by a GSK or designated, qualified laboratory. Refer to the 
study-specific Clinical Specimen Laboratory Manual for additional details.
Blood Specimens
A minimum of approximately 7 mL sample of blood will be drawn from all subjects at 
Scheduled Clinic Visits 1, 2, 3, 4, 5, 6, 7 and 8 (i.e., Year 3, 4, 5, 6, 7, 8, 9, and 10).
In addition, minimum of approximately 7 mL sample of blood will be drawn at 
Additional Clinic Visits 1.2, 2.2, 3.2, 4.2, 5.2, 6.2, and 7.2 only from those subjects who 
received booster vaccine during the previous Ad hoc Clinic Visit. The blood volume will 
not exceed 7 mL at each time point in order to provide the necessary serum volume 
(approximately half of the blood draw volume) for the serology assays.
The blood will be used for immunological assays. See section 7.0, Assessments for 
additional details.
The total amount of blood collected over the study period per subject will be maximum 
up to 105 mL over 7 years.
Urine Specimens
To confirm the pregnancy status, urine will be collected for pregnancy testing in those 
females of child bearing potential who are eligible to receive the booster dose at Ad hoc 
Clinic Visits i.e. Visit 1.1, 2.1, 3.1, 4.1, 5.1, 6.1, and 7.1 before vaccination. The 
pregnancy test will be performed at the study site.
3.6 
Stopping/Pausing Guidelines
There are no predetermined stopping rules other than circumstances for which subjects 
may not be eligible for additional study vaccinations as described in section 4.0, Selection 
of Study Population or may be withdrawn from the study according to the best interests of 
the subject as described in section 3.8, Premature Withdrawal from Study.
3.7 
Data Monitoring Committee
Data Monitoring Committees (DMCs) will not be utilized for this study.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 38 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
3.8 
Premature Withdrawal from Study (Amended 25 February 2019)
Subjects may withdraw at any time, or be dropped from the study at the discretion of the 
investigator should any untoward effects occur and/or for safety reasons. In addition, a 
subject may be withdrawn by the investigator or the Sponsor if he/she violates the study 
plan or for administrative reasons. The investigator or study coordinator must notify the 
Sponsor immediately when a subject has been withdrawn due to an adverse event.
The circumstances above are referred to as premature withdrawal from the study, and the 
reason for premature withdrawal should be clearly documented and detailed in the source 
documentation. The investigator should make every attempt to evaluate the subject’s 
safety, including resolution of ongoing AEs, at the time of premature withdrawal. When a 
subject withdraws, or is withdrawn, from the study, the procedures described in section 
5.5.1, Early Termination Visit should be completed if possible.
The reasons for premature withdrawal from the study include: Adverse event, death, 
withdrawal of consent, lost to follow-up, administrative reason, and protocol deviation. 
These reasons are described in greater detail below. Since these subjects will be 
considered censored for purposes of analysis, the time of their premature withdrawal 
should be meticulously recorded.
Adverse Event
For any subject withdrawn from study participation prior to the planned Study 
Termination Visit, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the AE CRF page by indicating 
“Withdrawn from study due to AE”. Any ongoing AEs at the time of study withdrawal 
must be followed until resolution or stabilization.
Subjects who develop a serious adverse event (SAE) judged to be possibly or probably 
related to the study vaccine, including hypersensitivity reactions, should not receive 
subsequent vaccination even if subject’s RVNA concentration is found to be <0.5 IU/mL 
based on the next yearly serology analysis.
Death
For any subject withdrawn from study participation due to death, this should be noted on 
the Study Termination CRF page and it should be notified to the Sponsor. For subjects 
who received a booster dose, which withdraw from the study due to death during the 
safety observation period (from the booster administration and until the day of next 
Scheduled Clinic Visit), the associated SAE that led to the death must be reported.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 39 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Withdrawal of consent
The subject or legal guardian can withdraw consent for participation in the study at any 
time without penalty or loss of benefit to which the subject is otherwise entitled. Reason 
for early termination should be deemed as “withdrawal of consent” if the subject 
withdraws from participation due to a non-medical reason (i.e., reason other than AE). If 
the subject requests complete withdrawal from the study, no further study interventions 
will be performed with the subject.
Lost to Follow-Up
For subjects who fail to show up for final Scheduled Clinic Visit, or for three consecutive 
Scheduled Clinic Visits, study staff are encouraged to make at least three documented 
attempts to contact the subject by telephone and at least one documented written attempt 
to contact the subject or legal guardian to encourage the completion of study termination 
procedures. In case an Ad hoc Visit is missed, the subject could come to the next 
following Scheduled Visit and having a blood draw according to protocol. In case 
RVNA concentrations <0.5 IU/mL, a booster may be given according to protocol.
These efforts to contact the subject should be recorded in the source document. The 
termination date for the subject to be captured on the Study Termination CRF page is the 
date of the last successful contact (clinic visit or telephone) with the subject.
Administrative Reason
Examples for subjects withdrawn from the study due to administrative reason can include: 
Sponsor decision to terminate the study, subject meeting a pre-specified withdrawal 
criterion, subject discontinuation for insurance issues, moving, no time, etc. This reason 
should be noted in the Study Termination CRF page and any ongoing SAEs at the time of 
study withdrawal must be followed until resolution/stabilization.
If the clinical study is prematurely terminated by the Sponsor, the investigator is to 
promptly inform the study subjects and local IRB/EC (Institutional Review Board/ Ethic 
Committee) and should assure appropriate therapy and follow up for the subjects. All 
procedures and requirements pertaining to the archiving of study documents should be 
followed. All other study materials (study medication/vaccines, etc.) must be destroyed 
either locally or returned to the Sponsor or depot, as applicable.
For subjects who are withdrawn from the study due to receipt of an excluded 
medication/vaccination or due to significant protocol non-compliance, this reason should 
be noted in the Study Termination CRF page.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 40 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Protocol Deviation
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. In general, subjects associated with protocol deviations 
may remain in the study unless continuation in the study jeopardizes the subject’s health, 
safety, or rights.
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact GSK or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are 
permitted. If the investigator feels a change to the protocol would improve the conduct of 
the study this must be considered a protocol amendment, and unless such an amendment 
is agreed upon by GSK and approved by the IRB/EC and health authorities it cannot be 
implemented. 
Any subject who becomes pregnant during the study, despite the protocol requirement for 
adequate contraception, will not receive further vaccination until delivery but should be 
encouraged to continue participating in the study. The site must complete a Pregnancy 
Report CRF (initial report) as soon as possible after learning of pregnancy occurrence 
(see section 7.1.6, Pregnancies for further details).
If the subject withdraws from the study for any of the above categories except death, the 
site will obtain permission from the subject to continue to remain in contact with her until 
the outcome of the pregnancy is known, even if the outcome is not known until after the 
subject reaches the end of follow-up period.
3.9 
End of Study
Most clinical trials intended to support the immunogenicity and safety of an 
Investigational Product proceed to full completion of planned sample size accrual.
Evaluation of the primary immunogenicity objectives requires the testing of biological 
samples from the study subjects, which can only be completed after all samples are 
collected. The last samples for the analysis of the primary objectives will be taken at Visit 
8. For the purpose of this protocol, end of study is defined as the completion of the testing 
of such biological samples, to be achieved no later than 8 months after collection of the 
last biological sample at the Scheduled Clinic Visit 8 (Year 10).
Should a subject have RVNA concentrations below 0.5 IU/mL at blood draw performed 
at the final Scheduled Clinic Visit (Year 10), the subject will be invited to receive a 
booster dose of the rabies vaccine outside the study following standard clinical practice
and there will be no further analyses performed on this additional vaccination.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 41 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
4.0 
SELECTION OF STUDY POPULATION
4.1 
Inclusion Criteria
In order to participate in this study, all subjects must meet ALL of the inclusion criteria 
described.
1. All individuals who were randomized to Conventional Rabies and JE vaccination or 
to Accelerated Rabies and JE vaccination or to Conventional Rabies groups during the 
parent study, who received the full PrEP regimen and completed the trial following 
V49_23 study protocol.
2. Individuals who have voluntarily given written informed consent after the nature of 
the study has been explained according to local regulatory requirements, prior to study 
entry.
3. Individuals who can comply with study procedures1.
4. Males
Or
Females of non-childbearing potential2
Or
Females of childbearing potential who are using an effective birth control method3
which they intend to use for at least 6 months after the booster vaccination. This 
criterion is applicable only for those subjects who receive a booster dose.
                                                
1 A subject and legal guardian is considered to be compliant if the Investigator judges that the subject will 
return for all the clinical visits as scheduled in the study.
2 A female is considered to be of non-childbearing potential prior to menarche and after natural or induced 
menopause. Natural menopause is recognized to have occurred after 12 consecutive months of amenorrhea 
for which there is no other obvious pathological or physiological cause. Induced menopause is recognized 
to have occurred after hysterectomy, after bilateral oophorectomy, or iatrogenic ablation of ovarian 
function.
3 The following birth control methods are considered effective:
-
Abstinence
-
Hormonal contraceptive (such as oral, injection, transdermal patch, implant) if used for at least 30 
days prior to informed consent or booster vaccination
-
Diaphragm with spermicide, tubal occlusion device
-
Intrauterine device (IUD)
-
Tubal ligation
-
Male partner using condom with spermicide
-
Male partner having been vasectomized at least six months prior to informed consent or booster 
vaccination

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 42 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Prior to receipt of booster vaccination during Ad hoc Clinic Visit, subjects must be 
evaluated to confirm that they are eligible. If subjects do not meet any of the original 
inclusion criteria listed above, they should not receive booster dose of rabies vaccine.
4.2 
Exclusion Criteria (Amended 25 February 2019)
Prior to extension study entry, each subject must not have:
1. Completed the parent study V49_23 without receiving the full 3 rabies vaccine doses 
following the assigned pre-exposure prophylaxis regimen.
2. History of exposure to suspected or confirmed rabid animal. 
3. Receipt of rabies immunoglobulins, rabies post exposure prophylaxis following 
completion of V49_23 study.
4. Hypersensitivity, including allergy, to any component of vaccines, medicinal products 
or medical equipment whose use is foreseen in this study.
5. Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws.
6. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 consecutive 
days within 90 days prior to informed consent or planning to receive them during the 
participation to the study.
7. Administration of antineoplastic and immunomodulating agents or radiotherapy 
within 90 days prior to informed consent or planning to receive them during the 
participation to the study.
8. Received immunoglobulins or any blood products within 180 days prior to informed 
consent or planning to receive them during the participation to the study.
9. Study personnel as well as their immediate family or household member.
10. Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the subject due to participation in the study.
Prior to Scheduled Visit, each subject must not have:
1. History of exposure to suspected or confirmed rabid animal. 
2. Receipt of rabies immunoglobulins, non-study rabies vaccine following completion 
of V49_23 study.
3. Hypersensitivity, including allergy, to any component of vaccines, medicinal 
products or medical equipment whose use is foreseen in this study.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 43 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
4. Clinical conditions representing a contraindication to intramuscular vaccination 
and blood draws.
5. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent or planning to receive 
them during the participation to the study.
6. Administration of antineoplastic and immunomodulating agents or radiotherapy 
within 90 days prior to informed consent or planning to receive them during the 
participation to the study.
7. Received immunoglobulins or any blood products within 180 days prior to informed 
consent or planning to receive them during the participation to the study.
8. Study personnel as well as their immediate family or household member.
9. Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the subject due to participation in the study.
Prior to booster vaccination, each subject eligible for booster vaccination (i.e.,
subjects with RVNA concentrations <0.5 IU/mL at the first visit of this extension study 
[Day 1, Year 3] or at the following year visits [Year 4 to Year 9]) should be in good 
health status and must not have none of the following:
1. Progressive, unstable or uncontrolled clinical conditions.
2. Abnormal function of the immune system resulting from:
a.
Clinical conditions.
b. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior the Ad hoc visit or receipt or planning to 
receive them during the participation to the study.
c.
Administration of antineoplastic and immunomodulating agents or radiotherapy 
within 90 days prior the Ad hoc visit or receipt or planning to receive them during 
the participation to the study.
3. Receipt of non-study rabies vaccine. 
4. Receipt of any other vaccines within 28 days prior to the booster dose or planning to 
receive any vaccine within 28 days from the booster dose.
5. Receipt of any investigational or non-registered medicinal product within 14 days 
before booster dose till next Scheduled Clinic Visit after booster dose administration.
6. Receipt of anti-malarial medications (e.g. Mefloquine) within 14 days before booster 
dose till next Scheduled Clinic Visit after booster dose administration.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 44 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Prior to receipt of booster study vaccination, subjects must be evaluated to confirm that 
they are in good health and they are eligible for subsequent vaccination. If subjects meet 
any of the original exclusion criteria listed above, they should not receive additional 
vaccinations.
4.3 
Criteria for Delay of Vaccination
There may be instances when individuals meet all eligibility criteria for booster 
vaccination yet have a transient clinical circumstance which may warrant delay of booster 
vaccination: body temperature elevation [≥38.0° C (≥ 100.4° F) within 3 days prior to 
intended booster study vaccination], or use of antipyretics and/or analgesic medications 
within 24 hours prior to vaccination. Under such circumstances, a subject may be 
considered eligible for booster vaccination after resolution of the acute febrile illness has 
occurred and inclusion/exclusion criteria have been rechecked, and if the subject is 
confirmed to be eligible.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 45 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
5.0 
STUDY PROCEDURES (Amended 25 February 2019)
The sections that follow provide an overview of the procedures that have to be followed 
in enrolling, evaluating, and following subjects who participate in this clinical study. 
Visits can be either Scheduled Clinic Visits or Ad hoc Clinic Visits or Additional Clinic 
Visits, as specified in the Table below and in the Time and Events Tables 2a and 2b.
Table 5.0-1
Study Procedures
Visit Category
Procedures
Scheduled Clinic Visits (or pre-vaccination clinic 
visits)
Section 5.1 describes procedures to be followed 
prior to study vaccination: informed consent/assent, 
screening, enrolment, randomization, blood draw, as 
applicable.
Ad hoc Clinic Visits (or vaccination clinic visits)
Section 5.2 describes procedures to be followed 
during each clinic visit involving booster 
vaccination: vaccination and post-vaccination 
procedures.
Additional Clinic Visits (or post-vaccination clinic 
visits) 
Section 5.3 describes follow-up clinic visits for 
those subjects who received a booster vaccination.
Unscheduled Visit(s)
Section 5.4 describes possible procedures to be 
followed at unscheduled clinic visits.
Study Termination Visit
Section 5.5 describes procedures to be followed at 
the last study visit for a subject (may include early 
termination visit).
5.1 
Scheduled Clinic Visits - Pre-vaccination Clinic Visit(s)
This section describes the procedures that must be performed for each potential subject 
prior to enrollment, including obtaining informed consent and screening.
5.1.1 Informed Consent
"Informed consent" is the voluntary agreement of an individual or his/her legal 
guardian(s) to participate in research. Consent must be given with free will of choice, and 
without undue inducement. The individual must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and potential 
benefits, and the requirements of the research to be able to make an informed decision.
Informed consent following local IRB/EC guidance must be obtained before conducting 
any study-specific procedure (i.e., all of the procedures described in the protocol). The 
process of obtaining informed consent should be documented in the subject source 
document in addition to maintaining a copy of the signed and dated informed consent.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 46 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
If a subject or legal guardian is unable to read, an impartial witness should be present 
during the entire informed consent discussion. An impartial witness is defined as a person 
who is independent from study conduct, who cannot be unfairly influenced by those 
involved with the study, who attends the informed consent process if the subject or the 
subject's legally acceptable representative cannot read, and who reads the informed 
consent form and any other written information supplied to the subject. After the written 
informed consent form and any other written information to be provided to subjects, is 
read and explained to the subject or legal guardian and after the subject or legal guardian 
has verbally consented to the subject’s participation in the study and, if capable of doing 
so, has signed and personally dated the informed consent form, the witness should sign 
and personally date the consent form. By signing the consent form, the witness attests that 
the information in the consent form and any other written information was accurately 
explained to, and apparently understood by the subject or legal guardian and that 
informed consent was freely given by the subject or legal guardian.
5.1.2 Screening
After an individual has consented to participate in the study and informed consent is 
signed, that individual will be assigned a unique Subject ID which she/he is carrying 
from V49_23 study (the parent study). The subject’s unique Screening Number will be 
documented in the Screening and Enrolment log. The eligibility of the subject will be 
determined based on the inclusion and exclusion criteria listed in section 4.0, Selection of 
Study Population and evaluated during this screening procedure.
Prior to study enrolment, demographic data will be collected from the subject, including: 
gender, height and weight.
Medical history will also be collected, including but not limited to any medical history 
that may be relevant to subject eligibility for study participation such as prior vaccinations
against a specific disease, concomitant medications, and previous and ongoing illnesses or 
injuries. Relevant medical history can also include any medical history that contributes to 
the understanding of an AE that occurs during study participation, if it represents an 
exacerbation of an underlying disease/pre-existing problem.
Review of systems is a structured interview that queries the subject or legal guardian as to 
any complaints the subject has experienced across each organ system. This will be 
performed before enrolment and used to guide physical examination.
If applicable, prior and concomitant medications or vaccinations taken prior to start of 
study should be collected (refer to section 6.5, Prior and Concomitant Medications and 
Vaccines for further details).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 47 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Collection of vital signs (heart rate, respiratory rate, blood pressure, and temperature) has 
to be done during all Ad hoc Visits prior booster administration. At Scheduled and 
Additional Visits, their measurement should be at the discretion of the investigator.
A general physical examination is to be performed by a qualified health care practitioner, 
in accordance with their institutional policy. “Qualified health care practitioner” refers 
to any licensed health care professional who is permitted by institutional policy to 
perform physical examinations and who is identified within the Study Staff Delegation of 
Responsabilities (SSDoR).
These data will be written in the source document (see section 9.1, Source 
Documentation). Should the physical assessment reveal any abnormal values or events, 
which fall under definition of SAE, these must be documented in the CRF Adverse 
Events Form and reported to sponsor.
On the first Scheduled Clinic Visit, approximately 7 mL of blood will be drawn from all 
subjects for the serology testing (Refer to section 3.5, Collection of Clinical Specimens)
and the subjects will be observed for at least 15 minutes after the blood draw for any AE.
Record any such observation in the subject’s source document only and not in the eCRF.
In the event that the individual is determined ineligible for study participation, he/she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrolment log. If the individual is determined to be eligible for the study, 
he/she will be enrolled into the study.
5.1.3 Enrolment
After signing the informed consent form, if an individual is determined to be eligible for 
study participation, the investigator will enroll the subject into the EDC (Electronic Data 
Capture) system.
5.1.4 Randomization
This is a non-randomized extension study. Enrolled subjects will be manually assigned a 
unique Subject ID which they are carrying from V49_23 study (the parent study). The 
Subject ID will be the subject’s unique identification number for all CRFs and associated 
study documentation that will be used for duration of the study. The Screening Number 
ceases to be used and remains in the Screening and Enrolment Log only.
Subject numbers (ID) will be pre-loaded into a centralized Randomization System on 
internet (SBIR).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 48 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
If for any reason, after enrolment the subject fails to undergo study procedures this is an 
Early Termination and the reason should be recorded in source document as specified in 
the Source Data Agreement. The information on these Early Termination subjects should 
be kept distinct in the source documentation from subjects who are screen failures, as 
described in section 5.1.2, Screening.
5.2 
Ad Hoc Clinic Visit(s) - Vaccination Clinic Visit(s)
The first dose of booster vaccination with rabies vaccine will be performed in a clinical 
visit occurring as soon as the results of the antibody assay will be available and within 
approximately 6 to 9 months from the blood draw taken during Scheduled Clinic Visit 1 
(Day1); it is termed as “Ad hoc Clinic Visit” 1.1.
Only for those subjects with RVNA concentrations <0.5 IU/mL at the first visit of this 
extension study (Day 1, Year 3) or at the following yearly visits (Year 4 to Year 9) a 
booster dose of PCEC rabies vaccine will be administered during the next planned Ad 
hoc Clinic Visit.
Should the subject be a low responder to a booster dose of the rabies vaccine provided 
during this extension study and not achieve adequate antibody concentrations following a 
booster injection neither at 7 days (following the blood drawn at the “Additional Clinic 
Visits” after the booster) nor at the next evaluation (following the blood drawn at the 
“Scheduled Clinic Visits” after the booster), a subsequent booster dose may be 
administered at the subsequent “Ad hoc Clinic Visit”. If the subject is still non-
responder, subsequent management should be at the discretion of the investigator.
Should a subject have RVNA concentrations below 0.5 IU/mL at blood draw performed 
at the final Scheduled Clinic Visit (Year 10), the subject will be invited to receive a 
booster dose of the rabies vaccine outside the study following standard clinical practice
and there will be no further analyses performed on this additional vaccination.
After completing the pre-vaccination procedures during Ad hoc Clinic Visit, administer 
the vaccine to the subject according to the procedures described in section 6.3, Vaccine 
Preparation and Administration.
Prior to administration of booster vaccination during Ad hoc Clinic Visit, confirm that the 
subject is eligible to receive booster study vaccination and does not meet any criteria for 
delaying of study vaccination as described in section 4.0, Selection of Study Population.
5.2.1 Post-vaccination Procedures
The following post-vaccination procedures will be performed on Ad hoc Clinic Visits.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 49 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
After vaccination, the subject will be observed for at least 30 minutes for any AEs. 
Record all safety data collected during this time in the subject’s source document. If an 
AE fulfils any of the seriousness criteria mentioned in section 7.1.4 it must be reported to 
the sponsor and therefore entered on the Adverse Event CRF.
The site should schedule with the subject or legal guardian the next subject study activity, 
the Additional Clinic Visit.
The subject or legal guardians should be reminded of the next planned study activity. The 
subject or legal guardian will be reminded to contact the site if there are any questions, 
and to contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency room visit.
5.2.2 Post-vaccination Reminder Calls
Not applicable.
5.3 
Additional Clinic Visit(s) - Post-vaccination Visit(s)
Post-vaccination visits will be performed approximately 7 days after a subject received 
booster dose of rabies vaccine.
5.3.1 Follow-up (Additional) Clinic Visit(s)
“Additional Clinic Visits” will be performed approximately 7 days after Ad hoc Clinic 
Visit. This is applicable for those subjects who received booster dose of rabies vaccine 
during Ad hoc Clinic Visit.
During the Additional Clinic Visit, the subject or legal guardian will be interviewed to 
determine if any AEs occurred and if any concomitant medications in conjunction to any 
SAEs or vaccines were taken/received in the time since the last clinic visit. The healthcare 
professional reviewing these data will discuss the symptoms (if any) reported by the 
subject and will determine if any additional diagnoses and/or AEs are present. AEs
reported by the subject or legal guardian at this Additional Clinic Visit must be recorded 
in the subject's source document and if there is any SAE then it must be entered in 
Adverse Events CRF, as specified in section 7.1, Safety Assessment.
In order to investigate the prompt boostability of immune responses, 7 mL of blood 
sample will be drawn during Additional Clinic Visit. The blood will be drawn only from 
those subjects who received booster dose of rabies vaccination during an Ad hoc Clinic 
Visit.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 50 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
During Scheduled Clinic Visit and Additional Clinic Visit, subjects will be observed for 
at least 15 minutes after the blood draw for any AE. Record any such observation in the 
subject’s source document only and not in the eCRF.
The site should schedule with the subject or legal guardian the next clinic visit.
The subject or legal guardian will receive a written reminder of the next planned study 
activity. The subject or legal guardian will be reminded to contact the site if there are any 
questions and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an 
emergency room visit.
5.3.2 Safety Follow-up Calls
Not applicable.
5.4 
Unscheduled Visits 
An unscheduled visit describes a non-routine study visit triggered by a specific event. 
These could include anticipated or unanticipated AEs or interventions.
There are no anticipated specific symptoms or events for which any unscheduled visit is 
expected.
5.5 
Study Termination Visit
The study termination visit will occur for all subjects on the Scheduled Clinic Visit 8 
(Year 10). The date of termination is the date of the last contact (clinic visit) in which the 
subject’s health status was assessed or, in cases where the subject does not agree to any 
further safety follow-up or blood draw; it is the date consent is withdrawn. This date 
should be recorded on the termination CRF page. For visit procedures to be performed for 
a subject whose planned study participation ends prematurely, please see section 5.5.1, 
Early Termination Visit.
At the last clinic visit, the following procedures will be performed: blood sampling for 
immunogenicity, interview of subject or legal guardian to collect SAEs and the associated 
concomitant medications/vaccinations (if the subject received the booster dose during the 
last Ad hoc Clinic Visit).
The site will review with the subject or legal guardian the plan of when information 
relating to the subject’s participation in the study may be available (e.g., study results). It 
will also be discussed how information relating to the subject’s participation in the study 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 51 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
will be shared with the subject’s healthcare provider, if the subject or legal guardian
chooses to share this information.
The site will complete the termination CRF page and this will mark the completion of the 
subject’s participation in the study.
5.5.1 Early Termination Visit
When a subject is withdrawn from treatment or withdraws from the study, the investigator 
will notify the Sponsor and, when possible, will perform the procedures listed below. The 
reason(s) for the early termination will be included in the subject’s source documentation. 
If the Early Termination Visit is a telephone call, collect as much information as possible. 
Early Termination Visits include subjects who were enrolled but not treated.
At the clinic visit or during the telephone call, the following procedures will be 
performed, as applicable: interview of subject/legal guardian to collect AEs, concomitant 
medications/vaccinations, blood sampling for immunogenicity.
The site will review with the subject or legal guardian the plan of when information 
relating to the subject’s participation in the study may be available (e.g., study results). It 
will also be discussed how information relating to the subject’s participation in the study 
will be shared with the subject’s healthcare provider, if the subject or legal guardian
chooses to share this information.
The site will complete the termination CRF page and this will mark the completion of the 
subject’s participation in the study.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 52 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
6.0 
TREATMENT OF SUBJECTS
The vaccine associated with this study is to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. 
All vaccines associated with this study must be checked for expiration date prior to 
use. Expired vaccines must not be administered to subjects.
6.1 
Study Vaccine(s) (Amended 25 February 2019)
Rabipur®, purified chick-embryo cell derived (PCEC) rabies vaccine, GSK Vaccines
GmbH (formerly Novartis Vaccines and Diagnostics GmbH), Marburg, Germany.
The vaccine presentation consists of powder (lyophilized vaccine) and solvent (water for 
injection) for solution for injection. For the composition of Rabipur® vaccine please refer 
to the SmPC supplied by GSK.
After reconstitution, a booster dose consists of 1.0 mL of PCEC rabies vaccine, 
containing rabies virus [inactivated strain Flury 6.6 Low Egg Passage (LEP)®] with a 
potency ≥2.5 IU/mL, and is to be administered via intramuscular (IM) injection.
The study vaccine should be stored in a secure and locked refrigerator at 2°C to 8°C.
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccine specific to this study is
Rabipur®, as described above.
6.2 
Non-Study Vaccines
Not applicable.
6.3 
Vaccine Preparation and Administration (Amended 25 February 2019)
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by personnel who are qualified to 
perform that function under applicable local laws and regulations for the specific study 
site.
From the beginning of the study until 2018, vaccine assignment was randomly done by 
the study staff. From 2019 onwards, the SBIR system has been implemented for 
vaccine assignment to the subjects. The study staff will access the system and will enter 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 53 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
the subject identification number. The system will provide a treatment number for each 
subject.
When SBIR is not available, please refer to the SBIR user guide or the Supply and 
Cold Chain Guidance for specific instructions.
The study vaccine must be prepared according to the Rabipur® SmPC before use. Refer to 
the SmPC of Rabipur® in investigator site file. Note that the vaccine needs to be 
reconstituted before use. Expired vaccines must NOT be administered.
A single dose of 1.0 mL should be administrated intramuscularly in deltoid area of non-
dominant arm by the designated and trained site staff. Subjects experiencing local AEs 
at the vaccination site could alternatively receive rabies vaccine in the deltoid muscle of 
the dominant arm.
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE:
Prior to booster vaccination, subjects must be determined to be eligible for study 
vaccination and it must be clinically appropriate in the judgment of the investigator to 
vaccinate. 
Eligibility for booster vaccination is determined by following the inclusion and exclusion 
criteria outlined in section 4.0, and the criteria outlined in section 4.3, Criteria for Delay 
of Vaccination.
If, after having received a booster dose, the subject does not reach the adequate antibody 
concentration of 0.5 IU/mL at two consecutive determinations, neither at 7 days after the 
booster dose (i.e. Additional Clinic Visit) nor at the next yearly evaluation (i.e. Scheduled 
Clinic Visit), an additional booster dose may be administered at the following Ad hoc 
Clinic Visit. If the subject is still non-responder, subsequent management should be at 
the discretion of the investigator.
Eligibility for non-study vaccines should be determined by the investigator, pending the 
review of the package insert of the relevant vaccine.
Study vaccines should not be administered to individuals with known hypersensitivity to 
any component of the vaccine.
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly. Before administering vaccine, the vaccination 
site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow the skin to dry. 
DO NOT inject intravascularly or intraglutealy.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 54 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment should be readily available in case of anaphylactic reactions following vaccine 
administration. For example, epinephrine 1:1000, diphenhydramine, and/or other 
medications for treating anaphylaxis should be available.
6.4 
Vaccine Administration Error or Overdose of Vaccine 
Vaccine administration error is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined when a dosage higher than the recommended booster dosage is administered.
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an AE, and if the vaccine administration error or overdose is 
associated with a SAE, it must be reported as such within 24 hours to the Sponsor.
6.5 
Prior and Concomitant Medications and Vaccines
All relevant prescription medications (e.g. immune suppressants, antimalarial drugs), 
vaccines and blood products taken or received by the subject between completion of 
V49_23 study and prior to the start of this extension study are to be recorded on the Prior 
and Concomitant Medications CRF.
In addition, the following are considered prior medications for this protocol: all 
medication/vaccines described in the inclusion and exclusion criteria of this protocol 
including: 

Receipt of rabies post exposure prophylaxis or booster dose of rabies vaccine 
following completion of V49_23 study.

Rabies immunoglobulins.

Systemic administration of corticosteroids (PO/IV/IM) for more than 14 consecutive 
days within 90 days prior to informed consent.

Administration of antineoplastic and immunomodulating agents or radiotherapy 
within 90 days prior to informed consent.

Immunoglobulins or any blood products within 180 days prior to informed consent.

Currently receiving anti-malarial medications (e.g. Mefloquine).

Any other vaccines within 28 days prior to the booster dose or planning to receive any 
vaccine within 28 days from the booster dose.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 55 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014

Any investigational or non-registered medicinal product within 14 days before booster 
dose till next Scheduled Clinic Visit after booster dose administration.
The use of antipyretics and/or analgesic medications within 24 hours prior to vaccination 
must be identified and the reason for their use (prophylaxis versus treatment) must be 
described in the source document and Concomitant Medications CRF. The use of 
antipyretics/analgesics within 24 hours prior to vaccine administration is a reason to delay 
study vaccination (see section 4.3, Criteria for Delay of Vaccination).
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present.
Concomitant medications include all medications (including vaccines) taken 
by/administered to subjects who experienced SAEs during the safety follow up period 
after administration of the rabies vaccine booster dose, and must be documented on the 
Concomitant Medications CRF.
When recording concomitant medications/vaccines, they should be checked against the 
study entry and continuation criteria in section 4.0, Selection of Study Population to 
ensure that the subject should be enrolled/continue in the study.
6.6 
Vaccine Supply, Labeling, Storage and Tracking
The Sponsor will ensure the following:

Supply the study vaccine.

Appropriate labeling of all study vaccines provided that complies with the legal 
requirements of each country where the study is to be performed.
The investigator must ensure the following:

Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including:
Confirmation that the vaccines were received in good condition
Confirmation to the Sponsor of the temperature range during shipment from the Sponsor 
to the investigator’s designated storage location

Proper storage of the study vaccines, including:
Storage in a secure, locked, temperature-controlled location.
Proper storage according to the instructions specified on the labels.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 56 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature.

Appropriate use of the study vaccines, including:
Use only in accordance with the approved protocol.
Proper handling, including confirmation that the vaccine has not expired prior to 
administration.
Appropriate documentation of administration of vaccines to study subjects including:
▪
Date, dosage, batch/lot numbers, expiration dates, unique identifying 
numbers assigned to subjects and study vaccines, and time of vaccine 
administration. This information will be maintained in an accountability log 
that will be reviewed by the site monitor.
▪
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were 
received, which vaccines were administered to subjects, which vaccines 
were destroyed locally, and which vaccines were returned to the Sponsor or
depot, as applicable.

Proper adherence to the local institutional policy with respect to destruction of study 
vaccines.

Complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of:
Copy of the site’s procedure for destruction of hazardous material.
Number of doses destroyed, date of destruction, destruction code (if available), method of 
destruction, and name of individual performing destruction.
In the event that the use cannot be authorized, the Sponsor will make every effort to 
replace the vaccine supply. All vaccines used in conjunction with this protocol must be 
stored separately from normal hospital/practice stocks to prevent unintentional use of 
study vaccines outside of the clinical study setting.
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the study.
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed either locally (upon approval from Sponsor) or returned to the 
Sponsor or depot, as applicable.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 57 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
7.0 
ASSESSMENTS (Amended 25 February 2019)
7.1 
Safety Assessment
The measures of safety used in this study are based on comparable routine clinical 
procedures. They include a close vigilance for, and stringent reporting of SAEs following 
booster vaccination.
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions.  
7.1.1 Solicited Adverse Events
No solicited local or systemic AEs or other solicited adverse events are intended to be 
collected in this study.
Solicited Local Adverse Events
No solicited local adverse events are intended to be collected in this study.
Solicited Systemic Adverse Events
No solicited systemic adverse events are intended to be collected in this study.
Other Solicited Adverse Events
There are no other solicited adverse events intended to be collected in this study.
7.1.2 Unsolicited Adverse Events
An unsolicited adverse event is an AE that was not solicited and that was spontaneously 
communicated by a subject or legal guardian who has signed the informed consent. In this 
study only SAEs and the associated concomitant medications following PCEC rabies
booster vaccinations will be collected, starting from the time the subject receives the 
booster dose until completion of safety follow up period, which is, the day of the next 
Scheduled Clinic Visit after booster vaccination or on the date of Early Termination 
Visit, whichever is earlier (see section 7.1.4, Serious Adverse Events and section 7.1.5,

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 58 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Methods for Recording Adverse Events and Serious Adverse Events), based on the 
subject’s interview during Clinic Visit. SAEs collected during physical exams at 
Scheduled and Ad hoc visits will be as well collected.
7.1.3 Evaluation of Adverse Events
During Scheduled Clinic Visit and Additional Clinic Visit, subjects will be observed for 
at least 15 minutes after the blood draw for any AE. Record any such observation in the 
subject’s source document only and not in the eCRF.
7.1.4 Serious Adverse Events
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following:

Death.

Is life-threatening (i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event 
which hypothetically might have caused death if it were more severe.

Required or prolonged hospitalization.

Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions).

Congenital anomaly/or birth defect.

An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above.
Adverse events which do not fall into these categories are defined as non-serious.
It should be noted that a serious adverse event need not, by definition, be severe.
In this study only SAEs and the associated concomitant medications following PCEC 
rabies booster vaccinations will be collected (see section 7.1.5, Methods for Recording 
Adverse Events and Serious Adverse Events).
The period of observation for SAEs extends from the time the subject receives the 
booster dose until completion of safety follow-up period (the day of the next Scheduled 
Clinic Visit after booster vaccination or on the date of Early Termination Visit, 
whichever is earlier).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 59 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
7.1.4.1 
Adverse Events of Special Interest
Adverse events of special interest (AESIs) are not assessed during the study.
7.1.5 Methods for Recording Adverse Events and Serious Adverse Events
All findings in subjects experiencing SAEs and any medication or other therapeutic 
measures used to treat the SAE in addition to the outcome of the SAE after PCEC 
rabies booster dose or collected during physical exams at Scheduled and Ad hoc visits, 
must be reported both on the VSAE Report Form which is part of the Investigator Site 
File and in the eCRF.
Investigator must report those events to his/her corresponding EC or applicable 
regulatory authorities in accordance with institutional policy/regulatory requirements 
and adequate documentation of this notification must be provided to the Sponsor.
During the course of the study, all SAEs which occur from the time of booster 
administration until completion of safety follow-up period (the day of the next 
Scheduled Clinic Visit after booster vaccination or on the date of Early Termination 
Visit, whichever is earlier), whether considered to be associated with the study 
vaccination or not, must be reported within 24 hours of the site becoming aware of the 
event to GSK or its designee. Specific instructions and contact details for collecting and 
reporting SAEs to GSK will be provided to the investigator.
After receipt of the initial report, representatives of GSK or its designee will contact the 
investigator if it is necessary to obtain further information for assessment of the event.
GSK or its designee must also comply with the applicable regulatory requirement(s)
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
known as SUSARs) to the regulatory authorities and the IRB/EC. If a SUSAR or other 
safety signal relating to use of one of the study vaccines is reported to GSK or its 
designee, the Sponsor will communicate the information to the investigator and the 
investigator will be responsible for submitting this information to the EC and other 
relevant authorities.
All SAEs will be evaluated by the investigator for relationship of the event to study 
vaccine. SAEs that are judged to be possibly or probably related to the study vaccine 
should be reported to the Sponsor as related/suspected events, irrespectively of time 
frame of SAEs reporting.
The relationship of the study vaccine to a SAE will be determined by the investigator
based on the following definitions:

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 60 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
1. Related/suspected
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the AE CRF page (see section 7.1.3, Evaluation of Adverse Events). 
2. Not Related
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship.
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current SmPC or an event that is by nature 
more specific or more severe than a listed event.
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the Medical History CRF.
If the onset of an event occurred before the subject entered the study (e.g., any pre-
planned hospitalization for conditions like cosmetic treatments or for non-emergency 
routine visits for a pre-existing condition), the hospitalization would not lead to an AE 
being classified as serious.
If the investigator judges that the hospitalization was prolonged as a result of the event
itself or was necessary due to a worsening of the pre-existing condition, the 
hospitalization would then be considered as a SAE.
Additionally, the investigator will evaluate whether the SAEs lead to withdrawal of 
subject from the study.
All SAEs will be monitored until resolution or until the investigator assesses them as 
chronic or stable. All subjects experiencing SAEs from the time the subject receives the 
booster dose until he or she completes the specified safety follow-up period (i.e. the day 
of next Scheduled Clinic Visit after booster vaccination or on the date of Early 
Termination Visit, whichever is earlier)  - whether considered associated with the use of 
the study vaccine or not - must be monitored until symptoms subside and any abnormal 
laboratory values have returned to baseline, or until there is a satisfactory explanation for 
the changes observed, or until death, in which case a full pathologist’s report should be 
supplied, if possible. The investigator’s assessment of ongoing SAEs at the time of each 
subject’s last visit should be documented in the subject’s source document.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 61 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
7.1.5.1 
Post-Study Events
Any SAE that occurs outside of the protocol-specified safety follow-up period (after 
Study Termination Visit or Early Termination Visit whichever is earlier) and the 
investigator considers to be caused by the study vaccine must be reported to GSK or its 
designee. 
7.1.6 Pregnancies
To ensure subjects’ safety, all pregnancies must be reported to GSK or delegate within 2 
weeks of site becoming aware of a pregnancy. If the subject agrees to submit this 
information, the pregnancy must be followed to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of 
any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
This follow-up should occur even if intended duration of safety follow-up for the study 
has ended.
Pregnancy data must be recorded on a Pregnancy Report CRF (initial report) and 
Pregnancy Follow-Up CRF (outcome report) and reported to GSK or delegate. 
Instructions and contact details for submitting the Pregnancy CRFs will be provided to the 
investigator.
Any pregnancy outcome meeting the definition of SAEs (see section 7.1.4, Serious 
Adverse Events) reported in subjects who received booster administration needs to be 
reported within 24 hours of the site becoming aware of the event to GSK or delegate 
using the VSAE Report Form and be recorded in the CRF(s).
The Pregnancy Form must also be updated for further internal processing.
Any pregnancy outcome meeting the definition of SAEs reported in subjects who have 
NOT received booster administration need to be reported within 24 hours of
the site becoming aware of the event to GSK or delegate using the VSAE Report Form, 
although such SAEs will not be a part of the Clinical database and do not need to be 
recorded in the CRF(s).
The Pregnancy Form must also be updated for further internal processing.
7.1.7 Safety Laboratory Measurements
This study has no safety laboratory measurements.
7.2 
Efficacy Assessment
This study has no efficacy measurements.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 62 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
7.3 
Immunogenicity Assessment
The measures of immunogenicity used in this study are standard, i.e., widely used and 
generally recognized as reliable, accurate, and relevant (able to describe the quality and 
extent of the immune response).

Protection against rabies is dependent on the presence of RVNA. WHO recommended 
method to measure RVNA serum concentrations is RFFIT. A neutralizing antibody 
titer of ≥0.5 IU/mL is regarded by the WHO as being an ‘adequate’ antibody response 
following rabies vaccination, and is used as a threshold in clinical trials.

Blood samples from all subjects at Scheduled Clinic Visits 1 through 8 (Year 3 
through Year 10), and, only from those subjects who received booster vaccination, 
also at Additional Clinic Visits 1.2 through 7.2, will be used for serology analysis. 
Refer to section 3.0, Study Design.

Testing will be conducted by a GSK or designated, qualified laboratory in a blinded 
manner towards the treatment arm. Refer to the Protocol Ancillary Document for 
names and details. 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 63 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
8.0 
STATISTICAL CONSIDERATIONS
8.1 
Endpoints
8.1.1 Primary Endpoint(s)
8.1.1.1 
Primary Safety Endpoint(s) (Amended 25 February 2019)
For subjects receiving PCEC rabies booster vaccination, SAEs and the associated 
concomitant medications will be collected starting from the time of booster administration 
until completion of safety follow-up period (the day of the next Scheduled Clinic Visit 
after booster vaccination or on the date of Early Termination Visit, whichever is 
earlier).
8.1.1.2 
Primary Efficacy Endpoint(s)
Not applicable. 
8.1.1.3 
Primary Immunogenicity Endpoint(s) (Amended 25 February 2019)

Time to first RVNA concentrations <0.5 IU/mL.  

Geometric Mean Antibody Concentrations (GMCs) and Geometric Mean ratio
(GMRs) for subjects receiving the booster dose, as measured by antibody 
concentration at 7 days after the booster dose vs. antibody concentration before the 
booster dose.

Percentages of subjects with RVNA concentrations ≥0.5 IU/mL, as measured by 
RFFIT assay at 7 days after the booster dose and at Year 3, 4, 5, 6, 7, 8, 9 and 10 
Scheduled Clinic Visits.
8.1.2 Secondary Endpoint(s)
8.1.2.1 
Secondary Safety Endpoint(s)
Not applicable.
8.1.2.2 
Secondary Efficacy Endpoint(s)
Not applicable. 
8.1.2.3 
Secondary Immunogenicity Endpoint(s) (Amended 25 February 2019)

GMCs at Year 3, 4, 5, 6, 7, 8, 9 and 10;

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 64 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014

Reverse Cumulative Distribution Plots (RCDPs) at Year 3, 4, 5, 6, 7, 8, 9 and 10;

Percentages of subjects with RVNA concentrations ≥0.5 IU/mL, as measured by 
RFFIT assay at Year 3, 4, 5, 6, 7, 8, 9 and 10.
8.1.3 Exploratory Endpoint(s)
8.1.3.1 
Exploratory Safety Endpoint(s)
Not applicable. 
8.1.3.2 
Exploratory Efficacy Endpoint(s)
Not applicable. 
8.1.3.3 
Exploratory Immunogenicity Endpoint(s)
Not applicable. 
8.2 
Success Criteria
8.2.1 Success Criteria for Primary Objective(s)
Not applicable. 
8.2.1.1 
Success Criteria for Primary Safety Objective(s)
Not applicable.
8.2.1.2 
Success Criteria for Primary Efficacy Objective(s)
Not applicable.
8.2.1.3 
Success Criteria for Primary Immunogenicity Objective(s)
Not applicable. 
8.2.2 Success Criteria for Secondary Objective(s)
8.2.2.1 
Success Criteria for Secondary Safety Objective(s)
Not applicable. 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 65 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
8.2.2.2 
Success Criteria for Secondary Efficacy Objective(s)
Not applicable. 
8.2.2.3 
Success Criteria for Secondary Immunogenicity Objective(s)
Not applicable.
8.3 
Analysis Sets
8.3.1 All Enrolled Set
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments.
8.3.2 All Exposed Set
All subjects in the enrolled set who receive a booster dose.
8.3.3 Safety Set
Safety Set
All subjects in the Exposed Set with unsolicited adverse event data.
Overall Safety Set
Not applicable.
8.3.4 Full Analysis Set (FAS) Immunogenicity Set
Full Analysis Set Immunogenicity
Time to first RVNA concentrations <0.5 IU/mL.  
All subjects in the All Enrolled Set who provide immunogenicity data until first time 
RVNA concentration is <0.5 IU/mL.
GMR for subjects receiving the booster dose, as measured by antibody concentration at 7 
days after the booster dose vs. antibody concentration before the booster dose.
All subjects in the All Enrolled Set who provide immunogenicity data after booster dose.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 66 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Percentages of subjects with RVNA concentrations ≥0.5 IU/mL, as measured by RFFIT 
assay at 7 days after the booster dose and at Year 3, 4, 5, 6, 7, 8, 9 and 10 Scheduled 
Clinic Visits.
All subjects in the All Enrolled Set who provide immunogenicity data after booster dose.
GMCs, percentages and RCDPs of subjects with RVNA concentrations ≥0.5 IU/mL, as 
measured by RFFIT assay at Year 3, 4, 5, 6, 7, 8, 9 and 10.
All subjects in the All Enrolled Set who provide immunogenicity data at relative time-
points. After having received the booster dose, subjects will not be included in these 
analyses any longer.
Further details on Full Analysis Immunogenicity sets are provided in the statistical 
analysis plan.  
8.3.5 Per Protocol (PP) Set Immunogenicity Set
All subjects in the FAS Immunogenicity who:

Correctly receive the booster dose (only for analysis of boostability).

Have no protocol deviations leading to exclusion (see section 8.3.8, Protocol 
Deviations) as defined prior to analysis.

Are not excluded due to other reasons defined prior to analysis (see section 8.3.8, 
Protocol Deviations)
Examples for subjects excluded due to other reasons than protocol deviations are:
Subjects who withdrew informed consent.
Analogously to FAS, inclusion of subjects in the PPS is defined by objective.
Further details on Per Protocol Immunogenicity sets are provided in the statistical 
analysis plan.  
8.3.6 Other Analysis Sets 
Not applicable.
8.3.7 Subgroups
Not applicable.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 67 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
8.3.8 Protocol Deviations
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. A protocol deviation may be a reason to remove data from 
an analysis set at the time of analysis. CSR-reportable protocol deviations will be defined 
as exclusionary from the analysis according to protocol objectives and endpoints, which 
will be specified in the statistical analysis plan. In some cases exclusion of data may be 
due to a reason other than a protocol deviation, e.g. early termination.
8.4 
Statistical Analysis Plan
8.4.1 Analysis of Demographic and Baseline Characteristics
Descriptive statistics (mean, standard deviation, median, minimum and maximum) for 
age, height and weight, body mass index (BMI) at enrolment will be calculated overall 
and by vaccine group.
Distributions of subjects by sex and ethnic origin will be summarized overall and by 
vaccine group.
8.4.2 Analysis of Primary Objective(s)
8.4.2.1 
Analysis of Primary Safety Objective
Number and percentages of SAEs will be summarized only for subjects receiving a 
booster dose by the vaccination regimen received in the parent study V49_23 and overall.
8.4.2.1.1 Analysis of Extent of Exposure
Not applicable.
8.4.2.1.2 Analysis of Solicited Local, Systemic and Other Adverse Events
Not applicable.
8.4.2.1.3 Analysis of Unsolicited Adverse Events (Amended 25 February 2019)
This analysis applies to all SAEs occurring during the study, judged either as probably 
related, possibly related, or not related to vaccination by the investigator, recorded in AE 
CRF, with a start date on or after the date of booster dose. SAE starting prior to booster 
dose will not be recorded. The original verbatim terms used by investigators to identify 
adverse events in the CRFs will be mapped to preferred terms using the MedDRA 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 68 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
dictionary. The serious adverse events will then be grouped by MedDRA preferred terms 
into frequency tables according to system organ class.
All reported serious adverse events, as well as serious adverse events judged by the 
investigator as at least possibly related to study vaccine, will be summarized according to 
system organ class and preferred term within system organ class. When a serious adverse 
event occurs more than once for a subject, the maximal severity and strongest relationship 
to the vaccine group will be counted.
Separate summaries will be produced for the following categories:

Serious adverse events.

Serious adverse events that are possibly or probably related to vaccine.

Serious Adverse event leading to withdrawal.

Deaths
Data listings of all serious adverse events will be provided by subject. In addition, serious 
adverse events in the categories above will be provided as listed data.
8.4.2.1.4 Analysis of Safety Laboratory Values
Not applicable.
8.4.2.2 
Analysis of Primary Efficacy Objective(s)
Not applicable.
8.4.2.2.1 Statistical Hypotheses
Not applicable.
8.4.2.2.2 Analysis Sets
Not applicable.
8.4.2.2.3 Statistical Methods
Not applicable.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 69 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
8.4.2.3 
Analysis of Primary Immunogenicity Objective(s)
8.4.2.3.1 Statistical Hypotheses
Not applicable.
8.4.2.3.2 Analysis Sets (Amended 25 February 2019)
All Enrolled Set.
FAS-1: Booster Immunogenicity Analysis Set.
Analyses on PPS will be conducted only if more than 10% of subjects have CSR-
reportable protocol deviations (by objective).
For analysis sets definition see section 8.3.
8.4.2.3.3 Statistical Methods (Amended 25 February 2019)
Time to first RVNA concentrations <0.5 IU/mL.
For each subject time to first RVNA concentrations <0.5 IU/mL will be calculated. 
Kaplan-Meier (KM) estimate of the survival function, along with 95% CIs, will be 
estimated and displayed per each vaccination regimen. Standard errors of the KM 
estimates will be based on the Greenwood’s method; 25th and 75th percentile and median 
survival will be provided if estimable.
In this setting, the event/failure will be represented by the administration of the booster 
dose. Subjects without event will be regarded as right-censored data. Dropouts will be 
considered as non-informative data and judged as Missing Completely At Random 
(MCAR) as an association between the missingness mechanism and the vaccine efficacy 
or safety is implausible. 
Group comparisons for first occurrences of a boost will be performed using the 
unadjusted Cox proportional hazard regression model (only treatment effect will be 
included). Ties will be handled with the exact method as it assumes that there is a true but 
unknown ordering for the tied event times. Hazard Ratios (HR) and 95% CIs will be 
computed. In case of not estimable HRs, alternative methods will be attempted.
It is expected that no or very few subjects will need more than one booster dose during 
the study conduct. Nevertheless, a contingency analysis will be performed counting the 
frequency of subjects who receive 0 booster, 1 booster, 2 boosters, 3 or more boosters.
If a relevant number of subjects will need more than one booster dose during the study 
conduct, the Andersen-Gill method will be used to analyze multiple events data. 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 70 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Geometric Mean Ratio (GMR).
RVNA GMCs will be based on the logarithmically transformed (base10) values.
For subjects receiving a booster dose, analysis of boostability will be conducted 7 days
and at also approximately 6 months after administration of the booster dose by providing 
GMRs and associated 95% CIs, considering the antibody value at the booster visit as 
baseline (denominator) and the antibody concentration at 7 days (and approximately at 6 
months) after booster as the numerator. 
Additionally, all boosted subjects will be pooled together and their RVNA concentrations 
analyzed using an ANOVA model that includes vaccine regimen group and time in study 
of the booster dose as factors in the model along with their interaction. For this analysis, 
values, as measured at day 7 (and also approximately at 6 months) after booster dose, will 
be used.
Percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL, as measured by RFFIT 
assay at 7 days after the booster dose and at subsequent scheduled clinical visit.
Percentages and 95% CIs will be presented by vaccine regimen.
8.4.3 Analysis of Secondary Objective(s)
Not applicable.
8.4.3.1 
Analysis of Secondary Safety Objective(s)
8.4.3.1.1 Analysis of Extent of Exposure
Not applicable.
8.4.3.1.2 Analysis of Solicited Local, Systemic and Other Adverse Events
Not applicable.
8.4.3.1.3 Analysis of Unsolicited Adverse Events
Not applicable.
8.4.3.1.4 Statistical Hypotheses
Not applicable.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 71 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
8.4.3.1.5 Analysis Sets
Not applicable.
8.4.3.1.6 Statistical Methods
Not applicable.
8.4.3.2 
Analysis of Secondary Efficacy Objective(s)
8.4.3.2.1 Statistical Hypotheses
Not applicable.
8.4.3.2.2 Analysis Sets
Not applicable.
8.4.3.2.3 Statistical Methods
Not applicable.
8.4.3.3 
Analysis of Secondary Immunogenicity Objective(s)
8.4.3.3.1 Statistical Hypotheses
Not applicable.
8.4.3.3.2 Analysis Sets
FAS-2: Long term Immunogenicity Analysis Set.
8.4.3.3.3 Statistical Methods
Geometric Mean Concentration (GMC).
RVNA GMCs will be based on the logarithmically transformed (base10) values.
GMCs with the associated 95% confidence intervals (CIs) will be computed for each 
vaccine group at Year 3, 4, 5, 6, 7, 8, 9 and 10 by taking the exponential of the 
corresponding log-transformed (least squares) means and 95% confidence intervals, from 
an ANOVA model with fixed factors for group and center. Group differences along with

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 72 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
95%CIs will also be computed. Subjects will be included in this analysis until they 
receive the booster dose and they will be excluded thereafter.
Reverse Cumulative Distribution Plots.
The reverse cumulative distribution plots will be provided at Year 3, 4, 5, 6, 7, 8, 9 and 10 
by treatment group.
Percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL.
As a form of supplementary information, also percentage of subjects with RVNA 
concentrations ≥0.5 IU/mL, as measured by RFFIT assay at Year 3, 4, 5, 6, 7, 8, 9 and 10
will be presented in a tabular fashion.
8.4.4 Analysis of Exploratory Objectives
Not applicable.
8.4.4.1 
Analysis of Exploratory Safety Objective(s)
Not applicable.
8.4.4.2 
Analysis of Exploratory Efficacy Objective(s)
Not applicable.
8.4.4.3 
Analysis of Exploratory Immunogenicity Objective(s)
Not applicable.
8.5 
Sample Size and Power Considerations of Primary Objectives
Not applicable.
8.6 
Interim Analyses
In order to understand complete evolution of the antibody decay over time and the effect 
of the booster dose, every year, an immunogenicity and safety analysis will be carried out 
and the results will be stored in the internal clinical data repository.
Two Clinical Study Reports (CSR) are planned: 

One interim CSR will be released after all subjects will complete Scheduled Clinic 
Visit 4 (i.e. Year 6). This CSR will include both immunogenicity and safety analyses 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 73 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
halfway through study. The interim CSR might be submitted to the Health Authority 
in case results support indication for the booster dose at a given time after the primary 
regimen.

The final CSR will be released at the completion of the study and will include all 
study data from Visit 1 (Year 3) to Visit 8 (Year 10).
For the interim and final CSR a full database lock will be required. For the other yearly 
analyses, a protected snapshot will be performed.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 74 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
9.0 
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING
In order to ensure consistency across sites, study monitoring and auditing will be 
standardized and performed in accordance with the Sponsor’s or delegated contract 
research organization’s (CRO) standard operating procedures and applicable regulatory 
requirements (e.g., FDA, EMA, and ICH guidelines).
Prior to enrolment of the first study subject, GSK or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. CRFs supplied by the Sponsor must 
be completed for each enrolled subject (see section 8.3.1, All Enrolled Set for definition 
of enrolled subject). Documentation of screened but not enrolled subjects must be 
maintained at the site and made available for review by the site monitor. Data and 
documents will be checked by the Sponsor and/or monitor.
9.1 
Source Documentation
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The kinds 
of documents that will serve as source documents will be agreed between Sponsor or 
delegate and investigator and designees and specified in the Source Data Agreement prior 
to subject enrolment.
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, dates of 
visits, adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, documentation of prior/concomitant medication/vaccines, study vaccine 
receipt/dispensing/return records, study vaccine administration information, any data 
collected by a telephone conversation with the subject or legal guardian and date of 
completion and reason.
The subject or legal guardian must also allow access to the subject’s medical records. 
Each subject or legal guardian must be informed of this prior to the start of the study and 
consent for access to medical records may be required in accordance with local 
regulations.
All safety data reported by subjects must be written down in source documents prior to 
entry of the data into CRFs. If there are multiple sources of information (e.g., verbal 
report of the subject, telephone contact details, medical chart) supporting the diagnosis of 
an adverse event, these sources must be identified in the source documents, discrepancies 
between sources clarified, the ultimate diagnosis must be justified and written in the 
source documents, and this diagnosis must be captured in the Adverse Event CRF (AE 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 75 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
CRF). The AE CRF must also capture which source(s) of information were used to 
determine the adverse event (e.g., subject recall, medical chart).
9.2 
Study Monitoring, Auditing and Source Data Verification
Prior to enrolment of the first study subject, GSK or its designee (e.g., a CRO) will 
develop a Clinical Monitoring Plan to specify how centralized and/or on-site monitoring, 
including clinical specimens reconciliation, will be performed for the study. Study 
progress will be monitored by GSK or its designee as frequently as necessary to ensure:

that the rights and well-being of human subjects are protected,

the reported study data are accurate, complete, and verifiable from the source 
documents and

the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements.
Contact details for the GSK team or its designee involved in study monitoring will be 
provided to the investigator. Study data recorded on CRFs will be verified by checking 
the CRF entries against source documents in order to ensure data completeness and 
accuracy as required by study protocol 
Data verification may also be performed through a centralized review of data (e.g., 
checking for outliers or other anomalies). Additional documents such as the investigator 
site file, pharmacy records, and informed consent documentation must also be available 
for review if requested. Arrangements for monitoring visits will be made in advance in 
accordance with the monitoring plan, except in case of emergency.
The investigator and/or site staff must make source documents of subjects enrolled in this 
study available for inspection by GSK or its representative at the time of each monitoring 
visit and Sponsor audits, when applicable. These documents must also be available for 
inspection, verification and copying, as required by regulations, by officials of the 
regulatory health authorities (e.g., FDA, European Medicines Agency and others) and/or 
ECs/IRBs. The investigator and study site staff must comply with applicable privacy, data 
protection and medical confidentiality laws for use and disclosure of information related 
to the study and enrolled subjects.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 76 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
10.0 
DATA MANAGEMENT
10.1 
Data Entry and Management (Amended 25 February 2019)
In this study, all clinical data (including, but not limited to, SAEs, concomitant 
medications, medical history, and physical assessments), and immunogenicity data will be 
entered onto CRFs in a timely fashion by the investigator and/or the investigator’s 
dedicated site staff. Data entered onto CRFs are stored on a secure website. The data 
collected on this secure website are assimilated into an EDC system, which is compliant 
with Title 21 Part 11 policies of the Code of Federal Regulations (FDA 1997). The data 
system includes password protection and internal quality checks. The EDC system will be 
designed and validated by the Sponsor prior to activation for data entry by sites. The 
investigator or designated delegate must review data entered and electronically sign the 
CRFs to verify their accuracy.
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have exclusively “read 
only” access.
10.2 
Data Clarification
As part of the conduct of the trial, the Sponsor may have questions about the data entered 
by the site, referred to as queries. The monitors and the Sponsor are the only parties that 
can generate a query. All corrections and clarifications will be entered into the EDC 
system and will be identified by the person entering the information, the reason for the 
change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed CRF, the investigator must confirm and endorse the changes.
10.3 
Data Protection
GSK respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations.
The Sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data (95/46/EC) confirms herewith compliance to Directive 95/46/EC in all stages of 
Data Management.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 77 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
11.0 
RECORD RETENTION
Investigators must retain all study records required by GSK and by the applicable 
regulations in a secure and safe facility. The investigator must consult a GSK 
representative before disposal of any study records, and must notify the Sponsor of any 
change in the location, disposition, or custody of the study files. Essential documents 
must be retained for 15 years. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a study and the quality 
of the data produced. These documents should be retained for a longer period, however, if 
required by the applicable national regulatory or institutional requirements. 
These principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 78 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
12.0 
USE OF INFORMATION AND PUBLICATION
GSK assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations.
GSK also assures that key results of this clinical study will be posted in a publicly 
accessible database within the required time-frame from the end of study as defined in 
section 3.9, End of Study.
In accordance with standard editorial, ethical practices and current guidelines of Good 
Publication Practice (Graf 2009), GSK will generally support publication of multicenter 
studies only in their entirety and not as individual center data. In this case, a coordinating 
investigator will be designated by mutual agreement prior to the start of the study. The 
coordinating investigator will also sign the clinical study report on behalf of the principal 
investigators (CPMP/EWP/2747/00). Authorship will be determined by mutual agreement 
and in line with International Committee of Medical Journal Editors authorship 
requirements. Any formal publication of the study in which contribution of GSK 
personnel exceeded that of conventional monitoring will be considered as a joint 
publication by the investigator and the appropriate GSK personnel.
GSK must be notified of any intent to publish data collected from the study and prior 
approval from GSK must be obtained prior to submission for publication.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 79 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
13.0 
ETHICAL CONSIDERATIONS
13.1 
Regulatory and Ethical Compliance
The study will be conducted in compliance with the protocol, GCP and applicable 
regulatory requirement(s).
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations: including European Directive 2001/20/EC, US Code of 
Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare, GSK
codes on protection of human rights, and with the ethical principles laid down in the 
Declaration of Helsinki (European Council 2001, US Code of Federal Regulations, ICH 
1997).
13.2 
Informed Consent Procedures
Eligible subjects may only be included in the study after providing written informed 
consent, as described in section 5.1.1, Informed Consent. Before the start of the study, the 
investigator will have the informed consent and any other materials that will be provided 
to the subjects reviewed and approved by the IRB/EC. This review and approval will be 
documented and stored with other study documents. The investigator or designee must 
fully inform the subject of all pertinent aspects of the study. A copy of the written 
informed consent will be given to the subject or the designee. The subject/designee must 
be allowed ample time to ask about the details of the study and to make a decision as to 
whether or not to participate in the study. The subject must sign the consent form 
indicating their agreement to participate in the study before any study-related procedures 
are conducted. The informed consent process may be conducted prior to any study related 
procedure on Day 1. If the subject is unable to read and write, a witness must be present 
during the informed consent discussion and at the time of informed consent signature.
Prior to the start of the study, GSK will provide to investigators a proposed informed 
consent form that complies with the ICH GCP guideline and regulatory requirements and 
is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by GSK before submission to the IRB/EC 
and a copy of the approved version must be provided to the GSK monitor after IRB/EC 
approval.
Women of childbearing potential should be informed that taking the study medication 
may involve unknown risks to the fetus if pregnancy were to occur during the study and 
agree that in order to participate in the study they must adhere to the contraception 
requirements indicated in the protocol for at least 6 months after the booster vaccination. 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 80 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
If case of doubts on the ability of a subject to adhere to these requirements, that subject 
should not be allowed in the study
13.3 
Responsibilities of the Investigator and IRB/EC
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined 
in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH 1997). A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/EC must be given to GSK before study initiation. Prior to study start and at any time 
the protocol is amended during study conduct, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol and 
to give access to all relevant data and records to GSK monitors, auditors, GSK Clinical 
Quality Assurance representatives, designated agents of  GSK, IRBs/ECs, and regulatory 
authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform GSK immediately that this request has been made.
The investigator also responsible for the following:

Maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties.

Demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period.

Demonstrating sufficient time and staffing to properly conduct and complete the study 
within the agreed study period.

Ensuring that all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions

Ensuring that appropriately trained health care professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any adverse event related to the study.

If permission to do so is given by the subject, ensuring that the subject’s primary 
healthcare provider is informed of the subject’s participation in the study.
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favourable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor(s), change of telephone 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 81 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol.
The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/IEC 
approval/favourable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted:
(a) to the IRB/IEC for review and approval/favourable opinion,
(b) to the Sponsor for agreement and, if required,
(c) to the regulatory authority(ies).
13.4 
Protocol Amendments
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or 
clarification that has no significant impact on the way the clinical study is to be conducted 
and no effect on subject safety (e.g., change of telephone number(s), logistical changes). 
Protocol amendments must be approved by GSK, health authorities where required, and 
the IRB/EC. In cases when the amendment is required in order to protect the subject 
safety, the amendment can be implemented prior to IRB/EC approval. Notwithstanding, 
the need for formal approval of a protocol amendment, the investigator is expected to take 
any immediate action required for the safety of any subject included in this study, even if 
this action represents a deviation from the protocol. In such cases, GSK should be notified 
of this action, the IRB/EC at the study site, and, if required by local regulations, the 
relevant health authority should be informed within 10 working days.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 82 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
14.0 
REFERENCE LIST
Code of Federal Regulations (1997): Food and Drug Administration, U.S. Department of 
Health and Human Services: Title 21, Part 11: Electronic Records Electronic Signatures. 
Federal Register 62: 13464
European Parliament (1995): Directive 95/46/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 281/31-39
European Parliament (2001): Directive 2001/20/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 121/34-44
Graf C, Battisti WP, Bridges D (2009). Good publication practice for communicating 
company Sponsored medical research: the GPP2 guidelines. BMJ; 339: b4330
ICH (1997) ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices E6 
(R1). Federal Register, 62 (90): 25691-25709
ICH (1998) ICH Harmonised Tripartite ICH Guideline for Statistical Principles for 
Clinical Trials E9. Federal Register, 63 (179): 49583
U.S. Department of Health and Human Services, Food and Drug Administration, CBER 
(2009): Guidance for Industry Patient-Reported Outcome Measures: Use in Medical 
Product Development to Support Labeling Claims
59th World Medical Association General Assembly (October 2008) Declaration of 
Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Seoul, 
Korea
World Health Organization. (2013) WHO Expert Consultation on Rabies.  Technical 
Report Series. Second Report.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 83 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
GlaxoSmithKline Biologicals
Vaccine Value & Health Science (VVHS)
Protocol Amendment 2
eTrack study number 
and Abbreviated Title
205214 [RABIES (V49)-018 BST 017 - V49_23E1]
Amendment number:
Amendment 2
Amendment date:
25 February 2019
Co-ordinating author:
 Scientific Writer
Rationale/background for changes: 

Clarification of the timeframe between each yearly Scheduled Visit: Visit 1 date 
has to be used as reference for calculating next visit date (e.g. Visit 1: 31 JAN 15, 
then Visit 2: 31 JAN 16 ± 28 days, Visit 3: 31 JAN 17 ± 28 days) (Table 2a).

Clarification of the time window between the Scheduled Clinic Visit and the Ad 
hoc Visit: the previous wording was not clear enough, team agreed to precise that 
booster administration at the Ad hoc Visit should happen between 6 to 9 months 
after the Scheduled Clinic Visit (Table 2b).

Clarification that physical exams have to be done by practitioners in accordance 
with their institutional policy (Table 2a and 2b, Section 5.1.2 Screening). It has 
been specified that collection of vital signs must be done during all Ad hoc Visits 
prior booster administration. During the other visits (Scheduled and Additional), 
they could be measured at the discretion of the investigator (Section 5.1.2 
Screening).

Clarification on the number of additional booster doses a subject may receive: if, 
after a first booster dose, the adequate RVNA level is not reached at two 
consecutive determinations, a subject may receive an additional booster. If he/she 
is still a non-responder, the investigator should manage at its discretion. (Synopsis; 
Section 3.1 Overview of Study Design; Section 5.2 Ad hoc Clinic Visits; Section 6.3 
Vaccine Preparation and Administration).

Clarification on premature withdrawal from the study: there was no mention on the
PPD

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 84 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
procedure to follow in case a subject misses the Ad hoc Visit and the possible 
booster dose. This has been added to the relevant section, specifying that in this 
case the subject could come to the next following Scheduled Visit and having a 
blood draw according to protocol. In case RVNA concentrations <0.5 IU/mL, a 
booster may be given. (Section 3.8 Premature Withdrawal from Study).

Clarification on Exclusion Criteria: prior to Scheduled Visit criteria have been 
added, as they were not previously detailed (only criteria prior to study entry and 
booster vaccination were stated). 
Some clarification to the criteria to be checked prior the Ad hoc Visit has been 
added: if a subject received corticosteroids, antineoplastic and immunomodulating 
agents or radiotherapy within 90 days prior the Ad hoc Visit (and not prior to 
informed consent as previously stated) or receipt or planning to receive them 
during the participation to the study, they have to be withdrawn. Subjects should be 
excluded if they received any non-study rabies vaccine (Section 4.2 Exclusion 
Criteria).

Clarification on assignment of the Subject ID: this is a unique ID number and is the 
same as the one attributed during the parental study V49_23 (Section 5.1.2 
Screening). It has been specified that since current year, 2019, a centralized 
Randomization System on internet (SBIR) has been implemented for treatment 
allocation. The study staff need to access the system and to enter the subject 
identification number for obtaining a treatment number for each subject (footnote e 
in Table 2b; Section 5.1.4 Randomization; Section 6.3 Vaccine Preparation and 
Administration).

Update the name of the document used for identification of the health care 
practitioners to Study Staff Delegation of Responsibilities (SS DoR) (Section 
5.1.2 Screening).

Global rewording of Section 7 Assessment for simplification and clarification 
of the text.

To clarify that ONLY SAEs (and the associated concomitant medications) 
experienced by subjects who received the rabies booster and those collected during 
Physical examinations must be reported period (Tables 2a and 2b; Section 3.4.1 
Data Collected from Subjects; Section 7.1.4 Serious Adverse Events).
Clarification of period of collection: for those subjects, SAEs and the associated 
concomitant medications will be collected starting from the time of booster 
administration until the completion of safety follow-up period (Study design and 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 85 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Safety Endpoint in Synopsis; footnote b in Table 2a; Section 3.1 Overview of 
Study Design; Section 7 Assessment; Section 7.1.4 Serious Adverse Events;
Section 8.1.1.1 Primary Safety Endpoints; Section 5.3.1 Follow-up Clinic 
Visit). Safety follow-up period is defined as the day of the next Scheduled 
Clinic Visit after booster vaccination or the date of Early Termination Visit, 
whichever is earlier.

To clarify the procedures for reporting AEs:
- SAEs (and any medication or other therapeutic measures used to treat the AE) 
will be recorded in the eCRF as well as in the VSAE form.
- Any AEs (e.g. after blood draw) will be recorded ONLY in the source documents 
(Section 3.4.2 Tools Used for Data Collection; Section 7.1.5 Methods for 
Recording Adverse Events and Serious Adverse Events).

Rewording of the paragraph related to the recording of pre-existing event or 
condition that results in hospitalization for clarification purpose (Section 
7.1.5 Methods for Recording Adverse Events and Serious Adverse Events).

Clarification for post-study events collection: all SAEs that occur outside the 
protocol-specified safety follow-up period and that the investigator considers 
to be caused by the study vaccine must be reported to GSK or its designee 
(Section 7.1.5.1 Post-Study Events).

Specification on vaccine preparation and administration: vaccine has to be 
administered intramuscularly in the deltoid area of the non-dominant arm. 
Alternatively, it can be administered in the deltoid area of the dominant arm
if subjects experience local AEs on primary vaccination site (Section 6.3 
Vaccine Preparation and Administration).

Clarification on vaccine tracking at the conclusion of the study: all unused 
supply vaccine and supplementary labels are destroyed either locally (upon 
approval from Sponsor) or returned to the Sponsor or depot, as applicable 
(Section 3.8 Premature Withdrawal from Study - Administrative reason; 
Section 6.6 Vaccine Supply, Labeling, Storage and Tracking). Authorization 
for use (AFU) wording has been removed throughout the protocol as it is no 
longer used (Section 6.6 Vaccine Supply, Labeling, Storage and Tracking).

To clarify the reporting of pregnancies: 
- Any pregnancy outcome meeting the definition of a SAE reported in 
subjects who received booster administration needs to be reported within 24 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 86 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
hours of the site becoming aware of the event to GSK or delegate using the
VSAE Report Form and be recorded in the CRF(s). The Pregnancy Form 
must also be updated for further internal processing.
- Any pregnancy outcome meeting the definition of SAEs reported in subjects who
have NOT received booster administration need to be reported within 24 hours of
the site becoming aware of the event to GSK or delegate using the VSAE Report 
Form, although such SAEs will not be a part of the Clinical database and do not 
need to be recorded in the CRF(s). The Pregnancy Form must also be updated for 
further internal processing. (Section 7.1.6 Pregnancies).

To correct some typographical errors.

To update the List of Abbreviations and acronyms throughout the text.
Amended text has been included in bold italics and deleted text in strikethrough in the 
following sections:
SYNOPSIS 
Study design and Safety Endpoint
For subjects receiving PCEC rabies booster vaccination, Serious Adverse Events (SAEs) 
and the associated concomitant medications will be collected starting from the time of 
booster administration and until the day of next Scheduled Clinic Visit completion of 
safety follow-up period (the day of the next Scheduled Clinic Visit after booster 
vaccination or on the date of Early Termination Visit, whichever is earlier).
Study Population and Subject Characteristics
Inclusion criteria: Subjects who signed the informed consent prior to the study entry,
Ad hoc Clinic Visits
The booster dose will be given in an “Ad hoc Clinic Visit” which is planned to occur as 
soon as the results of the antibody assay will be available and within approximately 6 to 9
months from the blood draw taken during a previous “Scheduled Clinic Visit”.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 87 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Additional Clinic Visit
If, after having received a booster dose, the subject does not reach the adequate antibody 
concentration (i.e., RVNA   ≥0.5IU/mL) at two consecutive determinations, neither at 7 
days after the booster dose (i.e. Additional Clinic Visit) nor at the next yearly evaluation 
(i.e., Scheduled Clinic Visit), an additional booster dose may be administered at the 
following Ad hoc Clinic Visit. If the subject is still non-responder, subsequent 
management should be at the discretion of the investigator.
Should a subject have RVNA concentrations below 0.5 IU/mL at blood draw performed 
at the final Scheduled Clinic Visit (Year 10), the subject will be invited the investigator
will invite the subject to receive a booster dose of the rabies vaccine outside the study 
following standard clinical practice and there will be no further analyses performed on 
this additional vaccination.
Statistical Analyses
For subjects receiving a booster dose, analysis of boostability will be conducted 7 days
(and also approximately 6 to 9 months) after administration of the booster dose by 
providing GMRs and associated 95% CIs, considering the antibody value at the booster 
visit as baseline (denominator) and the antibody concentration at 7 days (and also 
approximately at between 6 to 9 months) after booster as the numerator.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 88 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
TABLE 2a Scheduled Clinic Visits: For All Subjects 
Visit Type
Scheduled Clinic Visit
Final 
Scheduled 
Clinic Visit
Study Period
Day 1   Year 3
Year 4
Year 5
Year 6
Year 7
Year 8
Year 9
Year 10
Visit Window (Days)*
n/a
-28 to +28
-28 to +28
-28 to +28
-28 to +28
-28 to +28
-28 to +28
-28 to +28
Visit Number
1
2
3
4
5
6
7
8
Study Event
References
Screening and Safety
Informed Consent a
Section 5.1.1
X
Medical History
Section 5.1.2
X
X
X
X
X
X
X
X
Physical Examd
Section 5.1.2 
X
X
X
X
X
X
X
X
Exclusion/Inclusion Criteria
Section 4.0
X
X
X
X
X
X
X
X
Prior and Concomitant 
Medications
Sections 5.1.2 and
6.5
X
Assess SAEs and Relevant 
Concomitant Medications b
Sections 7.1.4, 5.1.2 
and 6.5
X
X
X
X
X
X
X
Observe for at Least 15 Minutes 
Post Blood Draw and Assess AEs 
(if any)
Section 7.1.3
X
X
X
X
X
X
X
X
Immunogenicity
Serology Blood Draw
Section 3.5
X
X
X
X
X
X
X
X
Study Completion Procedures
Study Termination c
Section 5.5
X

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 89 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
a Confirm consent form signed prior to any procedures.
b SAEs and the associated concomitant medications will be collected ONLY from those subjects who will receive booster vaccine during last the Ad hoc Clinic 
Visit, SAEs and the associated concomitant medications will be collected starting from the booster administration and until the day of next Scheduled Clinic 
Visit. starting from the time of booster administration until completion of safety follow-up period (the day of the next Scheduled Clinic Visit after booster 
vaccination or on the date of Early Termination Visit, whichever is earlier).
c Subjects who terminate the study early are recommended to complete certain study-related procedures. See section 5.5 for further details.
d Physical exams have to be done by practitioners in accordance with their institutional policy. Should the physical assessment reveal any abnormal values or 
events, which fall under definition of SAE, these must be documented in the CRF Adverse Events Form and reported to sponsor.
*Visit 1 date to be used as reference for calculating next visit date (e.g. V1: 31 JAN 15, V2: 31 JAN 16 ± 28 days, V3: 31 JAN 17 ± 28 days).
TABLE 2b Ad hoc and Additional Clinic Visit
Visit Type
Clinic Visit
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Study Period
Year 3, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 1
Year 3, 
7 days 
after Ad 
hoc Clinic 
Visit 1.1
Year 4,  
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 2
Year 4,
7 days 
after Ad 
hoc Clinic 
Visit 2.1
Year 5, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 3
Year 5, 
7 days 
after Ad 
hoc Clinic 
Visit 3.1
Year 6, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 4
Year 6, 
7 days 
after Ad 
hoc Clinic 
Visit 4.1
Year 7, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 5
Year 7, 
7 days 
after Ad 
hoc Clinic 
Visit 5.1
Year 8, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 6
Year 8, 
7 days 
after Ad 
hoc Clinic 
Visit 6.1
Year 9, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 7
Year 9, 
7 days 
after Ad 
hoc Clinic 
Visit 7.1
Visit Window (Days)
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
Visit Number
1.1
1.2
2.1
2.2
3.1
3.2
4.1
4.2
5.1
5.2
6.1
6.2
7.1
7.2
Study Event
References
Medical 
History c
Section 
5.1.2
X
X
X
X
X
X
X

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 90 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Visit Type
Clinic Visit
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Study Period
Year 3, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 1
Year 3, 
7 days 
after Ad 
hoc Clinic 
Visit 1.1
Year 4,  
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 2
Year 4,
7 days 
after Ad 
hoc Clinic 
Visit 2.1
Year 5, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 3
Year 5, 
7 days 
after Ad 
hoc Clinic 
Visit 3.1
Year 6, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 4
Year 6, 
7 days 
after Ad 
hoc Clinic 
Visit 4.1
Year 7, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 5
Year 7, 
7 days 
after Ad 
hoc Clinic 
Visit 5.1
Year 8, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 6
Year 8, 
7 days 
after Ad 
hoc Clinic 
Visit 6.1
Year 9, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 7
Year 9, 
7 days 
after Ad 
hoc Clinic 
Visit 7.1
Visit Window (Days)
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
Visit Number
1.1
1.2
2.1
2.2
3.1
3.2
4.1
4.2
5.1
5.2
6.1
6.2
7.1
7.2
Study Event
References
Physical Examc
Sections 
5.1.2 and
5.2
X
X
X
X
X
X
X
Pregnancy 
Testc, d
Sections 
3.5 and 
5.1.2
X
X
X
X
X
X
X
Verification of 
Relevant 
Exclusion/Inclu
sion Criteriac
Section 4.0
X
X
X
X
X
X
X
Vaccinatione
Section 5.2
X
X
X
X
X
X
X
30 Minutes 
Post Booster 
Injection 
Assessment
Section 
5.2.1
X
X
X
X
X
X
X

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 91 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Visit Type
Clinic Visit
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Study Period
Year 3, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 1
Year 3, 
7 days 
after Ad 
hoc Clinic 
Visit 1.1
Year 4,  
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 2
Year 4,
7 days 
after Ad 
hoc Clinic 
Visit 2.1
Year 5, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 3
Year 5, 
7 days 
after Ad 
hoc Clinic 
Visit 3.1
Year 6, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 4
Year 6, 
7 days 
after Ad 
hoc Clinic 
Visit 4.1
Year 7, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 5
Year 7, 
7 days 
after Ad 
hoc Clinic 
Visit 5.1
Year 8, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 6
Year 8, 
7 days 
after Ad 
hoc Clinic 
Visit 6.1
Year 9, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 7
Year 9, 
7 days 
after Ad 
hoc Clinic 
Visit 7.1
Visit Window (Days)
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
Visit Number
1.1
1.2
2.1
2.2
3.1
3.2
4.1
4.2
5.1
5.2
6.1
6.2
7.1
7.2
Study Event
References
Assess SAEs 
and Relevant 
Concomitant 
Medications f
Sections 
7.1.4, 5.1.2
and 6.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity
Serology Blood 
Draw
Section 3.5
X
X
X
X
X
X
X
Observe for at 
Least15 
Minutes Post 
Blood Draw 
and Assess AEs 
(if any)
Section 
7.1.3
X
X
X
X
X
X
X

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 92 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Visit Type
Clinic Visit
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Ad hoca
Addi-
tionalb
Study Period
Year 3, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 1
Year 3, 
7 days 
after Ad 
hoc Clinic 
Visit 1.1
Year 4,  
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 2
Year 4,
7 days 
after Ad 
hoc Clinic 
Visit 2.1
Year 5, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 3
Year 5, 
7 days 
after Ad 
hoc Clinic 
Visit 3.1
Year 6, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 4
Year 6, 
7 days 
after Ad 
hoc Clinic 
Visit 4.1
Year 7, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 5
Year 7, 
7 days 
after Ad 
hoc Clinic 
Visit 5.1
Year 8, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 6
Year 8, 
7 days 
after Ad 
hoc Clinic 
Visit 6.1
Year 9, 
approx.
between
6 to 9
months 
after 
Schedule
d Clinic 
Visit 7
Year 9, 
7 days 
after Ad 
hoc Clinic 
Visit 7.1
Visit Window (Days)
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
n/a
-1 to +1
Visit Number
1.1
1.2
2.1
2.2
3.1
3.2
4.1
4.2
5.1
5.2
6.1
6.2
7.1
7.2
Study Event
References
e Ad hoc Clinic Visit (which is planned to occur as soon as the results of the antibody assay will be available and within approximately 6 months from the blood 
draw taken during a previous “Scheduled Clinic Visit”) is only applicable for those subjects with RVNA concentrations <0.5 IU/mL during this extension 
study. See sections 3.1 and 3.9 for further details.  
f Additional Clinic Visit (within approximately 7 days from Ad hoc Clinic Visit) only applicable for subjects who will receive a booster dose of PCEC rabies 
vaccine during Ad hoc Clinic Visit. 
g Procedure to be performed prior to vaccination. Physical exams have to be done by practitioners in accordance with their institutional policy. Should the 
physical assessment reveal any abnormal values or events, which fall under definition of SAE, these must be documented in the CRF Adverse Events Form 
and reported to sponsor.
h Only for female subject of childbearing potential who are eligible to receive the booster dose. 
i GSK Biologicals’ Randomization System on Internet (SBIR) will be used for Treatment allocation.
j SAEs and the associated concomitant medications will be collected starting from the booster administration and until the day of next Scheduled Clinic Visit.
completion of safety follow-up period (the day of the next Scheduled Clinic Visit after booster vaccination or on the date of Early Termination Visit, 
whichever is earlier).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 93 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
LIST OF ABBREVIATIONS
AE
Adverse Eevent
eCRF
electronic Case Report Form
HR
Hazard Ratios
ICH
International Conference on for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
KM
Kaplan-Meier 
mg
Milligram
SBIR
Source DataBase for Internet Randomization
SmPC
Summary of Product Characteristics
1.0
BACKGROUND AND RATIONALE 
1.1
Background 
The incubation period in humans is usually several weeks to months, but ranges from <1 
week to >1 year (World Health Organization [WHO] 2013). 
More than 60,000 people die of rabies every year and 95% of these deaths occur in Asia 
and Africa (World Health Organization [WHO] 2013).
Pre-exposure prophylaxis is recommended for anyone who is at continual, frequent or 
increased risk for exposure to the rabies virus, as a result of their her/his residence or 
occupation, including travelers in high-risk areas (WHO 2013).
Protection against rabies is dependent on the presence of rRabies vVirus nNeutralizing 
aAntibodies (RVNA).
Rabipur® is a pPurified cChick-eEmbryo cCell cCulture (PCEC) rabies vaccine indicated 
for active immunization against rabies in individuals of all ages.
Although in clinical trials persistence of adequate antibody concentrations for 2 years 
after immunisation with Rabipur® without additional booster has been observed in 100% 
of subjects, and experience shows that Rabipur® booster doses are generally required 
every 2-5 years following the conventional PrEP regimen, as recommended by WHO and 
following current Rabipur® SmPC Summary of Product Characteristics (SmPC),

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 94 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
3.0 
STUDY DESIGN
3.1 
Overview of Study Design
Subjects who were randomized into one of the 3 rabies vaccination group regimens,
All sites will be trained in a uniform fashion and thatose sites will be monitored to ensure 
consistency in study execution across all centers. 
Vaccination procedures:
If, after having received a booster dose, the subject does not reach the adequate antibody 
concentration of 0.5 IU/mL at two consecutive determinations, neither at 7 days after the 
booster dose (i.e. Additional Clinic Visit) nor at the next yearly evaluation (i.e. Scheduled 
Clinic Visit), an additional booster dose may be administered at the following Ad hoc
Clinic Visit. If the subject is still non-responder, subsequent management should be at 
the discretion of the investigator.
Should a subject have RVNA concentrations below 0.5 IU/mL at blood draw performed 
at the final Scheduled Clinic Visit (Year 10), the subject will be invited investigator will 
invite the subject to receive a booster dose of the rabies vaccine outside the study 
following standard clinical practice and there will be no further analyses performed on 
this additional vaccination.
Post-vaccination evaluations:

Starting from the time of booster administration and until the day of next Scheduled
Clinic Visit: completion of safety follow-up period (the day of the next Scheduled 
Clinic Visit after booster vaccination or on the date of Early Termination Visit, 
whichever is earlier) SAEs and the associated concomitant medications will be 
recorded by interviewing the subject during next cClinic vVisit and based on the 
subject’s medical records.
(e.g. booster administration at the Ad hoc Clinic Visit 1.1 for subjects with RVNA 
concentrations <0.5 IU/mL at the Scheduled Clinic Visit 1).  
3.4.1   Data Collected from Subjects
The following data will be collected from each subject over the duration of their study 
participation:

Demographic Information.

Medical History.

Concomitant Medications (only when associated to a SAE).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 95 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
3.4.2    Tools Used for Data Collection
Data will be recorded in the subject’s source record and collected on electronic Case 
Report Forms (eCRFs).
Any safety information either within 30 minutes of post vaccination and/or up to the day 
of next Scheduled Clinic Visit and which can be considered an AE must be recorded in 
subject’s source document and it must be described as a verbally reported adverse event.
Any AE that occurs during the specified safety collection period which fulfils any of the 
seriousness criteria mentioned in section 7.1.4 must be reported to the sponsor via the 
Vaccines Serious Adverse Event (VSAE) Form which is part of the Investigator Site 
File and therefore entered on the Adverse Event CRF.
Any adverse event that is considered to be caused by the study vaccine and occurs 
outside the protocol-specified follow-up period should be reported to the sponsor 
(section 7.1.5.1, Post-study events).
3.8 
Premature Withdrawal from Study 
Lost to Follow-Up: For subjects who fail to show up for final Scheduled cClinic vVisit, 
or for three consecutive Scheduled Clinic Visits, study staff are encouraged to make at 
least three documented attempts to contact the subject by telephone and at least one 
documented written attempt to contact the subject or legal guardian to encourage the 
completion of study termination procedures. In case an Ad hoc Visit is missed, the 
subject could come to the next following Scheduled Visit and having a blood draw 
according to protocol. In case RVNA concentrations <0.5 IU/mL, a booster may be 
given according to protocol.
Administrative Reason: If the clinical study is prematurely terminated by the Sponsor, 
the investigator is to promptly inform the study subjects and local EC/IRB IRB/EC
(Institutional Review Board/ Ethic Committee) and should assure appropriate therapy 
and follow up for the subjects. All procedures and requirements pertaining to the 
archiving of study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be destroyed either locally or returned to the Sponsor or 
depot, as applicable.
4.0 
SELECTION OF STUDY POPULATION
4.2
Exclusion Criteria

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 96 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Prior to Scheduled Visit, each subject must not have:
7. History of exposure to suspected or confirmed rabid animal. 
8. Receipt of rabies immunoglobulins, non-study rabies vaccine following completion 
of V49_23 study.
9. Hypersensitivity, including allergy, to any component of vaccines, medicinal 
products or medical equipment whose use is foreseen in this study.
10. Clinical conditions representing a contraindication to intramuscular vaccination 
and blood draws.
11. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent or planning to receive 
them during the participation to the study.
12. Administration of antineoplastic and immunomodulating agents or radiotherapy 
within 90 days prior to informed consent or planning to receive them during the 
participation to the study.
13. Received immunoglobulins or any blood products within 180 days prior to informed 
consent or planning to receive them during the participation to the study.
14. Study personnel as well as their immediate family or household member.
15. Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the subject due to participation in the study.
Prior to booster vaccination, each subject eligible for booster vaccination should be 
in good health status and must not have none of the following:
2. Abnormal function of the immune system resulting from:
a.
Clinical conditions.
b. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent the Ad hoc visit or 
receipt or planning to receive them during the participation to the study.
c.
Administration of antineoplastic and immunomodulating agents or radiotherapy 
within 90 days prior to informed consent the Ad hoc visit or receipt or planning to 
receive them during the participation to the study.
3. Receipt of non-study rabies vaccine. 
4. 3. Receipt of any other vaccines within 28 days prior to the booster dose or planning 
to receive any vaccine within 28 days from the booster dose.
5. 4. Receipt of any investigational or non-registered medicinal product within 14 days

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 97 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
before booster dose till next Scheduled Clinic Visit after booster dose administration.
6. 5. Receipt of anti-malarial medications (e.g. Mefloquine) within 14 days before 
booster dose till next Scheduled Clinic Visit after booster dose administration.
5.0 
STUDY PROCEDURES
The sections that follow provide an overview of the procedures that have are to be 
followed in enrolling, evaluating, and following subjects who participate in this clinical 
study.
5.1.2
Screening
After an individual has consented to participate in the study and informed consent is 
signed, that individual will be given a unique Screening Number manually created by the 
investigator. will be assigned a unique Subject ID which she/he is carrying from 
V49_23 study (the parent study).
Collection of vital signs: (heart rate, respiratory rate, blood pressure, and temperature) 
has to be done during all Ad hoc Visits prior booster administration. At Scheduled and 
Additional Visits, their measurement should be at the discretion of the investigator.
A general physical examination is to be performed by a qualified health care practitioner., 
in accordance with their institutional policy. “Qualified health care practitioner” refers 
to any licensed health care professional who is permitted by institutional policy to 
perform physical examinations and who is identified within the Study Staff Signature Log
Study Staff Delegation of Responsabilities (SSDoR).
5.1.3
Enrollment
After signing the informed consent form, if an individual is determined to be eligible for 
study participation, the investigator will enroll the subject into the EDC (Electronic Data 
Capture) system.
5.1.4
Randomization
Subject numbers (ID) will be pre-loaded into a centralized Randomization System on 
internet (SBIR).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 98 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
5.2
Ad Hoc Clinic Visit(s) - Vaccination Clinic Visit(s)
The first dose of booster vaccination with rabies vaccine will be performed in a clinical 
visit occurring as soon as the results of the antibody assay will be available and within 
approximately 6 to 9 months.
Only for those subjects with RVNA concentrations <0.5 IU/mL at the first visit of this 
extension study (Day 1, Year 3) or at the following yearly visits (Year 4 to Year 9) a 
booster dose of PCEC rabies vaccine will be administered during the next planned Ad 
Hhoc Clinic Visit. 
Should the subject be a low responder to a booster dose of the rabies vaccine provided 
during this extension study and not achieve adequate antibody concentrations following a 
booster injection neither at 7 days (following the blood drawn at the “Additional Clinic 
Visits” after the booster) nor at the next evaluation (following the blood drawn at the 
“Scheduled Clinic Visits” after the booster), a subsequent booster dose may be 
administered at the subsequent “Ad hoc Clinic Visit”. If the subject is still non-
responder, subsequent management should be at the discretion of the investigator.
5.3.1
Follow-up (Additional) Clinic Visit(s)
During the Additional Clinic Visit, the subject or legal guardian will be interviewed to 
determine if any AEs occurred and if any concomitant medications in conjunction to any 
SAEs or vaccines were taken/received in the time since the last clinic visit.
In order to investigate the prompt boostability of immune responses, 7 mL of blood 
sample will be drawn during aAdditional cClinic vVisit
6.0 
TREATMENT OF SUBJECTS
6.1
Study Vaccine(s)
After reconstitution, a booster dose consists of 1.0 mL of PCEC rabies vaccine, 
containing rabies virus [inactivated strain Flury 6.6 Low Egg Passage (LEP)®] with a 
potency ≥2.5 IU/mL, and is to be administered via intramuscular (IM) injection.
6.3
Vaccine Preparation and Administration
From the beginning of the study until 2018, vaccine assignment was randomly done by 
the study staff. From 2019 onwards, the SBIR system has been implemented for 
vaccine assignment to the subjects. The study staff will access the system and will enter 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 99 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
the subject identification number. The system will provide a treatment number for each 
subject.
When SBIR is not available, please refer to the SBIR user guide or the Supply and 
Cold Chain Guidance for specific instructions.
A single dose of 1.0 mL should be administrated intramuscularly in deltoid area of non-
dominant arm by the designated and trained site staff. Subjects experiencing local AEs 
at the vaccination site could alternatively receive rabies vaccine in the deltoid muscle of 
the dominant arm.
If, after having received a booster dose, the subject does not reach the adequate antibody
concentration of 0.5 IU/mL at two consecutive determinations, neither at 7 days after the 
booster dose (i.e. Additional Clinic Visit) nor at the next yearly evaluation (i.e. Scheduled 
Clinic Visit), an additional booster dose may be administered at the following Ad hoc 
Clinic Visit. If the subject is still non-responder, subsequent management should be at 
the discretion of the investigator.
6.6
Vaccine Supply, Labeling, Storage and Tracking
Reconciliation of all vaccines received from the Sponsor. Reconciliation is defined as 
maintaining records of which and how many vaccines were received, which vaccines 
were administered to subjects, which vaccines were destroyed at the site locally, and 
which vaccines were returned to the Sponsor or depot, as applicable.
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed either locally (upon approval from Sponsor) or returned to the
Sponsor or depot, as applicable.
Confirmation by the Sponsor that the vaccines are authorized for use.
Not use of vaccines prior to receipt of authorization for use from the Sponsor.
Vaccines that have been stored differently from the manufacturer’s indications must not
be used unless the Sponsor provides written authorization for use.
7.0 
ASSESSMENTS
7.1      Safety Assessment
The measures of safety used in this study are based on comparable routine clinical 
procedures. They include a close vigilance for, and stringent reporting of SAEs following 
booster vaccination.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 100 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
7.1.2   Unsolicited Adverse Events
An unsolicited adverse event is an AE that was not solicited and that was spontaneously 
communicated by a subject or legal guardian who has signed the informed consent. In this 
study only SAEs and the associated concomitant medications following PCEC rabies 
booster vaccinations will be collected, starting from the time of booster administration 
and until the day of next Scheduled Clinic Visit, will be collected in the AE and 
concomitant medications eCRF pages. the subject receives the booster dose until 
completion of safety follow up period, which is, the day of the next Scheduled Clinic 
Visit after booster vaccination or on the date of Early Termination Visit, whichever is 
earlier (see sections 7.1.4 Serious Adverse Events and 7.1.5 Methods for Recording 
Adverse Events and Serious Adverse Events), based on the subject’s interview during 
Clinic Visit. SAEs collected during physical exams at Scheduled and Ad hoc visits will 
be as well collected.
7.1.4   Serious Adverse Events
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following:

Death.

Is life-threatening (i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event 
which hypothetically might have caused death if it were more severe.

Required or prolonged hospitalization.

Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions).

Congenital anomaly/or birth defect.

An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above.
Adverse events which do not fall into these categories are defined as non-serious.
It should be noted that a serious adverse event need not, by definition, be severe.
Serious adverse events will be captured both on the Vaccines Serious Adverse Event 
(VSAE) form as well as on the AE CRF. All SAEs will be evaluated by the investigator 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 101 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
for relationship of the event to study vaccine. SAEs that are judged to be possibly or 
probably related to the study vaccine should be reported to the Sponsor as
related/suspected events.
The relationship of the study treatment to an SAE will be determined by the investigator
based on the following definitions:
1. Related/suspected
The SAE is judged by the investigator to be possibly or probably related to the study
vaccine on the AE CRF page (see section 7.1.3, Evaluation of Adverse Events).
2. Not Related
The SAE is not related if exposure to the study vaccine has not occurred, or the
occurrence of the SAE is not reasonably related in time, or the SAE is considered
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or
arguments to suggest a causal relationship.
The relationship of the study vaccine to an SAE will be determined by the investigator.
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An
unexpected AE is one that is not listed in the current Summary of Product Characteristics
or the Investigator’s Brochure or an event that is by nature more specific or more severe
than a listed event.
In addition, a pre-existing event or condition that results in hospitalization should be
recorded on the Medical History CRF. If the onset of an event occurred before the subject
entered the study (e.g., any pre-planned hospitalization for conditions like cosmetic
treatments or for non-emergency routine visits for a pre-existing condition), the
hospitalization would not lead to an AE being classified as serious unless, in the view of
the investigator, hospitalization was prolonged as a result of participation in the clinical
study or was necessary due to a worsening of the pre-existing condition.
Additionally, the investigator will evaluate whether the SAEs lead to withdrawal of
subject from the study.
All SAEs will be monitored until resolution or until the investigator assesses them as
chronic or stable. All subjects experiencing SAEs from the time the subject receives the
booster dose until he or she completes the specified safety follow-up period (i.e. the day
of next Scheduled Clinic Visit after booster vaccination) - whether considered associated
with the use of the study vaccine or not - must be monitored until symptoms subside and
any abnormal laboratory values have returned to baseline, or until there is a satisfactory
explanation for the changes observed, or until death, in which case a full pathologist’s 
report should be supplied, if possible. The investigator’s assessment of ongoing SAEs at
the time of each subject’s last visit should be documented in the subject’s source
document.
In this study only SAEs and the associated concomitant medications following PCEC 
rabies booster vaccinations will be collected (see section 7.1.5 Methods for Recording 
Adverse Events and Serious Adverse Events).

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 102 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
The period of observation for SAEs extends from the time the subject receives the 
booster dose until completion of safety follow-up period (the day of the next Scheduled 
Clinic Visit after booster vaccination or on the date of Early Termination Visit, 
whichever is earlier).
7.1.5    Methods for Recording Adverse Events and Serious Adverse Events
Findings regarding Serious Adverse Events must be reported on an Adverse Events CRF,
and on the VSAE form, which is part of the Investigator Site File. All findings in subjects
experiencing AEs must be reported also in the subject's source document.
During the course of the study, all SAEs which occur from the time of booster
administration and until the day of next Scheduled Clinic Visit , whether considered to be
associated with the study vaccination or not, must be reported within 24 hours of the site
becoming aware of the event to GSK or its designee. Specific instructions and contact
details for collecting and reporting SAEs to GSK will be provided to the investigator.
All SAEs after PCEC rabies booster dose are also to be documented on the Adverse
Events CRF. Any medication or other therapeutic measures used to treat the AE will be
recorded on the appropriate CRF(s) in addition to the outcome of the SAE.
After receipt of the initial report, representatives of GSK or its designee will contact the
investigator if it is necessary to obtain further information for assessment of the event.
All SAEs after PCEC rabies booster dose must be reported by the investigator to his/her
corresponding EC or applicable regulatory authorities in accordance with institutional
policy/regulatory requirements and adequate documentation of this notification must be
provided to the Sponsor.
GSK or its designee must also comply with the applicable regulatory requirement(s)
related to the reporting of suspected unexpected serious adverse vaccine reactions (also
known as SUSARs) to the regulatory authorities and the IRB/EC. If a SUSAR or other
safety signal relating to use of one of the study vaccines is reported to GSK or its
designee, the Sponsor will communicate the information to the investigator and the
investigator will be responsible for submitting this information to the EC and other
relevant authorities.
All findings in subjects experiencing SAEs and any medication or other therapeutic 
measures used to treat the SAE in addition to the outcome of the SAE after PCEC 
rabies booster dose or collected during physical exams at Scheduled and Ad hoc visits, 
must be reported both on the VSAE Report Form which is part of the Investigator Site 
File and in the eCRF.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 103 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
Investigator must report those events to his/her corresponding EC or applicable 
regulatory authorities in accordance with institutional policy/regulatory requirements 
and adequate documentation of this notification must be provided to the Sponsor.
During the course of the study, all SAEs which occur from the time of booster 
administration until completion of safety follow-up period (the day of the next 
Scheduled Clinic Visit after booster vaccination or on the date of Early Termination 
Visit, whichever is earlier), whether considered to be associated with the study 
vaccination or not, must be reported within 24 hours of the site becoming aware of the 
event to GSK or its designee. Specific instructions and contact details for collecting and 
reporting SAEs to GSK will be provided to the investigator.
After receipt of the initial report, representatives of GSK or its designee will contact the 
investigator if it is necessary to obtain further information for assessment of the event.
GSK or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
known as SUSARs) to the regulatory authorities and the IRB/EC. If a SUSAR or other 
safety signal relating to use of one of the study vaccines is reported to GSK or its 
designee, the Sponsor will communicate the information to the investigator and the 
investigator will be responsible for submitting this information to the EC and other 
relevant authorities.
All SAEs will be evaluated by the investigator for relationship of the event to study 
vaccine. SAEs that are judged to be possibly or probably related to the study vaccine 
should be reported to the Sponsor as related/suspected events, irrespectively of time 
frame of SAEs reporting.
The relationship of the study vaccine to a SAE will be determined by the investigator
based on the following definitions:
1. Related/suspected
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the AE CRF page (see section 7.1.3, Evaluation of Adverse Events). 
2. Not Related
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship.

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 104 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current SmPC or an event that is by nature 
more specific or more severe than a listed event.
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the Medical History CRF.
If the onset of an event occurred before the subject entered the study (e.g., any pre-
planned hospitalization for conditions like cosmetic treatments or for non-emergency 
routine visits for a pre-existing condition), the hospitalization would not lead to an AE 
being classified as serious.
If the investigator judges that the hospitalization was prolonged as a result of the event 
itself or was necessary due to a worsening of the pre-existing condition, the 
hospitalization would then be considered as a SAE.
Additionally, the investigator will evaluate whether the SAEs lead to withdrawal of 
subject from the study.
All SAEs will be monitored until resolution or until the investigator assesses them as 
chronic or stable. All subjects experiencing SAEs from the time the subject receives the 
booster dose until he or she completes the specified safety follow-up period (i.e. the day 
of next Scheduled Clinic Visit after booster vaccination or on the date of Early 
Termination Visit, whichever is earlier)  - whether considered associated with the use of 
the study vaccine or not - must be monitored until symptoms subside and any abnormal 
laboratory values have returned to baseline, or until there is a satisfactory explanation for 
the changes observed, or until death, in which case a full pathologist’s report should be 
supplied, if possible. The investigator’s assessment of ongoing SAEs at the time of each 
subject’s last visit should be documented in the subject’s source document.
7.1.5.1    Post-Study Events
Any SAE that occurs outside of the protocol-specified safety follow-up period (from the 
time of booster administration and until the day of next Scheduled Clinic Visit) (after  
Study Termination Visit or Early Termination Visit whichever is earlier) and the 
investigator considersed to be caused by the study vaccine must be reported to GSK or its 
designee as spontaneous reporting. 
7.1.6       Pregnancies
To ensure subjects’ safety, all pregnancies must be reported to GSK or delegate within 2 
weeks of site becoming aware of a pregnancy. If the subject agrees to submit this 
information, the pregnancy must be followed to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of 

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 105 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
This follow-up should occur even if intended duration of safety follow-up for the study 
has ended.
Pregnancy data must be recorded on a Pregnancy Report CRF (initial report) and 
Pregnancy Follow-Up CRF (outcome report) and reported to GSK or delegate. 
Instructions and contact details for submitting the Pregnancy CRFs will be provided to the 
investigator.
Any pregnancy outcome meeting the definition of SAEs (see section 7.1.4, Serious 
Adverse Events) reported in subjects who received booster administration needs to be 
reported within 24 hours of the site becoming aware of the event to GSK or delegate 
using the VSAE Report Form and be recorded in the CRF(s).
The Pregnancy Form must also be updated for further internal processing.
Any pregnancy outcome meeting the definition of SAEs reported in subjects who have 
NOT received booster administration need to be reported within 24 hours of
the site becoming aware of the event to GSK or delegate using the VSAE Report Form, 
although such SAEs will not be a part of the Clinical database and do not need to be 
recorded in the CRF(s).
The Pregnancy Form must also be updated for further internal processing.
8.0 
STATISTICAL CONSIDERATIONS
8.1.1.1 Primary Safety Endpoint(s)
For subjects receiving PCEC rabies booster vaccination, SAEs and the associated 
concomitant medications will be collected starting from the time of booster administration 
and until the day of next Scheduled Clinic Visit. completion of safety follow-up period
(the day of the next Scheduled Clinic Visit after booster vaccination or on the date of 
Early Termination Visit, whichever is earlier).
8.1.1.3 Primary Immunogenicity Endpoint(s)
GMCs and GMRs Geometric Mean Antibody Concentrations (GMCs) and Geometric 
Mean ratio (GMRs) for subjects receiving the booster dose.
8.1.2.3 Secondary Immunogenicity Endpoint(s)
Geometric Mean Antibody Concentrations (GMCs) at Year 3, 4, 5, 6, 7, 8, 9 and 10

GSK
Confidential
Protocol V49_23E1
25 FEB 19 Final Protocol Amendment 2
Page 106 of 106
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 3 / Version Date: November 10, 2014
8.4.2.1.3 Analysis of Unsolicited Adverse Events
This analysis applies to all serious adverse events SAEs
8.4.2.3.2 Analysis Sets
Analyses on PPS will be conducted only if more than 10% of subjects have CSR-
reportable protocol deviations (by objective).
8.4.2.3.3 Statistical Methods
Kaplan-Meier (KM)
Hazard rRatios (HR)
10.0 DATA MANAGEMENT
10.1
Data Entry and Management
and immunogenicity data will be entered onto case report forms (CRFs) in a timely 
fashion by the investigator and/or the investigator’s dedicated site staff. Data entered onto 
CRFs are stored on a secure website. The data collected on this secure website are 
assimilated into an electronic data capture (EDC)